Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:11]([NH:18][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc(CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-methoxybenzaldehyde (5 g, 35 mmol) and benzylamine (3.8 g, 35 mmol) were added to sodium triacetoxyborohydride (10.4 g, 49 mmol) in dichloroethane (125 mL). The reaction was stirred at ambient temperature 2 hours, then concentrated. The mixture was diluted with dichloromethane (200 mL), washed with saturated aqueous sodium hydrogen carbonate (200 mL), brine (200 mL) and dried over magnesium sulfate. The crude amine was concentrated and purified by silica gel chromatography (70% ethyl acetate in hexanes) To afford N-benzyl-1-(4-methoxyphenyl)methanamine as an oil. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.59 (s, 2H), 3.64 (s, 2H), 3.71 (s, 3H), 6.86 (d, J=8.8 Hz, 2H), 7.28 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1)[CH2:17][CH3:18].O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:16]([C@H:19]1[CH2:24][CH2:23][C@H:22]([C:25]([O:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)=[CH:10][CH:11]=2)=[O:26])[CH2:21][CH2:20]1)[CH2:17][CH3:18]
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: Oc1ccc(-c2ccc(F)c(F)c2)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC[C@H]1CC[C@H](C(=O)Oc2ccc(-c3ccc(F)c(F)c3)cc2)CC1
Temperature: 60 °C

Procedure:
3,4-Difluoro-4'-hydroxybiphenyl (2.0 g, 10 mmols) was dissolved in dried pyridine (5 cc), followed by adding to the solution, a solution obtained by dissolving trans-4-propylcyclohexanecarboxylic acid chloride (2 g, 11 mmols) in dry toluene (10 cc), heating the mixture at 60° C. for 3 hours with stirring, then adding the resulting material to water (100 cc), then washing the separated toluene layer with 6N hydrochloric acid, 2N aqueous solution of NaOH and further with water, distilling off toluene from the toluene layer, and recrystallizing the residual crystals from ethyl acetate (10 cc) to obtain the objective 3,4-difluoro-4'-biphenylyl trans-4-propylcyclohexanecarboxylate (2.5 g, 70%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[OH:10][CH2:11][C@@H:12]([NH:19][C:20](=[O:36])[C:21]1[CH:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][CH:22]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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].CCOC(C)=O>[NH2:9][C:3]1[C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([NH:19][C@@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][OH:10])=[O:36])=[CH:22][CH:23]=2)=[N:7][C:6]([Br:8])=[CH:5][N:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: CC1(C)OB(c2ccc(C(=O)N[C@H](CO)c3ccccc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Nc1ncc(Br)nc1-c1ccc(C(=O)N[C@H](CO)c2ccccc2)cc1
Temperature: 120 °C
Yield: 118.5 %

Procedure:
To a solution of 3,5-dibromopyrazin-2-amine (826 mg, 3.27 mmol), (S)—N-(2-hydroxy-1-phenylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (600 mg, 1.634 mmol), and PdCl2(dppf).CH2Cl2 adduct (133 mg, 0.163 mmol) in DME (12.3 mL) was added 2 M Na2CO3 (4.08 mL). The reaction mixture was heated at microwave synthesizer (120° C., 10 min). The reaction mixture was worked uup with EtOAc. The organic layer was washed with sat NaHCO3, water and brine, dried over Na2SO4, filtered off, concentrated in vacuo. The crude product was purified with silica flash chromatography eluting with 0-100% of EtOAc (containing 10% of MeOH) in heptane, and triturated with ether to provide 800 mg of (S)-4-(3-amino-6-bromopyrazin-2-yl)-N-(2-hydroxy-1-phenylethyl)benzamide. LCMS (m/z): 415 (MH+), 0.73 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][N:11]2[S:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)=[O:4].[OH-].[K+].O>C(O)C>[CH3:24][C:19]1[CH:18]=[C:17]([S:14]([N:11]2[C:12]3[C:8](=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:13]=3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH:22]=[C:21]([CH3:23])[CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(C)cc(C)c1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(S(=O)(=O)N2CCc3ccc(C(=O)O)cc32)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
1-(3,5-Dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester (0.40 g, 1.17 mmol) was suspended in ethanol (2.00 mL) and treated with 3N KOH in water (1.17 mL, 3.51 mmol). The mixture was warmed at 50° C. and stirred for 1 hour, then warmed at 70° C. and stirred for 20 min. After cooling to room temperature, the volatiles were evaporated. The residue was dissolved in water (1.00 mL) and the pH set to 1 with 2N HCl. The precipitate was filtered, washing with water, then dried under high vacuum. 1-(3,5-Dimethyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid was obtained as an off-white solid, 0.38 g (98%), MS (ISP): m/e=330.3 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[O:25][N:24]=[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[CH2:16][CH2:15]1)[C:6]([C:32]([O:34][CH3:35])=[O:33])=[C:5]2[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1>[O:12]=[C:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[C:5]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:6]([C:32]([O:34][CH3:35])=[O:33])[N:7]1[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 34.4 %

