Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:36])[N:26]([CH3:35])[C:27]([CH3:34])=[CH:28][C:29]=2[C:30]([F:33])([F:32])[F:31])=[CH:20][CH:19]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[O:7].[OH-].[Na+]>C(O)C>[CH2:15]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:37])=[O:2])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:36])[N:26]([CH3:35])[C:27]([CH3:34])=[CH:28][C:29]=2[C:30]([F:32])([F:33])[F:31])=[CH:20][CH:19]=1)=[O:7])[CH3:16]
Reactant: CCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cccc(C)c1C(=O)N[C@@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)C(=O)O
Yield: 97 %

Procedure:
A solution of N-[(2-ethyl-6-methylphenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (74 mg, 0.14 mmol), and 1 N sodium hydroxide (2 mL, 2 mmol) in ethanol (3 mL) was heated to 40-45 C for 3 h. Then, the ethanol was removed under vacuum and the residue was diluted with water. The aqueous solution was washed with diethyl ether to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted with ethyl acetate. The combined organic extracts were washed with brine solution and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 68 mg (95% yield) of N-[(2-ethyl-6-methylphenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine (mp 219-221° C.). ES-HRMS m/e calcd for C27H27F3N2O4 (M+Na) 523.1815, found 523.1816.
Reaction SMILES: [CH3:1][C:2]1[S:16][C:5]2=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:10])[N:4]2[CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:24][CH2:1][C:2]1[S:16][C:5]2=[N:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1cnc2sc(C)cn2c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2sc(CBr)cn2c1=O
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A mixture of ethyl 2-methyl-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate (Preparation 8, 1.19 g), NBS (1.07 g) and benzoyl peroxide (25 mg) is heated to reflux in carbon tetrachloride (50 mL) for 6 h. After the mixture is cooled to rt, the precipitate is filtered. The precipitate is re-dissolved in methylene chloride (100 mL) and washed with water. The organic layer is separated, dried (MgSO4), and concentrated to afford 1.0 g (60%) of the title compound as a pale yellow solid. Physical characteristics: MS (ESI+) m/z 317, 319 (M+H)+. 1H NMR (CDCl3) δ9.80, 8.15, 4.42, 1.40.
Reaction SMILES: C[CH:2]([CH:6]([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:7][CH2:8][CH3:9])[C:3](O)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([S:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][OH:4])(=[O:11])=[O:12])=[CH:18][CH:17]=1
Reactant: CCCC(C(C)C(=O)O)S(=O)(=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(CCO)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
Part C: To a solution of 4.4 g (15 mmol) of methyl 3-[(4-methoxyphenyl)sulfonyl]hexanoic acid from Part B in 50 mL of anhydrous THF at zero° C. under nitrogen, was added 16.2 mL (0.6 g, 15 mmol) of a 1.0 M solution of lithium aluminum hydride in THF. After 1 hour, the reaction mixture was cooled to zero° C. and 0.6 mL of water was added, followed by 0.6 mL of 2.5 N sodium hydroxide solution and 1.8 mL of water, the reaction was filtered, the filtrate concentrated in vacuo, ethyl acetate and 5% citric acid solution were added, the organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried with magnesium sulfate, filtered and concentrated to afford 3.6 grams of pure 3-[(4-methoxyphenyl)sulfonyl]hexan-1-ol, m/z=273 (M+H).
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:28])[NH:23][CH2:24][C:25](O)=[O:26])[CH:18]=[CH:19][CH:20]=1.S(Cl)(Cl)=O>>[CH3:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:28])[NH:23][CH2:24][C:25]([N:1]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:26])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN(C(=O)CNC(=O)Nc1cccc(C)c1)c1ccccc1
Yield: 44.1 %

Procedure:
Working in a manner similar to that described in Example 28, but starting with ethyl 2-anilinoacetate (2.2 g), 2-[3-(3-methylphenyl)ureido]acetic acid (2.6 g) and thionyl chloride (1.50 g), and after recrystallization in isopropanol, ethyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate (2 g), m.p. 181° C., is obtained.
Reaction SMILES: [C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Se](=O)=[O:22]>>[C:1]([O:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=1)=[O:8])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1
Reactant: O=[Se]=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Yield: 70.6 %

Procedure:
Ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (0.3 g.) and selenium dioxide (0.11 g.) were treated according to a similar manner to that of Preparation (6-4) to give brown oil of ethyl 2-(2-t-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (0.22 g.).
Reaction SMILES: [OH:1][C:2]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+]>CO>[OH:1][C:2]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: O=Cc1cccc(Sc2ccccc2Cl)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Sc2ccccc2Cl)c1O
Yield: 102.7 %

