Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:16])=[CH:10][CH:9]=1.ClC1C=CC=C(C(OO)=[O:42])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:42][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([C:17]2[CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:16])=[CH:12][CH:13]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ccccn4)cc2)CO3)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4cccc[n+]4[O-])cc2)CO3)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 73.7 %

Procedure:
To a solution of N-[4-(2-pyridylmethyl)phenyl]-6-(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (250 mg) in tetrahydrofuran (10 ml) was added 3-chloroperbenzoic acid (70%, 0.21 g) at 0° C., and the mixture was stirred at room temperature for 14 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3) concentrated to give crystals, which were recrystallized from chloroform-ethanol to give N-[4-(1-oxidopyridin-2-ylmethyl)phenyl]-6-(4-methylphenyl)-2H-1-benzopyran-3-carboxamide (Compound 200) (191 mg) as pale yellow crystals.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[C:12]([Cl:17])=[N:13][CH:14]=[CH:15][CH:16]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccnc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1
Temperature: -5 °C
Reaction time: 8 h

Procedure:
3.9 g (28 mmol) of benzoyl chloride are added to 30 ml of pyridine while the temperature is maintained at approximately -5° C. A solution containing 3 g (23.3 mmol) of 3-amino-2-chloropyridine in 20 ml of pyridine is added to this solution using a pressure equalizing funnel. The reaction medium is left stirring overnight and then poured into a water/ice mixture. The solid obtained is then filtered off, washed several times with water and thereafter recrystallized in absolute ethanol.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:20])[C:7]([S:18][CH3:19])=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3].[OH:21]O>C(O)C.C(Cl)Cl>[OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:20])[C:7]([S:18]([CH3:19])=[O:21])=[C:8]2[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH3:3]
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: OO
Solvent: CCO
Solvent: ClCCl
Product: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 18 h

Procedure:
To a solution of allyl (4R,5S,6S)-6-((1R)-1-hydroxyethyl)-4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (100 mg) in ethanol (1.0 ml) was added a 30% aqueous solution of hydrogen peroxide (0.5 ml) and the mixture was allowed to stand at the ambient temperature for 18 hours. The solution was diluted with methylene dichloride and washed with water, 5% aqueous sodium thiosulfate solution and brine successively. The organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford allyl (4R,5S,6S)-6-((1R)-1-hydroxyethyl)-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (50.0 mg).
Reaction SMILES: C1C2C(COC(=O)[NH:17][C@H:18]([C:24]([NH:26][CH2:27][C@@H:28]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:25])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C)C=O>[C:44]([O:43][C:41](=[O:42])[NH:40][C@H:28]([CH2:27][NH:26][C:24](=[O:25])[C@@H:18]([NH2:17])[CH2:19][CH2:20][C:21]([NH2:23])=[O:22])[CH2:29][CH2:30][CH2:31][NH:32][C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])([CH3:45])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@H](CCC(N)=O)NC(=O)OCC1c2ccccc2-c2ccccc21)NC(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)[C@@H](N)CCC(N)=O)NC(=O)OC(C)(C)C

Procedure:
A solution of 33 mg (0.05 mmol) of 9H-fluoren-9-ylmethyl{(1S)-4-amino-1-[({(2S)-2,5-bis[(tert-butoxycarbonyl)amino]pentyl}amino)carbonyl]-4-oxobutyl}carbamate (Example 129A) in 1 ml of dimethylformamide is stirred after the addition of 4 mg (0.05 mmol) of piperidine at room temperature for 45 min. The solvent is evaporated and the crude product is reacted without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]([F:32])=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([CH2:23][N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)=[C:17]([O:30][CH3:31])[CH:16]=3)[CH:14]=2)[CH:3]=1.[CH3:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[CH3:31][O:30][C:17]1[CH:16]=[C:15]([C:13]2[CH:14]=[C:9]([C:4]3[CH:3]=[C:2]([C:37]4[CH:36]=[N:35][N:34]([CH3:33])[CH:38]=4)[N:7]=[CH:6][C:5]=3[NH2:8])[C:10]([F:32])=[N:11][CH:12]=2)[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(-c2cnc(F)c(-c3cc(Cl)ncc3N)c2)cc(OC)c1CN1CCCCC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnc(F)c(-c3cc(-c4cnn(C)c4)ncc3N)c2)cc(OC)c1CN1CCCCC1
Temperature: 100 °C
Yield: 70.2 %

