Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:21][C:22]1[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[O:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[O:6][C:7]([CH3:8])=[C:3]([CH2:2][O:21][C:22]3[CH:26]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[O:24][N:23]=3)[N:4]=2)=[CH:10][CH:11]=1)[CH3:20]
Reactant: CCOC(=O)Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: COC(=O)c1cc(O)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3cc(C(=O)OC)on3)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A mixture of ethyl [4-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)phenyl]acetate (2.00 g), methyl 3-hydroxyisoxazole-5-carboxylate (0.974 g), anhydrous potassium carbonate (0.941 g) and N,N-dimethylformamide (40 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered through silica gel. The filtrate was concentrated to give methyl 3-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)isoxazole-5-carboxylate as colorless crystals (2.02 g, yield 81%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 124-126° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=O)[N:11]([CH2:12][CH3:13])[C:6]=2[N:5]=[C:4]([CH3:15])[N:3]=1.Cl.[OH-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[C:6]=2[N:5]=[C:4]([CH3:15])[N:3]=1
Reactant: CCN1C(=O)COc2c(Cl)nc(C)nc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1CCOc2c(Cl)nc(C)nc21
Temperature: 115 °C

Procedure:
A solution of 2.0 g (8.81 mmole) of 4-chloro-6,7-dihydro-8-ethyl-2-methylpyrimido [5,4-b][1,4]oxazin-7-one in 25 ml of tetrahydrofuran was added dropwise to 3.5 ml of cold (0° C.) borane-methyl sulfide complex in tetrahydrofuran. After the completion of the addition, the mixture was heated at its reflux temperature for three hours. The mixture was cooled and 14 ml of 6N hydrochloric acid was slowly added. This mixture was heated for one hour at 115° C., and was then cooled and neutralized with ammonium hydroxide. The mixture was extracted with chloroform, and the organic layer was then dried and evaporated to provide an oil residue which crystallized on cooling. Nuclear magnetic resonance spectral analysis showed the product to be 4-chloro-6,7-dihydro-8-ethyl-2-methylpyrimido [5,4-b][1,4]oxazine.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:27][C:28]1([CH3:42])[O:33][C:32]2[CH:34]=[CH:35][C:36]([C:38]([OH:40])=O)=[CH:37][C:31]=2[C:30](=[O:41])[O:29]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:26]=[CH:25][C:16]([CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:38]([C:36]3[CH:35]=[CH:34][C:32]4[O:33][C:28]([CH3:27])([CH3:42])[O:29][C:30](=[O:41])[C:31]=4[CH:37]=3)=[O:40])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1(C)OC(=O)c2cc(C(=O)O)ccc2O1
Reactant: CCCCCCNCc1ccc(C#Cc2ccc(CCCC)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)C(=O)c1ccc2c(c1)C(=O)OC(C)(C)O2
Yield: 47.7 %

