Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[OH:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:18]([OH:24])[CH:19]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: Nc1ccc(F)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Temperature: 140 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (0.5 g), 2-amino-5-fluorophenol (265.0 mg), p-toluenesulfonic acid monohydrate (75.0 mg) and dioxane (5.0 ml) were combined in a microwave tube. The mixture was heated at 140° C. for 15 min under microwave irradiation. Then the mixture was allowed to cool to room temperature and a precipitate formed. The precipitate was collected by filtration, washed with dioxane, methanol and Et2O to yield the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[N:17]1[CH:22]=[C:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C@@H:30]([NH2:32])[CH3:31])=[CH:26][CH:25]=2)[CH:20]=[N:19][CH:18]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C@H:30]([C:27]2[CH:26]=[CH:25][C:24]([O:23][C:21]3[CH:20]=[N:19][CH:18]=[N:17][CH:22]=3)=[CH:29][CH:28]=2)[CH3:31])[N:7]=1)([CH3:15])[CH3:14]
Reactant: C[C@H](N)c1ccc(Oc2cncnc2)cc1
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(Oc3cncnc3)cc2)n1
Temperature: 110 °C
Reaction time: 48 h
Yield: 9.9 %

Procedure:
To the solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (43 mg, 0.169 mmol) in NMP (0.7 mL) was added (S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethanamine (41 mg, 0.169 mmol) and DIEA (88 μL, 0.507 mmol). The brown reaction mixture was stirred at 110° C. for 2 days. The reaction mixture was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The separated organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine. The organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography [C-18] to provide (S)-4-isopropyl-3-(2-(((S)-1-(4-(pyrimidin-5-yloxy)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (7 mg) as its trifluoroacetic acid salt.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:19])[C:3]=1[C:20](=O)[CH2:21][CH3:22].[CH2:24]([O:26][NH2:27])[CH3:25].Cl>O1CCCC1>[CH2:24]([O:26][N:27]=[C:20]([C:3]1[C:4](=[O:19])[CH2:5][CH:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH2:7][C:2]=1[OH:1])[CH2:21][CH3:22])[CH3:25]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Reactant: CCON
Agent: Cl
Solvent: C1CCOC1
Product: CCON=C(CC)C1=C(O)CC(c2ccc(NS(C)(=O)=O)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
Into 10 ml of tetrahydrofuran was dissolved 1.5 g of 3-hydroxy-5-(4-methanesulfonamidophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 0.5 g of ethoxyamine. The mixture was kept at room temperature for 15 hours and poured into ice water. And then the mixture was acidified with hydrochloric acid and it was extracted with chloroform. The chloroform solution was washed with water and extracted with 15 ml of an aqueous solution cotaining 5% of sodium hydroxide. The solution was acidified with hydrochloric acid and the crystal sedimented was extracted with chloroform and the solution was washed with water and it was dried with magnesium sulfate. Then, it was distilled off under a reduced pressure and thus, 1.4 g of the objective compound was obtained. It was colorless crystals having a melting point of 115°-116° C.
Reaction SMILES: [NH2:1][CH:2]([C:9]([CH3:13])([CH3:12])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:14][C:15]1[C:20]([C:21]#[N:22])=[CH:19][C:18]([F:23])=[C:17](Cl)[N:16]=1.CCN(CC)CC>C(#N)C>[Cl:14][C:15]1[N:16]=[C:17]([NH:1][CH:2]([C:9]([CH3:12])([CH3:13])[CH2:10][CH3:11])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:18]([F:23])=[CH:19][C:20]=1[C:21]#[N:22]
Reactant: CCOC(=O)CC(N)C(C)(C)CC
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(Nc1nc(Cl)c(C#N)cc1F)C(C)(C)CC