Procedure:
To a suspension of 2-hydroxy-3-(2-chlorophenylthio)benzaldehyde (5.8 g) in methanol (50 ml) was added sodium borohydride (820 mg) at temperature below 15° C. with stirring. The mixture was treated in a similar manner to that of Example 21-(5) to give oily 2-hydroxy-3-(2-chlorophenylthio)benzyl alcohol (6 g). This oily substance was left to stand at room temperature to give crystals.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=O.[CH:21]([NH2:23])=O.CN(C=O)C.C(O)=O>C(O)(C)C>[OH:9][C:7]1[C:6]2[CH:5]=[C:4]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[NH:3][C:2]=2[N:1]=[CH:21][N:23]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)[nH]c1N
Solvent: CC(C)O
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2cc3c(O)ncnc3[nH]2)cc1

Procedure:
2.5 g (97 mmol) of 2-amino-3-ethoxycarbonyl-5-(4-nitro-phenyl)-pyrrole, 19.4 ml of formamide, 9.7 ml of DMF and 3.1 ml of formic acid are stirred together at 150° C. for 22 hours. 1 ml of isopropanol is added to the hot reaction mixture. The reaction mixture is cooled and the product that has precipitated is filtered off. The product is washed in succession three times with 10 ml of ethanol each time, twice with 10 ml of isopropanol each time and twice with 10 ml of hexane each time, yielding the title compound in the form of rust-brown crystals which are used for the next step; MS: (M)+ =256.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:9][C:10]([F:19])([F:18])[C:11]1[CH:12]=[C:13](I)[CH:14]=[CH:15][CH:16]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:19])([F:18])[F:9])[CH:16]=2)[CH:7]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: Cc1ccc(=O)[nH]c1
Product: Cc1ccc(=O)n(-c2cccc(C(F)(F)F)c2)c1
Yield: 78 %

Procedure:
The reaction of 5-methyl-2-(1H)-pyridone with -3-trifluoromethyl-iodobenzene by the procedure of Example 1, gives a 78% yield of 5-methyl-1(3'-trifluoromethylphenyl)-2-(1H)-pyridone.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:22]([O:23]C(=O)C2C=CC=CC=2)[C@H:21]([CH3:32])[O:20][C@H:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:11]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][O:33][C@H:11]2[C@@H:10]([OH:9])[C@@H:22]([OH:23])[C@H:21]([CH3:32])[O:20][C@@H:12]2[S:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(CO[C@H]2[C@@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CO[C@H]2[C@@H](O)[C@@H](O)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a solution of crude phenyl 6-deoxy-3,4-di-O-benzoyl-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside β-13 in 20 mL of MeOH is added NaOMe (200 mg, 3.8 mmol). The reaction mixture is stirred at room temperature for 2 h and then neutralized with Amberlite resin. The solution is filtered, washed several times with MeOH and concentrated in vacua. The crude product is purified by flash chromatography (60% EtOAc/petroleum ether) to afford 1.01 g (72%, 3 steps) of phenyl 6-deoxy-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-14): Rf 0.35 (50% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.56-7.52 (m, 2H, ArH), 7.31-7.27 (m, 5H, ArH), 6.89-6.88 (m, 2H, ArH), 4.93 (d, J=9.9 Hz, 1H, H-1), 4.71 (d, J=11.2 Hz, 1H, CH2), 4.55 (d, J=11.2 Hz, 1H, CH2), 4.13 (t, J=2.6 Hz, 1H, H-3), 3.83 (s, 3H, OCH3), 3.73-3.63 (m, 1H, H-5), 3.38 (dd, J=3.3, 9.9 Hz, 1H, H-2), 3.21 (dt, J=3.3, 9.6 Hz, 1H, H-4), 2.58 (s, 1H, OH) 2.34-2.30 (d, 1H, OH), 1.33 (d, J=6.3 Hz, 3H, H-6).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[CH:44][CH:43]=4)[CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].Cl[CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62].C(N(CC)CC)C>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:41][C:42]4[CH:43]=[CH:44][C:45]([O:48][CH2:49][C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)=[CH:46][CH:47]=4)[CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Reaction time: 1 h

Procedure:
A mixture of EXAMPLE 4C (0.30 g) and (2-(chloromethoxy)ethyl)trimethylsilane (0.094 g) in tetrahydrofuran (4 mL) was treated with triethylamine (0.122 g) at room temperature. The reaction was stirred for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[S:10][C:9]([C:11]([OH:13])=[O:12])=[C:8]([CH3:14])[CH:7]=1.[CH3:15]O>>[Br:5][C:6]1[S:10][C:9]([C:11]([O:13][CH3:15])=[O:12])=[C:8]([CH3:14])[CH:7]=1
Reactant: CO
Reactant: Cc1cc(Br)sc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1sc(Br)cc1C