Procedure:
A solution of N-{4-[(4-butylphenyl)ethynyl]benzyl}-1-hexanamine (144 mg, 0.41 mmol), 2,2-dimethyl-4-oxo-4H-1,3-benzodioxine-6-carboxylic acid (92 mg, 0.41 mmol), EDC.HCl (87 mg, 0.46 mmol), HOBT (61 mg, 0.46 mmol) and DIEA (105 μL, 0.62 mmol) in DCM (10 mL) was stirred at rt overnight. Then the reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3, a saturated aqueous solution of NH4Cl and brine. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silicagel (EtOAc/c-Hex (20/80)) to give 108 mg (47%) of the title compound as a colorless oil. HPLC, Rt: 6.14 min (purity: 99.9%). 1H NMR (CD3Cl3) δ: 0.82 (m, 3H), 0.91 (t, J=7.3 Hz, 3H), 1.32-1.40 (m, 10H), 1.57 (m, 2H), 1.72 (s, 6H), 2.59 (t, J=7.6 Hz, 2H), 3.16-3.41 (m, 2H), 4.40-4.72 (m, 2H), 7.00 (m, 2H), 7.14 (d, J=8.3 Hz, 2H), 7.25 (m, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.1 Hz, 2H), 7.61 (m, 1H), 8.03 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([O:19]CC3C=CC=CC=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2]>[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-].CO>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCc3ccccc3)ccc21
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
20% palladium hydroxide carbon (4.00 g) was added to a methanol (400 mL) solution of 1-ethyl-7-benzyloxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (39.8 g, 113 mmol), and catalytic hydrogenation reaction was performed at room temperature at ordinary pressure. The reaction solution was filtered to remove a catalyst, and methanol was distilled off. Ethanol (120 mL) was added to the resulting residue, and the mixture was heated while stirring. After the dissolution was confirmed, water (40 mL) was added, and the mixture was heated again. After the temperature was cooled to near room temperature, stirring was performed under ice cooling for 1 hour. Precipitated crystals were then collected by filtration. The resulting crystals were washed with 50% ethanol (40 mL), and dried at 60° C., thereby obtaining 24.3 g of white, powdery 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (yield: 82%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([O:12]CC2C=CC=CC=2)[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]>FC(F)(F)C(O)=O>[N+:1]([C:4]1[CH:11]=[C:10]([OH:12])[C:9]([O:20][CH3:21])=[CH:8][C:5]=1[C:6]#[N:7])([O-:3])=[O:2]
Reactant: COc1cc(C#N)c([N+](=O)[O-])cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)c([N+](=O)[O-])cc1O
Yield: 61.7 %

Procedure:
2-nitro-4-benzyloxy-5-methoxybenzonitrile (3 g, 10.6 mmol) was treated with trifluoroacetic acid (30 ml) at reflux for 0.5 hour. The solvent was evaporated, the residue triturated with ether to give a yellow solid of title compound (1.27 g, 62%).
Reaction SMILES: [O:1]=[C:2]1[CH:7]2[CH2:8][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:10][CH2:11][N:6]2[CH2:5][CH2:4][NH:3]1.[H-].[Na+].I[CH3:25]>C1COCC1>[CH3:25][N:3]1[CH2:4][CH2:5][N:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH2:8][CH:7]2[C:2]1=[O:1]
Reactant: CI
Reactant: O=C1NCCN2CCN(C(=O)OCc3ccccc3)CC12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN2CCN(C(=O)OCc3ccccc3)CC2C1=O
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
To a solution of (+/−)-benzyl 9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (160 mg, 0.553 mmol) in THF (5 mL) at 0° C. was added sodium hydride (24.33 mg, 0.608 mmol). The ice bath was removed and stirred for 10 min; saw bubbling but some NaH solid still remained. Then iodomethane (0.038 mL, 0.608 mmol) was added and after stirring for 10 min at room temperature, most NaIl solid was dissolved. After another 30 min, LC-MS indicated completion. It was quenched with water and diluted with EtOAc. After separating the layers, the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with water, brine, dried over MgSO4, filtered and concentrated. Purification via flash chromatography (0-5% MeOH in DCM, 12 g) gave (+/−)-benzyl 8-methyl-9-oxohexahydro-1H-pyrazino[1,2-a]pyrazine-2(6H)-carboxylate (120 mg) as a light yellow oil.
Reaction SMILES: [SiH](CC)(CC)CC.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:25])=[C:13]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:24])=[CH:19][CH:18]=2)=O)[CH:14]=1.C(S(O)(=O)=O)(F)(F)F>C(O)(C(F)(F)F)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:25])=[C:13]([CH2:15][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][Br:24])=[CH:19][CH:18]=2)[CH:14]=1
Reactant: O=C(c1ccc(CBr)cc1)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Br)cc1Cc1ccc(CBr)cc1
Reaction time: 3 h