Procedure:
A solution of ethyl 3-amino-4,4-dimethyl-hexanoate, 27a, (0.24 g, 1.28 mmol), 2,6-dichloro-5-fluoro-pyridine-3-carbonitrile (0.29 g, 1.53 mmol) and Et3N (0.43 mL, 3.07 mmol) in acetonitrile (4.8 mL) was stirred at 70° C. overnight. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (10-40% EtOAc/Hexanes gradient) to provide 205 mg of ethyl 3-[(6-chloro-5-cyano-3-fluoro-2-pyridyl)amino]-4,4-dimethyl-hexanoate; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.75 minutes (M+H) 342.04.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([O:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12]CC2C=CC=CC=2)[CH:7]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:22])[CH:4]([O:20][CH3:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: COC(=O)C(Cc1cccc(OCc2ccccc2)c1)OC
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(Cc1cccc(O)c1)OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compounds of 3-(3-benzyloxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 291, Step 3) (3.15 g, 10.49 mmol) and Pd 10% on activated carbon (0.558 g, 0.524 mmol) were placed in a 250-ml round bottom flask equipped with a magnetic stirring bar. 100 mL of methanol was added, and hydrogen was bubbled through the solution for 10 minutes. The flask was sealed with a rubber septum, and a balloon containing 250 mL of hydrogen was connected to the flask through a needle. The mixture was stirred at room temperature for 5 hours and then concentrated to dryness under vacuum. The residue was taken up in ethyl acetate and filtered through a pad of celite. Concentration of the mixture afforded an oil, 1H-NMR (CDCl3, 200.15 MHz): 7.15 (dt, 1H, J=1.1, 7.0), 6.79–6.68 (m, 3H), 5.27 (br s, 1H), 3.98 (dd, 1H, J=7.5, 5.6), 3.73 (s, 3H), 3.35 (s, 3H), 2.97 (d, 1H, J=3.8), 2.97 (d, 1H, J=9.1).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([O:39]CC)=[O:38])=[CH:33][C:32]=2[I:42])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>C(O)C.[OH-].[K+].O>[OH:1][C@@H:2]([CH2:18][N:19]([C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:32]=2[I:42])=[CH:26][CH:25]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(Oc2ccc(N(CC(C)C)C[C@H](O)COc3cccc4[nH]c5ccccc5c34)cc2)c(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(Oc2ccc(C(=O)O)cc2I)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.3 %

Procedure:
(S)-4-[2-hydroxy-3-([4-(4-carboethoxy-2-iodophenoxy)phenyl]-2-methylpropylamino)propoxy]carbazole (386 mg, 0.54 mmol) was dissolved in a mixture of ethanol (20 ml) and aqueous potassium hydroxide (20 ml, 5.ON) and was stirred at ambient temperature for 16 hours. The crude reaction mixture was concentrated in vacuo and the residue acidified with 5.0N HCl. The solution was allowed to stir for one hour at 0° C. and then concentrated in vacuo to afford a white solid. The residue was suspended in water and filtered, and the solids washed with cold water. The solids were triturated with pentane and dried to afford product as a white solid (370 mg, 100%). NMR, MS, IR, HPLC
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:16])=[O:15].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>C(#N)C>[CH3:18][N:19]([CH3:24])[S:20]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([NH2:17])(=[O:15])=[O:16])(=[O:22])=[O:21]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)S(=O)(=O)Oc1ccccc1S(N)(=O)=O
Reaction time: 0.17 h
Yield: 70.1 %

Procedure:
4.0 g (29 mmol) of potassium carbonate were added to a solution of 5.0 g (29 mmol) of 2-hydroxybenzenesulfonamide in 200 ml of acetonitrile at 25° C. Stirring was carried out for 10 minutes, after which 4.1 g (29 mmol) of dimethylaminosulfonyl chloride were added dropwise at 25° C. and stirring was continued for a further 16 hours at this temperature. The volatile constituents were removed under reduced pressure from a water pump, the residue was taken up in ethyl acetate, the solution was dried over Na2SO4 and the solvent was removed under reduced pressure from a water pump. The remaining residue was stirred vigorously for 1 hour with 100 ml of diethyl ether. The crystalline product was filtered off under suction and dried at 40° C. under reduced pressure. 5.7 g of the title compound were obtained in this manner.
Reaction SMILES: Cl.[CH3:2][CH:3](NCCC(O)=O)[CH2:4][CH2:5][CH2:6]C.[CH3:14][NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.BrCCCCC.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][N:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC(C)NCCC(=O)O
Reactant: CNCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCBr
Solvent: CC(C)=O
Product: CCCCCN(C)Cc1ccccc1