Procedure:
The compound prepared in Example 96 (0.050 g) was suspended in dry tetrahydrofuran (10 mL) and cooled to −78° C. n-Butyl lithium (2.5 mol/L solution in hexane, 0.03 mL) was added dropwise and the reaction was allowed to stirred at −78° C. for 5 minutes. A saturated aqueous ammonium chloride solution was added and the reaction mixture was warmed to room temperature. The mixture was partitioned between a saturated aqueous ammonium chloride solution and ethyl acetate. The organics were washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel to obtain the title compound (0.015 g) having the following physical data.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.S(Cl)(Cl)=O.[CH2:13](O)[CH3:14]>>[CH:1]1([C:6]([O:8][CH2:13][CH3:14])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CCO
Reactant: O=C(O)C1CC=CC1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C1CC=CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a stirred solution of cyclopent-3-enecarboxylic acid (10 g, 89.3 mmol) in anhydrous ethanol (30 mL) was added sulfurous dichloride (15.9 g, 134 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was poured into water. The resulting mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (2.5% ethyl acetate in petroleum ether) to give the desired product (6.7 g, 47.9 mmol, yield=54%) as a yellow oil which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 5.66 (s, 2H), 4.18-4.10 (m, 2H), 3.16-3.05 (m, 2.66 (s, 2H), 2.63 (s, 2H), 1.29-1.24 (t, J=9.4, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:23][C:20]([F:21])([F:22])[C:19]1[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96 %

Procedure:
To a clear solution of 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester in anhydrous dichloromethane (15 mL) was added TFA (8 mL) dropwise. The yellow solution was stirred at room temperature for 2.5 hour. Reaction was complete as determined by TLC. TFA was removed under reduced pressure. The residue was redissolved in dichloromethane (50 mL), and washed with sat. K2CO3 solution first, then washed with brine and dried over Na2SO4, filtered and concentrated down to give 1-(3-trifluoromethyl-pyridin-2-yl)-piperazine as a light yellow oil (1.19 g, 96.0% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][CH2:7][CH:6]([N:15]([CH3:17])[CH3:16])[CH2:5]2>C(O)C.[Pd]>[CH3:16][N:15]([CH3:17])[CH:6]1[CH2:5][C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=[CH:2][CH:3]=2)[NH:8][CH2:7]1
Reactant: CN(C)C1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C1CNc2c(N)cccc2C1
Reaction time: 18 h
Yield: 100.4 %

