Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[C:15]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[N:13]=[C:12]([NH:14][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:11]=[CH:10][CH:9]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
2.0 g (7.2 mmol) of 6-(diphenylphosphino)-2-aminopyridine from example 14.3.1 were dissolved in 40 ml of dichloromethane and admixed with 1.6 ml (1.2 g, 10.8 mmol) of triethylamine and 0.16 g (0.7 mmol) of 4-dimethylaminopyridine (DMAP). After cooling to 0° C. (H2O/ice), 1.2 ml (1.2 g, 8.8 mmol) of pivaloyl chloride were slowly added dropwise and the mixture was kept at this temperature for 3 h. The mixture was allowed to warm to room temperature overnight and the solvent was then removed under reduced pressure. The residue was purified by filtration together with cyclohexane/ethyl acetate (1:1) through a short silica gel column (3×10 cm). The solvent was removed under reduced pressure and the resulting oil crystallized by digesting with petroleum ether (40/60). The solid was filtered off, washed with petroleum ether (40/60) and dried under reduced pressure. 2.25 g (6.2 mmol, 86.1%) of 6-(diphenylphosphino)-2-pivaloylaminopyridine were obtained as a beige-colored solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][C:9](=[O:12])[C:10](=[CH:15][N:16]([CH3:18])[CH3:17])[CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Solvent: O
Product: CCOC(=O)N1CCC(=O)C(=CN(C)C)C1

Procedure:
To a round bottomed flask was loaded 8.56 grams of 4-oxo-piperidine-1-carboxylic acid ethyl ester, 10.3 ml of dimethylformamide dimethylacetal, and the mixture was refluxed at 90° C. for two hours. Then it was poured into 75 ml water and extracted with 2×250 ml dichloromethane. The combined organic layers was washed with 50 ml brine and dried over magnesium sulfate. Filter off the drying agent and concentrate gave 28 grams of 3-Dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid ethyl ester. This material (12.8 grams) was then loaded into a round bottomed flask along with 3.42 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 100 ml 2-methoxyethanol. The mixture was refluxed for 18 hours. Then it was cooled down to 23° C. and concentrated to 5 ml. Then 50 ml ethyl ether was added and the precipitate was filtered and vacuum dried to yielded 1.5 grams of product. MS: 278.1 (M+H). H-NMR (CDCL3): δ 8.60 (s, 1H), 4.98 (s, 2H), 4.78 (s, 2H, CH2), 4.22 (q, 2H, J=4.8 Hz), 3.75 (t, 2H, CH2, J=4 Hz), 3.51 (t, 2H, J=4 Hz), 1.32 (m, 3H, CH3, J=4.8 Hz).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>O1CCCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=1[CH3:18])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCCC(=O)c1cnc2c(C)cccc2c1Cl
Solvent: C1CCOC1
Product: CCCC(=O)c1cnc2c(C)cccc2c1Nc1ccccc1C
Yield: 20.4 %

Procedure:
3-Butyryl-4-chloro-8-methylquinoline (4.95 g, 20 mmol), 2-methylaniline (4.27 ml, 40 mmol) and tetrahydrofuran (20 ml) were heated at reflux for 30 minutes, the solvent evaporated and the residue triturated with ethyl acetate/ethanol. The hydrochloride salt was filtered off, converted to free base and recrystallised from ethyl acetate/petroleum ether then from aqueous methanol, to give 3-butyryl-4-(2-methylphenylamino)-8-methylquinoline (1.3 g), m.p. 110°-112°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH:4]([OH:6])[CH3:5].[H-].[Na+].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH2:12]([O:6][CH:4]([CH3:5])[C:3]([O:2][CH3:1])=[O:7])[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: COC(=O)C(C)O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(±)-Methyl-2-hydroxypropanoate (7.6 g, 74 mmol) was dissolved in tetrahydrofuran (100 mL), cooled to 0° C. and treated with sodium hydride (3.6 g, 60% dispersion, 89 mmol, 1.2 equiv) portionwise over 45 minutes. The mixture was warmed to ambient temperature, stirred for 30 minutes, and then cooled to 0° C. Allyl bromide (8.4 mL, 96 mmol, 1.3 equiv) was added, the mixture was warmed to ambient temperature and stirred for an additional 14 hours. Sodium bicarbonate (10 mL, aqueous saturated) was added slowly and the mixture was stirred for 30 minutes before being poured into water (500 mL). The aqueous layer was extracted with ethyl acetate (2×300 mL) and the combined organic extracts were washed once with brine, dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:15]2)=[CH:9]1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1>ClCCl>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:26]2[CH2:25][CH2:24][CH:23]([C:16]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[N:14]([CH2:13][C:10]4[CH:11]=[CH:12][O:8][CH:9]=4)[CH:15]=3)[CH2:28][CH2:27]2)[CH:33]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1cnc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CN2CCC(c3cn(Cc4ccoc4)c4ncccc34)CC2)c1
Yield: 86.9 %