Procedure:
The present invention provides an alternate process for the synthesis of 3-[N-(methylpentyl)amino]propionic acid (III) wherein N-methyl benzyl amine is condensed with 1-bromo pentane in presence of potassium carbonate, using acetone as solvent to give N-methyl N-pentyl benzyl amine. This is debenzylated using palladium on carbon as catalyst and alcohol as solvent. The resulting product N-methyl pentyl amine is condensed with methyl acrylate in toluene to get 3-[N-(methylpentyl)amino]propionate, which is further hydrolysed to obtain Intermediate III.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][C:4]1([CH3:16])[CH3:15])[CH3:2].O=P(Cl)(Cl)Cl.CN([CH:25]=[O:26])C>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:25]=[O:26])=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][C:4]1([CH3:15])[CH3:16])[CH3:2]
Reactant: CCN1c2cc(O)ccc2C(C)=CC1(C)C
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1c2cc(O)c(C=O)cc2C(C)=CC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 100 ml flask, 1.0 g (4.60 mmol) of Compound 4 30.0 ml of dry DMF and 0.76 g (5.00 mmol) of POCl3 were added, and the mixture was stirred at room temperature for 24 hours under nitrogen gas flow. After evaporation of the solvent under reduced pressure, the reaction mixture was dissolved in ethyl acetate and then washed with water. The resultant was dried over anhydrous sodium sulfate and the residue was purified by column chromatography (SiO2, n-hexane:ethyl acetate=1:1) to obtain the desired product.
Reaction SMILES: [OH:1][C@@H:2]([CH2:15][N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[CH2:3][NH:4]C(=O)OCC1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15][N:16]1[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]1
Reactant: CN1CCN(C[C@H](O)CNC(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C[C@H](O)CN)CC1
Reaction time: 12 h
Yield: 106.9 %

Procedure:
Benzyl N-[(2R)-2-hydroxy-3-(4-methylpiperazin-1-yl)propyl]carbamate 20d (830 mg, 2.70 mmol) was dissolved in 40 mL of methanol followed by the addition of palladium/carbon (85 mg, 10%), filled with hydrogen three times. The reaction solution was stirred for 12 hours and filtered. The filtrate was concentrated under reduced pressure to obtain the crude title compound (2R)-1-amino-3-(4-methylpiperazin-1-yl)propan-2-ol 20e (500 mg) as a light yellow oil, which was used in the next step without further furification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CCCCOC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}phenyl)carbonyl](methyl)amino}propanoate (460 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (428 mg, 99%) as a pale-yellow solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH3:29])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[S:28])[NH:19]C(=O)C3C=CC=CC=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O>[C:1]1([CH2:7][N:8]([CH3:29])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH2:19])=[S:28])=[CH:15][CH:16]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(CCc1ccc(NC(=S)NC(=O)c2ccccc2)cc1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(CCc1ccc(NC(N)=S)cc1)Cc1ccccc1
Temperature: 90 °C
Yield: 96 %

Procedure:
A mixture of 3-(4-(2-(benzylmethylamino)ethyl)phenyl)-1-benzoyl-2-thiourea (step (e), 2.4 g, 5.95 mmol) and 2.5N aqueous sodium hydroxide (20 ml) was heated at 90° C. for 35 minutes with stirring. The warm reaction mixture was then poured into water (60 ml) with stirring. The product was extracted into three portions of methylene chloride. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to dryness to yield 1.71 g of crude 1-(4-(2-((phenylmethyl)(methyl)amino)ethyl)phenyl)-2-thiourea. The product was crystallized from benzene, m.p. 119°-21.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:19]([NH:21][NH:22][S:23]([NH:26][CH2:27][C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl.O1CCC[CH2:41]1>CO.O>[CH3:41][CH:27]([NH:26][S:23]([NH:22][NH:21][C:19](=[O:20])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:32][CH:33]([CH3:34])[CH3:35])(=[O:24])=[O:25])[C:28]([OH:30])=[O:29]
Reactant: C1CCOC1
Reactant: COC(=O)CNS(=O)(=O)NNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NNS(=O)(=O)NC(C)C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 0.431 g of methyl(E)-2-[[2-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]hydrazino]sulphonamido]acetate in 10 ml of tetrahydrofuran and 5 ml of methanol was treated with 0.040 g of lithium hydroxide monohydrate and the mixture was left to stir overnight. A further 0.020 g of lithium hydroxide monohydrate was added and stirring continued for 4 hours. The mixture was then diluted with water, acidified using 2M aqueous hydrogen chloride, and extracted with ethyl acetate. The ethyl acetate fraction was dried over anhydrous magnesium sulphate and evaporated to give 0.462 g of methyl(E)-2-[[2-[2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleryl]hydrazino]sulphonamido]acetic acid as an oil.
Reaction SMILES: [C:1]1([CH3:29])[C:2]([S:7]([O:10][C:11]2[CH2:17][CH:16]3[N:13]([C:14](=[O:18])[CH2:15]3)[C:12]=2[C:19]([O:21]CC2C=CC=CC=2)=[O:20])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.C.C(=O)(O)[O-].[Na+:35]>O1CCOCC1.O.[Pd]>[C:1]1([CH3:29])[C:2]([S:7]([O:10][C:11]2[CH2:17][CH:16]3[N:13]([C:14](=[O:18])[CH2:15]3)[C:12]=2[C:19]([O-:21])=[O:20])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:35]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)[O-])N2C(=O)CC2C1
Reaction time: 0.5 h