Procedure:
A degassed mixture of 6′-chloro-5-(3,5-dimethoxy-4-piperidin-1-ylmethylphenyl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (830 mg, 1.40 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (577 mg, 2.78 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (151 mg, 0.19 mmol) in 1N aqueous potassium fluoride solution (10 mL) and acetonitrile (6 mL) was heated under microwave irradiation at 100° C. for 20 minutes. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 20 g column, ISCO, 0-10% methanol in DCM) to afford the title compound as a white solid (494 mg, 54%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.55 (dd, J=2.5, 1.0 Hz, 1H), 8.22 (dd, J=8.8, 2.5 Hz, 1H), 8.16 (d, J=0.6 Hz, 1H), 7.92 (s, 1H), 7.85 (d, J=0.8 Hz, 1H), 7.37 (s, 1H), 6.95 (s, 2H), 4.35 (s, 2H), 4.01 (s, 6H), 3.95 (s, 3H), 3.61-3.22 (br m, 2H), 3.19-2.90 (br m, 2H), 2.02-1.47 (br m, 6H).
Reaction SMILES: [CH:1]1([N:4]([CH3:28])[C:5]2[C:6]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=3)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([N:4]([CH3:28])[C:5]2[C:6]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)=[N:7][C:8]3[C:13]([N:14]=2)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=3)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ccc4c3)c(N(C)C3CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ccc2c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-[cyclopropyl(methyl)amino]-2-(1H-indol-5-yl)quinoxaline-6-carboxylate (71 mg, 0.19 mmol) in methanol (20 mL) and water (1.0 mL) was added sodium hydroxide (22.9 mg, 0.57 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (10 mL), adjusted pH to 4 with HCl (3N) to give the precipitate, which was collected by filtration to afford 3-[cyclopropyl(methyl)amino]-2-(1H-indol-5-yl)quinoxaline-6-carboxylic acid of as a yellow solid (20.4 mg, 30%).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[N:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N:4][CH:3]=1
Reactant: CCOC(=O)CCc1ncc(C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(CCC(=O)O)s1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 3-(5-methylthiazol-2-yl)propanoate (0.2 g, 1 mmol) in THF/water (3 mL/3 mL) was added lithium hydroxide (61 mg, 1.5 mmol) portionwise at room temperature. The resulting mixture was stirred for 3 h. The solvent was evaporated and the residue was acidified with conc. HCl to adjust the pH to 1-2. The mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate and concentrated to afford 3-(5-methylthiazol-2-yl)propanoic acid (0.17 g, 87.7% yield) as a colorless oil. LCMS retention time 0.436 min; LCMS MH+ 172.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[N:14]([O-])=O.[Na+].[ClH:18]>O>[ClH:18].[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:4][CH:3]=1)[NH2:14]
Reactant: O=N[O-]
Reactant: CS(=O)(=O)NCc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)NCc1ccc(NN)cc1
Temperature: -55 °C
Yield: 100 %

Procedure:
To a suspension of 18.0 g (89.9 mmol, 1.0 equiv.) of N-[(4-aminophenyl)methyl]methanesulfonamide in 85 ml of water and 175 mL of concentrated aqueous hydrochloric acid at 0° C. was added a solution of 6.21 g (89.9 mmol, 1.0 equiv.) of sodium nitrite in 85 mL of water. The reaction mixture was stirred for fifteen minutes. Meanwhile a solution of 101.6 g of stannous chloride dihydrate in 175 mL of concentrated aqueous hydrochloric acid was prepared and cooled to -55° C. The solution of the diazonium salt was filtered into the stannous chloride solution. The reaction was maintained between -55° C. and -35° C. for one hour. The crystalline material was collected by filtration and dried under high vacuum at 65° C. for 16 hours to yield 23.9 g (>100%) of crude N-[(4-hydrazinylphenyl)methyl]methanesulfonamide hydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=1)(=[O:7])=[O:6]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: CN(C)CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CN(C)CCS(=O)(=O)c1ccc(N)cc1