Procedure:
To a stirred solution of Et3SiH (17 mL) and (5-bromo-2-chlorophenyl)(4-(bromomethyl)phenyl)methanone (intermediate AH) (20.75 g, 54 mmol) in TFA (100 mL) at 30° C. was added CF3SO3H (0.05 mL). Within a few minutes the temperature of the solution increased causing it to reflux violently. After 3 h, the volatiles were removed under reduced pressure. The residue was poured into brine and extracted 3× with ethyl acetate. The combined organic layers were washed 3× with H2O, 2× with aqueous Na2SO4 and 2× with brine, and dried over Na2SO4. The solvent was evaporated under reduced pressure, and the product was purified by column chromatography to obtain pure intermediate AI (15.5 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[C:8]1([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:4])[C:2]#[CH:3]
Reactant: C#CC(=O)OCC
Reactant: OCCCCCCCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: C#CC(=O)OCCCCCCCc1ccccc1

Procedure:
A mixture of 1 g of ethyl propiolate, 2.94 g of 7-phenylheptanol and 0.01 g of p-toluenesulfonic acid in 30 ml of benzene was refluxed for twelve hours. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 7-phenylheptyl propiolate (compound 3).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:26])([F:25])[F:24])[C:11]([C:27]([O:29]CC)=[O:28])=[CH:10]2)=[O:5].[OH-].[Li+]>CO.C1COCC1>[CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([F:24])([F:25])[F:26])[C:11]([C:27]([OH:29])=[O:28])=[CH:10]2)=[O:5]
Reactant: CCOC(=O)c1cc2cc(NC(=O)CC(C)(C)C)ccc2n1Cc1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)CC(=O)Nc1ccc2c(c1)cc(C(=O)O)n2Cc1ccccc1C(F)(F)F
Temperature: 90 °C

Procedure:
105 mg (0.26 mmol) of ethyl 5-[(3,3-dimethylbutanoyl)amino]-1-[2-(trifluoromethyl)benzyl]-1H-indole-2-carboxylate from Example LXIII are dissolved in 1 ml each of methanol and THF, and 0.26 ml (0.52 mmol) of 2M lithium hydroxide solution is added. The mixture is heated at 90° C. for one hour. After cooling, the mixture is, for work-up, diluted and extracted with aqueous hydrochloric acid and ethyl acetate. The organic phase is dried with sodium sulphate, filtered and dried under reduced pressure.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][NH2:15])[C:8]1=[O:16])=[O:5])C>Cl>[C:4]([CH2:6][N:7]1[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][NH2:15])[C:8]1=[O:16])([OH:5])=[O:3]
Reactant: CCOC(=O)Cn1c(C)cnc(NN)c1=O
Agent: Cl
Product: Cc1cnc(NN)c(=O)n1CC(=O)O
Yield: 90.1 %

Procedure:
A solution of the compound of Example 4 (6.3 g, 0.028 mol) in HCl (6N, 160 mL) was heated at 60 to 70° C. for 2 hours. The reaction mixture was concentrated under vacuum to afford the title compound (5.0 g, 91%) as a yellow solid, which used in the next step without further purification. 1H NMR (D2O) δ2.18 (s, 3H), 4.8 (s, 2H) , 6.71 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-])=O)=[N:9][CH:10]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
A mixture of 117b (2 g, 10 mmol), MeOH (10 mL), Pd/C (120 mg) in methanol (8 mL) was stirred fat 25° C. under H2 (50 Psi) overnight. The Pd/C was removed by filtration and the filtrate was concentrated under reduced pressure to give 117c (1.7 g, 98%). MS: [M+H]+ 173.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([N:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[NH:17][CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].N>O>[C:24]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]([C:12]([N:9]2[CH2:10][CH2:11][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH2:8]2)=[O:13])[CH2:15][CH2:16]1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(N1CCC(c2cccnc2)C1)N1CCNc2ccccc21
Agent: N
Solvent: O
Product: CC(=O)N1CCN(C(=O)N2CCC(c3cccnc3)C2)c2ccccc21