Procedure:
A mixture of 6-bromo-1,2,3,4-tetrahydro-8-nitro-N,N-dimethyl-3-quinolinamine (1.15 g, 3.8 mmol) and 10% palladium charcoal (0.5 g) in ethanol (150 mL) was hydrogenated for 18 hours. The solution was filtered and the ethanol evaporated to give 0.73 g of 1,2,3,4-tetrahydro-N3, N3 -dimethyl-3,8-quinolinediamine as an oil.
Reaction SMILES: C(S([NH:7][C:8]1([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][O:10][CH2:9]1)=O)(C)(C)C.Cl.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>CO.O1CCOCC1>[CH2:26]([O:25][C:23]([NH:7][C:8]1([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][O:10][CH2:11]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(C)C1(NS(=O)C(C)(C)C)COC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)C(C)C1(NC(=O)OCc2ccccc2)COC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}propanoate (Preparation 34, 40 g, 140 mmol) in methanol (400 mL) at 0° C. was added a 4M solution of hydrogen chloride in 1,4-dioxane (72 mL). After 2 hours, a 4M aqueous solution of sodium hydroxide (400 mL) was added drop-wise until pH 7 was achieved whilst maintaining the temperature at 0° C. The methanol was removed in vacuo. The resulting solution was stirred with tetrahydrofuran (150 mL) and a 1M aqueous solution of sodium hydrogen carbonate (180 mL) at 0° C. Benzyl chloroformate (33.7 g, 187 mmol) was added and the reaction mixture stirred at room temperature for 18 hours. The organics were removed in vacuo and the resulting solution extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](B(O)O)=[CH:11][C:10]=2[CH:17]=1)[CH3:2].[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[C:27]([N+:33]([O-:35])=[O:34])=[N:28][C:29](Br)=[CH:30][CH:31]=1)[CH3:25])([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[C:27]([N+:33]([O-:35])=[O:34])=[N:28][C:29]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:17][C:10]=3[CH:11]=2)=[CH:30][CH:31]=1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Br)nc1[N+](=O)[O-]
Reactant: CCOCOc1ccc2oc(B(O)O)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCOc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])n3)cc2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a degassed solution of 5-ethoxymethoxy-benzofuran boronic acid (4) (140 mg, 0.593 mmol) in ethanol (10 mL), (6-bromo-2-nitro-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester (7) (151 mg, 0.455 mmol), Pd(PPh3)2Cl2 (42 mg, 0.059 mmol) and Et3N (127 μL, 0.909 mmol) were added. The reaction mixture was stirred at 100° C. for 30 minutes in a microwave reactor. Volatiles were removed under reduced pressure. The residue was diluted with water (15 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 20% ethyl acetate in hexane. Evaporation of solvent gave title compound 8 (170 mg) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[SH:12][CH2:13][C:14]([OH:16])=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:16])[CH2:13][S:12][C:10]2=[S:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CS
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Product: O=C1CSC(=S)N1c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 6.12 g. (0.03 m.) of 3,4-dichlorophenyl isothiocyanate, 2.8 ml. (3.68 g., 0.04 m.) of mercaptoacetic acid and a few drops of triethylamine is heated in a pressure bottle at 110°-130°C. for 2 hours. The cooled reaction mixture is filtered to give 3-(3',4'-dichlorophenyl)-rhodanine, m.p. 176°-178°C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][CH2:24][S:25][CH3:26])[C:20](=[O:27])[C@H:19]([NH:28]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:28][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][CH2:24][S:25][CH3:26])[C:20]1=[O:27]
Reactant: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate (77 mg, 0.186 mmol) in dichloromethane (10 mL). After 30 min, the solution was concentrated and azeotroped with toluene (2×). Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 315.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[NH2:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[N:9]=1)=[O:6].C[O:21][C:22](=[O:35])[CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH:32]=O)=[C:27]([CH3:34])[CH:26]=1>>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]([C:4]2[CH:16]=[CH:17][C:18]3[N:19]=[C:32]([C:28]4[C:27]([CH3:34])=[CH:26][C:25]([CH2:24][CH2:23][C:22]([OH:35])=[O:21])=[CH:30][C:29]=4[CH3:31])[NH:1][C:2]=3[CH:3]=2)=[O:6])=[N:9][C:10]=1[CH3:15]
Reactant: COC(=O)CCc1cc(C)c(C=O)c(C)c1
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)nc1C
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(CCC(=O)O)cc4C)[nH]c3c2)nc1C