Procedure:
A solution of dimethyl-[2-(4-nitro-benzenesulfonyl)-ethyl]-amine (0.39 mmol) in ethanol (15 mL) is hydrogenated for 90 minutes at atmospheric pressure over 10% Pd/C. The mixture is filtered through a pad of diatomaceous earth and concentrated under reduced pressure to give 4-(2-dimethylamino-ethanesulfonyl)-phenylamine as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].[N:13](OCCC(C)C)=[O:14]>CO>[N:13](=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)[C:10](=[O:12])[CH3:11])[OH:14]
Reactant: C#Cc1ccc(CC(C)=O)cc1
Reactant: CC(C)CCON=O
Solvent: CO
Product: C#Cc1ccc(C(=NO)C(C)=O)cc1
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
8 g of Na (=0.35 mol) are dissolved at room temperature in 300 ml of methanol. 44 g (=0.28 mol) of 4-ethynylphenylacetone are added to this solution and 34.2 g (0.29 mol) of isopentyl nitrite are allowed to run in dropwise in the course of a few minutes, during which the reaction mixture warms to about 32° C. It is stirred for 1.5 hours, then evaporated. 48.5 g (=93.2% of theory) of 1-hydroximino-1-(4′-ethynylphenyl)propan-2-one are obtained; H-NMR: 2.47(s); 3.07(s); 7.20(m); 7.48(m); 8.01(s).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH3:5][C:6]1([CH3:17])[CH2:10][C:9]2[CH:11]=[CH:12][C:13]([CH:15]=[O:16])=[CH:14][C:8]=2[O:7]1.[Cl-].[NH4+].Cl>O1CCCC1>[CH3:5][C:6]1([CH3:17])[CH2:10][C:9]2[CH:11]=[CH:12][C:13]([CH:15]([CH:2]([CH3:4])[CH3:3])[OH:16])=[CH:14][C:8]=2[O:7]1
Reactant: CC(C)Br
Reactant: CC1(C)Cc2ccc(C=O)cc2O1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc2c(c1)OC(C)(C)C2
Yield: 67.8 %

Procedure:
18.7 g of 2-bromopropane in 30 ml of absolute tetrahydrofuran are added dropwise to 3.6 g of Mg filings in 15 ml of absolute tetrahydrofuran. The mixture is stirred under reflux for 1 hour and is then cooled to 5°-10° C. At this temperature, 23 g of 2,2-dimethyl-2,3-dihydrobenzofuran-6-aldehyde in 100 ml of absolute tetrahydrofuran are added dropwise. The reaction mixture is stirred overnight and is then cautiously decomposed with a cold saturated ammonium chloride solution and a few milliliters of 10% strength hydrochloric acid, sufficient to dissolve the precipitate. The mixture is then extracted three times by shaking with ether and the combined ether extracts are washed with sodium bisulfate solution, sodium bicarbonate solution and water, dried over sodium sulfate and concentrated under reduced pressure. 19.5 g of 2,2-dimethyl-2,3-dihydrobenzofuran-6-yl-(α-isopropyl)-carbinol are obtained in the form of a yellowish oil, which is sufficiently pure for the subsequent reactions. (Yield 68%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: O=C=Nc1ccccc1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 4 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
A suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.7 mmol) in THF (30 mL) was cooled to 4° C. Phenyl isocyanate (0.3 g, 2.7 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The solid was collected and slurried with ethanol (10 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-phenyl-urea (0.7 g, 89%) as a white solid: mp 328-330° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.36-2.64 (m, 2H), 2.86-2.98 (m, 1H), 4.37-4.58 (m, 4H, 2CH2), 5.12-5.19 (dd, J=5.0 and 13.2 Hz, 1H, CH), 6.71 (t, J=5.7 Hz, 1H, NH), 6.89 (t, J=7.3 Hz, 1H, Ar), 7.21 (t, J=7.6 Hz, 2H, Ar), 7.38 (d, J=7.6 Hz, 2H, Ar), 7.48-7.65 (m, 3H, Ar), 8.61 (s, 1H, NH), 11.03 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.67, 46.20, 51.58, 117.80, 121.20, 121.54, 128.29, 128.62, 130.33, 131.64, 135.59, 139.90, 140.29, 155.22, 168.09, 171.01, 172.84; Anal. calcd. for C21H20N4O4: C, 64.28; H, 5.14; N, 14.28. Found: C, 64.36; H, 4.96; N, 14.17.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][C:49]=1[NH2:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:50][C:49]4[CH:51]=[C:52]([CH3:55])[CH:53]=[CH:54][C:48]=4[CH3:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: Cc1ccc(C)c(N)c1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)Nc2cc(C)ccc2C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 2,5-dimethylaniline (Aldrich) to give the title product. LC-MS (ES+) 768 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[O:7][CH:6]([CH2:11][C:12]1[NH:13][CH:14]=[CH:15][N:16]=1)[C:5]2=[O:17].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH:6]([CH2:11][C:12]3[NH:16][CH:15]=[CH:14][N:13]=3)[CH:5]([OH:17])[C:4]=2[CH:3]=1
Reactant: O=C1c2cc(Cl)ccc2OC1Cc1ncc[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1c2cc(Cl)ccc2OC1Cc1ncc[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dissolve 5-chloro-2-(1'-imidazolylmethyl)coumaran-3-one (10 gms., 21 mmols.) in methanol (100 ml.), cool the solution to 0°-5° C. and add sodium borohydride (1.0 gms., 26.4 mmols.). Stir the reaction mixture overnight at room temperature and evaporate the methanol in vacuo. Add water (200 ml.) to the resultant residue and stir for 30 minutes. Filter and wash the resultant residue with water to give 5-chloro-2,3-dihydro-3-hydroxy-2-(1'-imidazolylmethyl)benzo(b)furan.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[CH2:14]([O:16][P:17]([O:21]CC)[O:18][CH2:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][P:17]([CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: ClCc1cnc(-c2ccccc2)o1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cnc(-c2ccccc2)o1)OCC
Yield: 59.8 %