Procedure:
0.25 g of 1-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline and 1.05 ml of acetic anhydride are placed in a 10 ml round-bottomed flask. The reaction medium is brought to reflux for two hours and then a solution of ammonia in water is added at 0° C. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel with a dichloromethane/methanol 95/5 mixture. 0.284 g of 1-acetyl-4-[(3-(pyridin-3-yl)pyrrolidin-1-yl)carbonyl]-1,2,3,4-tetrahydroquinoxaline is obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[CH:10]1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:4]#[C:5][CH2:6][CH2:7][C:10]2[O:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: c1ccc2ocnc2c1
Product: Fc1ccc(C#CCCc2nc3ccccc3o2)nc1
Yield: 9.8 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-5-fluoropyridine (200 mg, 1.14 mmol) and 2-but-3-ynyl)benzo[d]oxazole (195 mg, 1.14 mmol, Example 8(A)). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) and SCX column (DCM/MeOH 100:0 to 94:6, DCM/MeOH 94:5:1 to 90:8:2) to yield 15 mg (56 μmol, 5%) of 2-(4-(5-fluoropyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.Br[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)(C(F)(F)F)=O>CS(C)=O>[Cl:17][C:16]1[C:11]([N:1]2[CH2:2][CH:3]=[C:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)C1=CCNCC1
Reactant: Clc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1=CCN(c2ncccc2Cl)CC1
Temperature: 90 °C

Procedure:
1,2,3,6-Tetrahydro-4-pyridinecarboxylic acid (7.0 g, 47 mmol) and 2-bromo-3-chloropyridine (11.0 g, 57 mmol) were combined in DMSO (100 mL) and treated with anhydrous K2CO3 (8.0 g, 58 mmol). The mixture was heated at 90° C. overnight, allowed to cool to room temperature, and then concentrated under reduced pressure. The residue in dichloromethane (200 mL) was cooled to −78° C. and treated with an excess of TFA (10 mL, 130 mmol) dropwise. The mixture was allowed to warm to room temperature and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [C:1]([N:4]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C@@H:5]([CH2:13][OH:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2].[Br-].[Na+].Cl[O-].[Na+].C(=O)(O)[O-].[Na+].O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1.O.ClCCl>[C:1]([N:4]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C@@H:5]([CH:13]=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: O=C(O)N(Cc1ccccc1)[C@@H](CO)Cc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C[C@@H](Cc1ccccc1)N(Cc1ccccc1)C(=O)O
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
N-Carboxybenzyl-D-phenylalaninol (100 g ;0.35M) is dissolved in ethyl acetate/toluene (1:1; 1.5-2.0 L) or dichloromethane (1.0-2.0 L) and a solution of sodium bromide (18.0-25.2 g; 0.175-0.25M) in water (50-250 mL) added. The resulting two phase mixture is stirred and cooled to 0°-5° C. under a nitrogen atmosphere. 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical (TEMPO) (0.055-0.55 g; 3.5-35 mM) is added. A solution of buffered sodium hypochlorite, freshly prepared by dissolving sodium bicarbonate (10-25 g; 0.12-0.3M) and commercial sodium hypochlorite solution (6-12.5% w/w; 250-584 g; 0.42-0.49M) in water (25-250 g), is added over a period of one hour with fast agitation, maintaining the reaction temperature <5° C. A solution of sodium thiosulfate pentahydrate (21.8-122 g; 0.088-0.49M) in water (64 -370 mL) is then immediately added and the reaction mixture efficiently stirred until excess oxidants have been quenched as demonstrated by starch/iodide test. Agitation is stopped and the mixture allowed to settle at 5°-10° C. After 15 minutes, the phases are separated. The organic phase is then washed with aqueous sodium bicarbonate solution (3% w/w; 500 mL) and aqueous sodium chloride solution (3% w/w; 500 mL). The organic phase is concentrated by vacuum distillation to a volume of approximately 300 mL maintaining the heating bath <20° C. Heptane (750 mL) is added and the vacuum distillation optionally continued to precipitate the product, while maintaining the heating bath <20° C. The precipitate is filtered, washed with heptane (2×200 mL) and dried under vacuum at 20° C. to constant weight to yield N-carboxybenzyl-D-phenylalaninal (90 g; 90% yield) as a white crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Reactant: Oc1ccccc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccccc2)NS(=O)(=O)c2ccc(F)cc2)cc1
Yield: 80.4 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzene-sulfonylamino)-3-methanesulfonyloxypropanamide (500 mg) was reacted with phenol (187 mg) to obtain (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-phenoxypropanamide (400.58 mg).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([O:10]C)=[O:9])=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].O>C1COCC1>[O:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[C:8]([OH:10])=[O:9])=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccccc1-c1cnco1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1-c1cnco1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
To a solution of methyl 2-(1,3-oxazol-5-yl)benzoate (4.0 g) in THF (40 mL) was added 2 N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature stirred for 2 days. To the reaction mixture was added water, and the mixture was washed with tert-butyl methyl ether. The pH of the obtained aqueous layer was adjusted to 2 with 2N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate/petroleum ether to give the title compound (3.3 g)
Reaction SMILES: C(C1C=CC=CC=1C(O)O[SiH](C)C)(C)(C)C.[C:17]([C:21]1[CH:32]=[C:31](Br)[C:30](OC)=[CH:29][C:22]=1[CH:23]([Br:28])[O:24][SiH:25]([CH3:27])[CH3:26])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=1[CH:23]([Br:28])[O:24][SiH:25]([CH3:26])[CH3:27])([CH3:20])([CH3:18])[CH3:19]
Reactant: COc1cc(C(Br)O[SiH](C)C)c(C(C)(C)C)cc1Br
Agent: C[SiH](C)OC(O)c1ccccc1C(C)(C)C
Product: C[SiH](C)OC(Br)c1ccccc1C(C)(C)C
Yield: 32 %