Procedure:
The title compound was prepared from 3,4-diamino-N-(5,6-dimethylpyridin-2-yl)-benzamide and 3-(4-formyl-3,5-dimethylphenyl)-propionic acid methyl ester (from Example 6-17) analogous to the final two steps of Example 6-17. 1H-NMR (DMSO-d6, 400 MHz): δ 10.58 (s, 0.5H), 10.53 (s, 0.5H), 8.41 (s, 0.5H), 8.23 (s, 0.5H), 7.92 (m, 2.5H), 7.72 (d, J=8.6 Hz, 0.5H), 7.56 (m, 2H), 7.08 (s, 2H), 2.84 (t, J=7.4 Hz, 2H), 2.58 (t, J=7.4 Hz, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.09 (s, 6H). MS (m/z) 392.3 (M−1); Retention time=1.09 min (Method 10).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:45]([C:48](=[O:53])NCCC)=[CH:44][CH:43]=1)=O)C2>>[C:48]([N:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)(=[O:53])[CH2:45][CH2:44][CH3:43]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc(C2CCNCC2)cc1)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: CCCC(=O)N1CCC(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 278, substituting butyryl chloride for acetyl chloride and N-[4-(piperidin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 7.46-7.49 (m, 2H), 7.34-7.39 (m, 2H), 7.28-7.33 (m, 2H), 7.11-7.14 (m, 2H), 4.75-4.76 (bs, 4H), 4.52-4.57 (m, 1H), 3.94-4.00 (m, 1H), 3.03-3.11 (m, 1H), 2.64-2.75 (m, 1H), 2.51-2.63 (m, 1H), 2.31 (t, J=7.4 Hz, 2H), 1.73-1.81 (m, 2H), 1.47-1.59 (m, 3H), 1.32-1.47 (m, 1H), 0.85-0.95 (m, 3H); MS (ESI(+)) m/e 392 (M+H)+.
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:10]([OH:20])/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=O)(C)(C)C.O1CCNC1=O.CS(Cl)(=O)=O>>[CH2:21]([C@H:9]1[C@H:10](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[O:20][C:6](=[O:5])[NH:8]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)CCC/C=C/[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C1NCCO1
Product: COC(=O)CCC/C=C/[C@@H]1OC(=O)N[C@H]1Cc1ccccc1