Procedure:
0.3 ml of triethylamine were added over a solution of 0.4 g (1.42 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine in 5 ml of dichloromethane. A solution of 0.39 g (1.71 mmol) of 3-bromomethyl-benzoic acid methyl ester in 2 ml of dichloromethane was added and the crude mixture was stirred at room temperature for 18 hours. The mixture was diluted with 25 ml of dichloromethane and it was washed with water and brine. The organic phase was dried over magnesium sulphate and after filtration and evaporation, 0.53 g of the crude residue were obtained. The crude mixture was purified by flash chromatography over silica gel affording 0.3 g (49% of yield) of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:20]([C:23]1[CH:28]=[CH:27][C:26](O)=[CH:25][CH:24]=1)([O-:22])=[O:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)\[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: CCCC/C(=C\C=C\C(=O)O)c1cccc(OC)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC/C(=C\C=C\C(=O)Oc1ccc([N+](=O)[O-])cc1)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
As in Example 115, (E,E)-5-(3-methoxyphenyl)-2,4-nonadienoic acid (4.48 g) and 4-nitrophenol (2.97 g) in 25 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide 3.59 g). The mixture was stirred at room temperature for 3 days and after the normal work up, the crude product was crystallized from 2-propanol yield 5.6 g of (E,E)-5-(3-methoxyphenyl)-2,4-nonadienoic acid 4-nitrophenyl ester, mp 81.5°-83° C.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC([Si](C)(C)[O:23][CH2:24][C:25]1[N:26]=[N:27][N:28]([CH3:49])[C:29]=1[CH2:30][O:31][Si:32]([C:45]([CH3:48])([CH3:47])[CH3:46])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(C)C>CCO>[CH3:48][C:45]([Si:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:31][CH2:30][C:29]1[N:28]([CH3:49])[N:27]=[N:26][C:25]=1[CH2:24][OH:23])([CH3:46])[CH3:47]
Reactant: Cn1nnc(CO[Si](C)(C)C(C)(C)C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: Cn1nnc(CO)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 50 °C
Yield: 88.3 %

Procedure:
Pyridinium para-toluenesulfonate (0.99 g, 3.94 mmol) was added to a stirred solution of 4-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-1-methyl-1H-1,2,3-triazole (1.77 g, 3.56 mmol) in EtOH (50 ml) and then heated at 50° C. for 6 h. The reaction mixture was concentrated under reduced pressure, then taken up in EtOAc (100 ml) and washed with H2O (100 ml), 2N NaOH (100 ml) and brine (100 ml). After drying, the solvents were removed under reduced pressure and the mixture was purified by column chromatography on silica using 10-100% Et2O/iso-hexanes as eluent to yield the desired hydroxymethyltriazole (1.20 g, 89%). 1H NMR (360 MHz, CDCl3) δ 7.68-7.60 (41H, m), 7.50-7.34 (6H, m), 4.78 (2H, s), 4.46 (2H, s), 4.02 (3H, s), 1.04 (9H, s). m/z (ES+) 382 (M+H+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[CH2:27][CH2:26]2>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[CH:24]=2)[C:28](=[O:32])[CH2:27]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(Br)CC2=O
Temperature: 85 °C
Reaction time: 3 h