Procedure:
After thionyl chloride was added to methanol, 5-bromo-3-methylthiophene-2-carboxylic acid was added thereto and the resulting solution was heated and refluxed to obtain methyl 5-bromo-3-methylthiophene-2-carboxylate. EI: 234, 236.
Reaction SMILES: [C:1](#[N:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:14][C:15]([CH3:22])([CH3:21])[CH2:16][C:17](OC)=[O:18].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:14][C:15]([CH3:22])([CH3:21])[CH2:16][C:17](=[O:18])[CH2:2][C:1]#[N:3]
Reactant: COC(=O)CC(C)(C)C
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)CC#N
Temperature: 25 °C

Procedure:
In a 500 mL dried round-bottom flask, acetonitrile (6.31, 153.6 mmol) dissolved in THF (50 mL) was treated with LiHMDS (156.3 mL, 1.0 M solution in THF) at −78° C. To this solution was added methyl 3,3-dimethylbutanoate in THF (50 mL) at −78° C. The solution was warmed to rt, and NaHCO3 (100 mL, saturated solution) was added. The layers were separated and the aqueous layer was extracted with ether (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the desired product, which was used in the next step without purification. 1H NMR (300 MHz, CD2Cl2) δ 3.47 (s, 2H), 2.44 (s, 2H), 1.03 (s, 9H).
Reaction SMILES: Cl[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][S-:20].[Na+]>CS(C)=O.O>[CH3:19][S:20][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Clc1onc(-c2ccccc2)c1-c1ccccc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1onc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 83.7 %

Procedure:
To a stirred solution of 5-chloro-3,4-diphenylisoxazole (Step 1) (1.75 g, 6.84 mmol) in DMSO (30 mL) was added sodium thiomethoxide (0.58 g, 8.21 mmol). After stirring for 30 hours at room temperature, the reaction was diluted with water and extracted twice with Et2O . The combined ethereal phases were washed with NaHCO3 saturated solution, KHSO4 solution (0.25N), and brine, dried over MgSO4, filtered and concentrated in vacuo yielding 5-methylthio-3,4-diphenylisoxazole (1.53 g, 84%): mp 83°-86° C. 1H NMR (CDCl3 /300 MHz) 7.50-7.18 (m, 10H), 2.63 (s, 3H). FABLRMS m/z 268 (M+H). FABHRMS m/z 268.0781 (M+H C16H14NOS requires 268.0796). Anal. Calc'd for C16H13NOS: C, 71.88; H, 4.90; N, 5.24. Found: C, 71.71; H, 4.95; N, 5.17.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[NH2:16][C:17]1[CH:18]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>O>[F:24][C:23]([F:25])([F:26])[C:19]1[CH:18]=[C:17]([NH:16][CH2:2][CH2:3][NH:4][C:5]2[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccccc1NCCBr
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1NCCNc1cccc(C(F)(F)F)c1
Temperature: 110 °C
Yield: 37.8 %

Procedure:
Ethyl N-(2-bromoethyl)aminobenzoate (3.3 g, 12 mmol), 3-aminobenzotriflouride (1.5 mL, 12 mmol) and triethylamine (2 mL, 14 mmol) were mixed in dimethyltormamide (25 mL). The reaction mixture was heated at 110° C. for five hours. The cooled reaction mixture was poured into water and extracted with diethyl ether. Purification by column chromatography on silica gel using dichloromethane as eluent gave 1.6 g of the desired material.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([C:15](=[O:17])[CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N2CCN(c3cccc(Cl)c3)CC2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-(3-chloro-phenyl)-piperazine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C22H25ClN2O5 [M+H]+: 433.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: BrCCCCCBr
Reactant: O=C1CCc2ccccc2N1
Product: O=C1CCc2ccccc2N1CCCCCBr

Procedure:
from 3,4-dihydroquinolin-2(1H)-one and 1,5-dibromopentane
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[S:24]([CH3:27])(=[O:26])=[O:25])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:19]3[CH:23]=[CH:22][N:21]=[C:20]3[S:24]([CH3:27])(=[O:26])=[O:25])[O:11][C:12]=2[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1oc(-n2ccnc2S(C)(=O)=O)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To a solution of methyl 3-{4-(4-chlorophenyl)-2-[2-(methylsulfonyl)-1H-imidazol-1-yl]-5-oxazolyl}propionate (1.4 g) in 1,4-dioxane (7 mL) was added 2N aqueous sodium hydroxide solution (3.5 mL) and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water, and acidified with 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from methanol to give 3-{4-(4-chlorophenyl)-2-[2-(methylsulfonyl)-1H-imidazol-1-yl]-5-oxazolyl}propionic acid (1.22 g, yield 90%) as colorless prism crystals. melting point: 166–167° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][C:24]([NH2:27])([CH3:26])[CH3:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][N:14]1[CH2:23][C:24]([NH:27][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:25])[CH3:26]
Reactant: CC(C)(N)CN1CCc2ccccc2C1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(CN1CCc2ccccc2C1)NC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 117 %