Procedure:
A mixture of benzyl 3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (30 mg) and 10% palladium on powdered charcoal (25 mg) in dioxane (3 ml) and water (1 ml) containing sodium bicarbonate (7 mg) is hydrogenated at 40 psi for 30 mins. The mixture is filtered to remove the catalyst which is washed with several portions of H2O (3×3 ml). The combined filtrate is washed with ethyl acetate (3×2 ml), concentrated in vacuo to ca. 2 ml, and lyophilized to afford sodium 3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.F[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[CH:14]=[N:13][CH:12]=[CH:11][C:16]=2[C:17]([OH:19])=[O:18])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1cc(I)ccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Temperature: -78 °C
Yield: 59 %

Procedure:
4-Iodo-2-methylaniline (233 mg, 1.00 mmol) and 3-fluoropyridine-4-carboxylic acid (141 mg, 1.00 mmol) were dissolved in dry THF (6.0 ml) under argon and the mixture was cooled to −78° C. A solution of LiHMDS (1.0M in THF, 3.5 ml) was added and the reaction mixture was allowed to warm to ambient temperature. After 36 h the reaction was quenched by adding solid NH4Cl. After filtration the volatiles were removed in vacuo and the crude material was purified by flash chromatography using silica gel and a gradient of 0-10% methanol in DCM as eluent to give 208 mg (588 μmol; 59% yield) of pure desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[O:10])=[CH:4][C:3]=1[F:19].[CH3:20][O:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+].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]>[F:19][C:3]1[CH:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[O:10])[CH:6]=[CH:7][C:2]=1[C:27]1[C:22]([O:21][CH3:20])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ncccc1B(O)O
Reactant: Cc1ccccc1NC(=O)Nc1ccc(Br)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1-c1ccc(NC(=O)Nc2ccccc2C)cc1F

Procedure:
1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.1 g) was added to a stirred and degassed solution of 1-(4-bromo-3-fluorophenyl)-3-o-tolylurea (0.5 g, 1.5 mmol) and 2-methoxypyrid-3-ylboronic acid (258 mg, 1.7 mmol) in dimethyl formamide (10 mL) and aqueous sodium carbonate in water (5 mL, 2N). The reaction mixture was stirred at 100° C. for 18 hours, then allowed to cool. The solution was concentrated, then ethyl acetate (75 mL) was added and the organic phase was washed with water (3×75 mL). The organic phase was dried (anhydrous magnesium sulfate), concentrated and purified by chromatography on silica gel (20 to 40% v/v ethyl acetate in hexane) to afford the title compound as an oil.
Reaction SMILES: O1CCCC1.[OH:6][CH:7]([C:9]1[NH:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)[CH3:8].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].N1C=CN=C1>O>[Si:18]([O:6][CH:7]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)[CH3:8])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(O)c1nc2ccccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 50 ml of tetrahydrofuran containing 2.5 g (15.4 mmoles) of 1-hydroxyethylbenzimidazole, 2.3 g (15.4 mmoles) of t-butyldimethylsilyl chloride and 1.0 g (15.4 mmoles) of imidazole was allowed to stir overnight at room temperature. The reaction mixture was poured into water and the product extracted with ethyl acetate (2×100 ml). The combined extracts were dried over magnesium sulfate and concentrated in vacuo to a colorless oil, 3.5 g. The intermediate was purified by chromatography on 100 g of silica gel using chloroform as the eluent, 3.11 g.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Agent: Cl
Product: O=C(/C=C/c1ccc(F)cc1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-fluorophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 275 (MH+).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:11]1[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12]1.[Na]>CN(C=O)C.O.C(O)(=O)C>[C:2]1([CH2:1][O:8][CH2:12][CH:13]([OH:11])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCC1CO1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCC(O)COCc1ccccc1
Temperature: 80 °C

Procedure:
Benzyl alcohol (108 g, 1.0 mol) is added to a suspension of 50% sodium hydride-mineral oil (48 g, 1.0 mol) in DMF (200 ml) at room temperature. The mixture is then heated to 80° C. for two hours. A solution of 1,2-epoxydecane* (85 ml) in DMF (50 ml) is added slowly to the sodium salt over 30 minutes and the mixture is then heated at 80° C. for 20 hours. The reaction mixture is cooled, diluted with water, neutralized with acetic acid, and extracted with ether. The ether extract is concentrated to give an oil which is distilled to give the desired product (131 g), bp 178°-180° C./4 mm.