Procedure:
N-bromosuccinimide (12.1 g, 67.9 mmol) and 2,2′-azobisisobutyronitrile (0.1 g, 0.6 mmol) were added to a solution of 5-methoxy-1-indanone (10.0 g, 61.7 mmol) in carbon tetrachloride (104 mL). The reaction mixture was stirred for 3 hours at 85° C. and then allowed to cool to room temperature. The reaction mixture was filtered through Celite, which was then washed with CH2Cl2 (100 mL). The filtrate was washed with brine (50 mL), dried over MgSO4, and concentrated to afford the subtitle compound, which was used without further purification. MS calculated for C10H9BrO2+H: 241, observed: 241.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH:13]1([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:13]1([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH2:2][C:3]3[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=3[C:5]([O:7][CH3:8])=[O:6])=[CH:26][CH:27]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccccc1CBr
Reactant: Oc1ccc(C2CCc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1COc1ccc(C2CCc3ccccc32)cc1
Yield: 94.5 %

Procedure:
A mixture of methyl 2-(bromomethyl)benzoate (10.00 g, 43.7 mmol), 4-(1-indanyl)phenol (11.47 g, 54.5 mmol), and potassium carbonate (13.27 g, 96.0 mmol) in DMF was heated at 60° C. for 4h, then was allowed to stir at room temperature for 3d. The resulting reaction mixture was partitioned between ether and water, then the organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 4% ethyl acetate in hexanes to afford 14.8 g of methyl 2-[4-(1-indanyl)phenoxymethyl]benzoate as a colorless oil.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]([C@@H:18]([NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]3[C:36]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:30]4[C:25]3=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH3:19])=[CH:16][C:15]3[C:10](=[C:11]([Cl:38])[CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:39])=CC=1>FC(F)(F)C(O)=O>[Cl:38][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9](=[O:39])[NH:8][C:17]([C@@H:18]([NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH3:19])=[CH:16]2
Reactant: COc1ccc(Cn2c([C@H](C)NC(=O)OCC3c4ccccc4-c4ccccc43)cc3cccc(Cl)c3c2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2cccc(Cl)c2c(=O)[nH]1
Temperature: 25 °C

Procedure:
(S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-2-(4-methoxybenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (344) (80 g, 142 mmol, 1.0 eq) was dissolved in 2,2,2-trifluoroacetic acid (300 mL) and the resulting mixture was stirred at reflux for 2 h. The mixture was allowed to cool to RT and then concentrated in vacuo. The residue was poured into water and then neutralized with NH3.H2O to adjust the pH value to 6-7 under 0° C. The resulting mixture was stirred at RT for 30 min. The solid was collected by filtration, rinsed with water (2×50 mL) and dried in vacuo to afford (S)-(9H-fluoren-9-yl)methyl 1-(8-chloro-1-oxo-1,2-dihydroisoquinolin-3-yl)ethylcarbamate (345).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[CH2:11][C@@H:12](O)[CH2:13][CH3:14])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)C>[CH2:13]([C@H:12]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)[C:10](=[O:16])[CH2:11]1)[CH3:14]
Reactant: CC[C@H](O)CC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Reaction time: 1.5 h
Yield: 182.6 %

Procedure:
To a suspension containing 200 mg (0.77 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-hydroxypentanoic acid amide produced in Example 2, triphenylphosphine (1,188 mg, 1.53 mmol), and tetrahydrofuran (1 mL), a tetrahydrofuran solution (1 mL) containing 309.8 mg (1.53 mmol) of diisopropyl azodicarboxylate was added dropwise at room temperature for 5 minutes. After stirring at the same temperature for further 1.5 hours, the solvent was removedby distillation under reduced pressure to obtain an oil. When diethyl ether cooled to 0° C. was added to the oil, a solid was precipitated, which was removed by vacuum filtration. The filtrate was concentrated under reduced pressure to obtain a white solid (342.0 mg). The reaction yield of the product was determined by the method described in Example 7 to be 30%.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N+](C1C=C([N+]([O-])=O)C=CC=1C(O)=O)([O-])=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C@H:3]([CH3:4])[CH2:2][CH:1]=[O:5])=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(Cn2ccc3ccccc32)cc1
Reactant: C/C=C/C=O
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@H](CC=O)c1cn(Cc2ccccc2)c2ccccc12
Temperature: -40 °C
Reaction time: 70 h
Yield: 79.3 %