Procedure:
5-Chloromethyl-2-phenyl oxazole (870 mgs, 4.50 mmol) and triethylphosphite (1.17 ml, 6.75 mmol) were heated at reflux for 3 h, cooled, the excess triethylphosphite removed under reduced pressure and the residue column chromatographed (0 to 5% MeOH/CH2Cl2, 10 g silica) to give the title compound (794 mgs, 2.69 mmol, 60%); δH (CDCl3) 1.30(6H,t,J 7 Hz,OCH2CH3), 3.30(2H,d,JP-H 22 Hz,CH2 -P) 4.10(4H,m,OCH2CH3), 7.00(1H,d,JP-H 3 Hz,CH-4), 7.40(3H,m,Ph), 8.00(2H,m,Ph).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:24])=O>CN(C=O)C.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:24])=[O:17])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)ccc1CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(OCc2ccccc2)ccc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Using a similar procedure to that described in the portion of Example 17 that is concerned with the preparation of starting materials, 2-(4-benzyloxy-2-methoxyphenyl)acetic acid (0.1 g) was reacted with oxalyl chloride (0.093 ml) and DMF (3 drops) in methylene chloride (5 ml). The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated to give 2-(4-benzyloxy-2-methoxyphenyl)acetyl chloride. A mixture of the material so obtained, 3-amino-4,5-dimethylisoxazole (0.062 g), diisopropylethylamine (0.065 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (5 ml) was stirred at ambient temperature for 14 hours. The resultant mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and ethyl acetate as eluent. There was thus obtained N-(4,5-dimethylisoxazol-3-yl)-2-(4-benzyloxy-2-methoxyphenyl)acetamide; 1H NMR: (DMSOd6) 1.77 (s, 3H), 2.28 (s, 3H), 3.55 (s, 2H), 3.74 (s, 3H), 5.09 (s, 2H), 6.54 (m, 1H), 6.63 (d, 1H), 7.09 (d, 1H), 7.33 (m, 1H), 7.39 (m, 2H), 7.45 (m, 2H), 10.15 (br s, 1H); Mass Spectrum: M+H+ 367.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][NH2:10])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:29]=1[O:30][CH2:31][C:32](Cl)=[O:33]>O1CCCC1>[Cl:2][C:3]1[CH:8]=[C:7]([NH:9][NH:10][C:32]([CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:37]([Cl:39])=[CH:38][C:28]=2[Cl:27])=[O:33])[CH:6]=[CH:5][C:4]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1
Reactant: CC1(C)CON(Cc2ccc(NN)cc2Cl)C1=O
Reactant: O=C(Cl)COc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CON(Cc2ccc(NNC(=O)COc3ccc(Cl)cc3Cl)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 2-[(2-chloro-4-hydrazinophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone hydrochloride (1.5 g, 0.0049 mole) and triethylamine (1.4 ml) in tetrahydrofuran (100 ml) was cooled to 10° C. and 2,4-dichlorophenoxyacetyl chloride (0.80 g, 0.0067 mole) was added in one portion. The reaction mixture was stirred overnight at ambient temperature. Triethylamine hydrochloride was removed by filtration, and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel, eluting with 60:40 ethyl acetate:heptane. Appropriate fractions were combined and concentrated under reduced pressure. The residual solid was recrystallized from ethyl acetate:heptane to yield 2-[[2-chloro-4-[(2,4-dichlorophenoxy)methylcarbonylhydrazo]phenyl]methyl]-4,4-dimethyl-3-isoxaolidinone as a yellow solid; m.p. 149°-150° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:37]([OH:39])=[O:38])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27]CC4C=CC=CC=4)=[C:22]([CH2:35][CH3:36])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@@H:18]([C:37]([OH:39])=[O:38])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH2:35][CH3:36])[CH:21]=3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]=2[NH:3]1
Reactant: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O

Procedure:
810 mg (1.38 mmol) (R)-2-(4-benzyloxy-3-ethyl-5-methyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 25 mL MeOH were combined with 80 mg of 10% Pd/C and hydrogenated at RT and 3 bar hydrogen until the reaction came to an end. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i.vac. The residue was triturated with DIPE, suction filtered and dried.