Procedure:
To a solution of 3-nitrobenzoylchloride (0.14 g, 0.75 mmol) and 43 (0.15 g, 0.76 mmol) in anhydrous CH2Cl2 (7 mL) was added DMAP (10 mg). The reaction was stirred at room temperature overnight before it was diluted with EtOAc (100 mL). Upon sequential washings with 1 N NaOH (2×100 mL), water (200 mL), the organic mixture was dried (Na2SO4) and concentrated under reduced pressure to give 44 (0.31 g,˜100%) as a thick dark oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[N+](=[CH2:26])=[N-]>CO.C(OCC)C.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:9][C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:26])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](O[C@H](c1ccccc1)c1ccc(Br)cc1)C(=O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)O[C@H](c1ccccc1)c1ccc(Br)cc1

Procedure:
To a solution of (2S)-2-{[(R)-(4-bromophenyl)(phenyl)methyl]oxy}-4-methylpentanoic acid from step 2 example 1, (2.5 g, 6.6 mmol) in methanol (25 mL) at 0° C. was added portionwise diazomethane in diethyl ether until the yellow color persisted. A few drops of acetic acid were then added to quench the excess diazomethane. The colorless solution was concentrated and then the volatiles were coevaporated twice with n-heptane. The oil was pumped on to remove the last traces of solvent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]=[C:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1>[Pd].CCO>[CH3:1][O:2][C:3](=[O:12])[CH2:4][CH:5]1[CH2:6][CH2:7][N:8]([CH3:11])[CH2:9][CH2:10]1
Reactant: COC(=O)C=C1CCN(C)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CC1CCN(C)CC1

Procedure:
(1-Methyl-piperidin-4-ylidene)-acetic acid methyl ester (Step A) was stirred under H2 overnight (1.1 g of 10% Pd/C and 200 mL EtOH), filtered and evaporated to give (1-methyl-piperidin-4-yl)-acetic acid methyl ester as a yellow oil/white solid.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[C:13]([C:35]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH:36]=2)[CH:12]=1)([CH3:10])[CH3:9])(C)(C)C.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O>C1COCC1>[CH3:41][C:38]1([CH3:42])[CH2:39][CH2:40][C:35]([C:13]2[CH:12]=[C:11]([C:8]([CH3:9])([CH3:10])[CH2:7][OH:6])[CH:16]=[CH:15][C:14]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[CH:36][CH2:37]1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)CO[Si](C)(C)C(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC=C(c2cc(C(C)(C)CO)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step, 2.20 g, 3.45 mmol) and tetrabutylammonium fluoride hydrate (4.52 g, 17.3 mmol) in 25 mL of THF was stirred at 50° C. for 3 h. After cooling to RT, the mixture was treated with 100 mL of EtOAc and washed with saturated aqueous NH4Cl (20 mL), H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (0-4% MeOH/DCM) to afford the title compound (1.25 g, 92%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C23H28N4O2, 393.2 (M+H). found 393.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]([CH3:18])[C:14](OC)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl.[NH2:27][OH:28].C[O-].[Na+]>CO>[OH:28][NH:27][C:14](=[O:15])[CH:13]([N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]
Reactant: NO
Reactant: COC(=O)C(C)N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)C(C)C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-[[4-methoxybenzenesulfonyl](benzyl)amino]propionate (2.1 g, 6.01 mmol) is dissolved in methanol (20.0 mL). To this solution is added hydroxylamine hydrochloride (0.84 g, 12.0 mmol), followed by the addition of sodium methoxide (7.0 mL of a 4.37M solution). The reaction is stirred overnight at room temperature. The reaction is worked up by first removing all the solvent, and partitioning between ethyl acetate/hexane (2/1) and saturated sodium bicarbonate. The aqueous phase is extracted well with ethyl acetate/hexane, the combined organic layers are dried (MgSO4), and the solvent is evaporated. The product is purified by silica gel chromatography (ethyl acetate) to give N-hydroxy-2-[[4-methoxybenzenesulfonyl](benzyl)amino]propionamide, m.p. 149°-151° C.