Procedure:
Prepared according to the general procedure from crotonaldehyde (125 μL, 1.50 mmol), 1-benzyl-1H-indole (104 mg, 0.500 mmol), 2,4-dinitrobenzoic acid (21.2 mg, 0.100 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −60° C. for 41 h, at which time an additional 125 μL (1.50 mmol) of crotonaldehyde was added. The reaction was continued for an additional 70 h, at which time an additional 42 μL (0.50 mmol) of crotonaldehyde was added. The reaction was continued at this temperature for an additional 5 h, at which time the temperature was raised to −40° C. for 2 h, then −10° C. for an additional 2 h to provide, after silica gel chromatography (15:85 EtOAc/hexanes), the title compound as a colorless oil (110 mg, 80% yield, 89% ee). IR (film) 3062, 3030, 2965, 2925, 2877, 2820, 2724, 1722, 1613, 1589, 1549, 1496, 1480, 1468, 1452, 1392, 1372, 1356, 1331, 1303, 1251, 1203, 1174, 1017 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.4, 2.4 Hz, 1H, CHO), 7.66 (dt, J=0.6, 7.5 Hz, 1H, ArH), 7.33-7.08 (m, 8H, ArH), 6.92 (s, 1H, NCH), 5.28 (s, 2H, NCH2), 3.70 (dt, J=6.9, 21 Hz, 1H, ArCH), 2.89 (ddd, J=2.4, 6.6, 16.5 Hz, 1H, CH2CO); 2.72 (ddd, J=1.8, 7.8, 15.9 Hz, 1H, CH2CO); 1.44 (d, J=6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 202.7, 137.5, 131.9, 128.8, 127.6, 126.9, 126.8, 124.6, 122.0, 119.6, 119.3, 119.2, 110.0, 51.2, 50.1, 26.1, 21.0; HRMS (CI) exact mass calcd for (C19H19 NO) requires m/z 277.1467, found m/z 277.1464. [α]D=+3.5 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (2:98 isopropanol/hexanes, 1 mL/min); S isomer tr=26.5 min and R isomer tr=29.5 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:47])[NH:14][CH2:15][C:16]([N:18]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH:21]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH2:20][CH:19]2[C:40](=[O:46])[NH:41][CH2:42][CH:43]([CH3:45])[CH3:44])=[O:17])[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+]>CO.O>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH:22]1[N:18]([C:16](=[O:17])[CH2:15][NH:14][C:13](=[O:47])[NH:12][C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[C:4]([OH:5])=[O:3])[CH:19]([C:40](=[O:46])[NH:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:20][CH:21]1[S:30]([C:33]1[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(C(=O)NCC(C)C)CC(S(=O)(=O)c3ccc(C)cc3)C2c2ccccc2F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)C2CC(C(=O)NCC(C)C)N(C(=O)CNC(=O)Nc3cccc(C(=O)O)c3)C2c2ccccc2F)cc1
Yield: 6.3 %

Procedure:
A The process is performed as described in Example 1A, but starting with 3 g of (2RS,4SR,5RS)-1-{2-[3-(3-ethoxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-(4-methylphenyl)sulphonylpyrrolidine and 0.252 g of potassium hydroxide in a mixture of 80 cm3 of methanol and 20 cm3 of distilled water. After treatment, 0.18 g of (2RS,4SR,5RS)-3-(3-{2-[5-(2-fluorophenyl)-2-isobutylcarbamoyl-4-(4-methylphenyl)sulphonyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid is obtained [Rf=0.6; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 0.96 (d, J=6.5 Hz, 6H: C(CH3)2); 1.85 (mt, 1H: CH); from 2.30 to 2.55 and 2.82 (2 mts, 1H each: CH2 at 3); 2.48 (s, 3H: CH3); 3.07 (mt, 2H: NCH2); from 3.60 to 3.80 and 3.88 (mt and d respectively, J=17 Hz), 1H each: COCH2N); 4.00 (mt, 1H: H4); 4.78 (t, J=7 Hz, 1H: H2); 5.71 (very broad s, 1H: H5); from 6.95 to 7.65 (mt, 6H: aromatic H); 7.49 (d, J=7.5 Hz, 2H: H of the aromatic at 4 (H ortho to the CH3)); 7.86 (d, J=7.5 Hz, 2H: H of the aromatic at 4 (H meta to the CH3)); 8.02 (mt, 1H: aromatic H (H2: ortho to the COOH)); 8.22 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6))].
Reaction SMILES: [N:1]([N+]([O-])=O)=[O:2].[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[NH:13][CH2:14][CH2:15][Cl:16])[CH2:7][CH:8]([CH3:10])[CH3:9]>O1CCCC1.C(O)(=O)C>[CH2:6]([N:11]([CH:18]([OH:33])[C@H:19]1[O:25][C@:23]([CH2:26][CH2:27][CH2:28][CH3:29])([OH:24])[C@H:22]([OH:30])[C@@H:21]([OH:31])[C@@H:20]1[OH:32])[C:12](=[O:17])[N:13]([CH2:14][CH2:15][Cl:16])[N:1]=[O:2])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)NCCCl)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC[C@]1(O)O[C@H](C(O)N(CCC(C)C)C(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O
Yield: 60.4 %