Procedure:
This compound was prepared from 2-(tert-butyl)dimethylsilyloxybenzyl alcohol (8) (2.81 g, 11.8 mmol) in the manner previously described for the synthesis of benzyl bromide 6, affording 1.14 g (32%) of the silyloxybenzyl bromide as a colorless oil. 1H NMR (400 MHz, CDCl3) δ0.30 [s, 6H, Si(CH3)2 ], 1.07 [s, 9H, SiC(CH3)3 ], 4.54 (s, 2H, CH2Br), 6.83 (d, 1H, J=6.2 Hz, Ar--H), 6.93 (dd, 1H, J=7.1, 7.1 Hz, Ar--H), 7.19 (ddd, 1H, J=9.4, 7.9, 1.6 Hz, Ar--H) 7.34 ppm (dd, 1H, J=5.8, 1.6 Hz, Ar--H). ##STR4##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:26]([CH3:25])[C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:15][C@@H:10]3[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:12][C@@H:11]3[CH2:13]2)[CH:17]=[N:18][CH:19]=1)=[O:23])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CNCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CN(Cc1ccccc1)C(=O)c1cncc(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)c1

Procedure:
The product from Example 33B and N-methylbenzylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 437 (M+H)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH2:18][C@H:19]([O:21][C:22]3[CH:27]=[N:26][C:25]([CH:28]4[CH2:30][CH2:29]4)=[CH:24][N:23]=3)[CH2:20][C@H:14]2[CH2:13]1)=[O:11])C)(C)(C)C.Cl>O1CCOCC1>[CH:28]1([C:25]2[N:26]=[CH:27][C:22]([O:21][C@H:19]3[CH2:18][N:15]4[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C@H:9]([NH:7][CH3:6])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:13][C@@H:14]4[CH2:20]3)=[N:23][CH:24]=2)[CH2:30][CH2:29]1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
The product from Example 193A (11 mg, 0.022 mmol) in a mixture of 1,4-dioxane (0.5 mL) and hydrogen chloride solution (4 N in 1,4-dioxane) (0.5 mL, 2.00 mmol) was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (4.3 mg, 49%). 1H NMR (300 MHz, CDCl3) δ ppm 0.83-1.02 (m, 4 H) 1.19-3.25 (m, 13 H) 3.49-3.97 (m, 2 H) 4.42 (d, J=17.90 Hz, 1 H) 4.58-4.90 (m, 1 H) 5.20-5.42 (m, 1 H) 7.20-7.42 (m, 5 H) 7.86-8.07 (m, 2 H); MS (ESI) m/z 408 (M+H)+.