Procedure:
The configuration inversion at C-7 of the methyl (5E,7R,8S)-8-[(tert-butoxycarbonyl)amino]-7-hydroxy-9-phenyl-non-5-enoate (4) is obtained in three steps. Initially the amino alcohol (4) is converted to oxazolidinone by treating with methanesulfonyl chloride (Benedetti, F.; Norbedo, S. Tetrahedron Lett. 2000, 39, 10071); thus methyl (5E)-6-[(4S,5S)-4-benzyl-2-oxo-1,3-oxazolidin-5-yl]hex-5-enoate (14) is obtained. The oxazolidinone is reprotected at the nitrogen with di-tert-butyl dicarbonate to give (4S,5S)-tert-butyl 5-[(E)-5-(methoxycarbonyl)pent-1-enyl]-4-benzyl-2-oxooxazolidin-3-carboxylate (15) which is then hydrolysed under controlled conditions (two equivalents of K2CO3, or Cs2CO3) in aqueous methanol. The methyl (5E,7S,8S)-8-[(tert-butoxycarbonyl)amino]-7-hydroxy-9-phenyl-non-5-enoate (16) with (S) configuration at the C7 thus obtained is then converted, by applying the aforedescribed method for the synthesis of benzyl 3-((2R,3R)-3-{[(1S,2S)-1-hydroxy-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}oxiran-2-yl)propylcarbamate (9), to benzyl 3-((2S,3S)-3-{[(1R,2S)-1-hydoxy-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}oxiran-2-yl)propylcarbamate (17). By deprotecting this epoxyamine by catalytic hydrogenation, tert-butyl (1S,2R,3R)-1-benzyl-2,3-dihydroxy-3-[(2R)-pyrrolidin-2-yl]propylcarbamate (18) is thus obtained which is converted into the corresponding [(1S,2R,3R)-3-amino-4-phenyl-1-[(2R)-pyrrolidin-2-yl]butan-1,2-diol] (13) by treating with TFA. Opening the epoxide ring of benzyl 3-((2S,3S)-3-{[(1R,2S)-1-hydoxy-2-[(tert-butoxycarbonyl)amino]-3-phenylpropyl}oxiran-2-yl)propylcarbamate (17) with lithium bromide and Amberlist 15 (Bonini, C. et al. Synth. Commun. 1992, 22, 1863; Bonini, C., Righi, G. Synthesis 1994, 225) gives the bromoalcohol benzyl (4R,5R,6R,7S)-4-bromo-7-[(tert-butoxycarbonyl)amino]-5,6-dihydroxy-8-phenyl-octylcarbamate (19) which, by catalytic hydrogenation, cyclizes to give tert-butyl (1S,2R,3R)-1-benzyl-2,3-dihydroxy-3-[(2S)-pyrrolidin-2-yl]propylcarbamate (20); finally, deprotecting the primary amino group with TFA gives [(1S,2R,3R)-3-amino-4-phenyl-1-[(2S)-pyrrolidin-2-yl]butan-1,2-diol] (12).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8]1)(=O)=O.[I-:21].[Na+]>CC(C)=O>[I:21][CH2:6][C@H:7]1[O:12][CH2:11][C@@H:10]([CH3:13])[N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8]1
Reactant: [I-]
Reactant: C[C@@H]1CO[C@H](COS(C)(=O)=O)CN1Cc1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@@H]1CO[C@H](CI)CN1Cc1ccccc1
Yield: 66.7 %

Procedure:
To a solution of [(2S,5R)-5-methyl-4-(phenylmethyl)-2-morpholinyl]methyl methanesulfonate (8.0 g, 26.7 mmol) in acetone (80 mL) stirred under nitrogen at room temp was added sodium iodide (20.03 g, 134 mmol), and the reaction mixture was stirred at reflux overnight. The reaction was cooled and concentrated under reduced pressure. Then to the residue was added water (50 mL) and CH2Cl2 (60 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (60 mL). The combined organic layers were washed with 1 M Na2S2O3 (2×30 mL), then water (20 mL), dried (Na2SO4), and concentrated to afford the crude product. Purification by silica gel chromatography (300-400 mesh), eluting with Hex/EtOAc (2:1 to 3:2) and monitoring in iodine afforded the title compound (5.9 g) as a yellow oil. LC-MS (ES) m/z=332 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C@@H:5]([O:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:9][CH:8]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4](=[O:24])[C@@H:5]([O:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC

Procedure:
The compound of (2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 1) (1.2 gr, 3.5 mmol) was solved in dichloromethane (5 ml) and trifluoroacetic acid was added (5 ml). The mixture was stirred for an hour, and the crude was concentrated to afford a yellow oil. 1H-NMR (CDCl3, 200.15 MHz): 7.16 (d, 2H, J=8.3), 6.75 (d, 2H, J=8.3), 4.89 (s, 2H), 4.14 (c, 2H, J=6.9), 3.94 (t, 1H, J=6.9), 3.57 (dc, 1H), 3.35 (dc, 1H), 2.92 (d, 2H, J=6.9), 1.23-1.10 (2t, 6H).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:15]C1C=CC(CBr)=CC=1.COP(OC)OC>>[CH3:15][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COP(=O)(Cc1ccc(F)cc1)OC
Reactant: Cc1ccc(CBr)cc1
Agent: COP(OC)OC
Product: COP(=O)(Cc1ccc(C)cc1)OC

Procedure:
Following the procedure of Compound 11, 4-methylbenzyl bromide is reacted with trimethylphosphite.