Procedure:
Dinitrogen trioxide gas (0.6 g) was introduced into a solution of 3-isopentyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)urea (2.15 g, 5.23 mmol), synthesized in the above-mentioned way, in a mixture of tetrahydrofuran (50 ml) and acetic acid (8 ml) with well stirring at 0° to 5° C. After continuation of stirring for 2 hours, the resulting solution was vacuum-concentrated at 25° C. and purified by column chromatography (packing: Kiesel gel 60; eluent: chloroform/methanol 10:1), giving 1.44 g of 3-isopentyl-3-(n-butyl α-D-glucopyranose-6-yl)-1-(2-chloroethyl)-1-nitrosourea; yield 62.6%, m.p. 66°-68° C., [α]D20 +65.2° (C 1.0, methanol).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C@@H:22]1[CH2:34][OH:35])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19]([C@H:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:23][C@@H:22]1[CH:34]=[O:35])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)[C@@H](CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)[C@@H](C=O)C1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 69 %

Procedure:
To a stirring solution of anhydrous DMSO (1.8 mL, 25.36 mMol) in CH2Cl2 (40 mL) at −78° C. was added oxalyl chloride (2 mL, 23.78 mMol) slowly. After 20 min, a sample of (3R,4S)-tert-butyl 4-(benzyloxycarbonyl)-3-(hydroxymethyl)piperidine-1-carboxylate (5.78 g, 15.85 mMol) dissolved in CH2Cl2 (30 mL) was added to the reaction slowly. Stirring was continued for 1 h. Triethylamine (6.6 mL, 47.55 mMol) was added dropwise. Stirring was then continued with a gradual warm up to 0° C. over 1 h. Partitioned the mixture between water and CH2Cl2. Aqueous layer was re-extracted with CH2Cl2. Combined organic layer was washed with brine and dried (Na2SO4). Filtered, concentrated and chromatographed to get the desired product, (3R,4S)-tert-butyl 4-(benzyloxycarbonyl)-3-formylpiperidine-1-carboxylate as a pale oil (3.8 g, yield=67%).
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH:6]1[CH2:10][O:9][C:8]2([CH:18](Br)[CH2:17][CH2:16][C:15]3[N:14]([S:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]2=3)[O:7]1)([CH3:3])[CH3:2].N1CCOCC1>>[CH:1]([NH:4][CH2:5][CH:6]([OH:7])[CH2:10][O:9][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][N:14]2[S:20]([C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCC(Br)C32OCC(CNC(C)C)O2)cc1
Solvent: C1COCCN1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(OCC(O)CNC(C)C)cccc32)cc1
Yield: 29 %

Procedure:
In a flask equipped with a reflux condenser is placed 4'-isopropylaminomethyl-5-bromo-1-p-toluenesulfonyl-4,5,6,7-tetrahydroindole-4-spiro-2'-[1,3]dioxolane (100 parts) and morpholine. The solution is refluxed for 20 hours. After cooling, the reaction mixture is concentrated in vacuo to leave resin. Chromatographic purification of the resin affords 4-(3-isopropylamino-2-hydroxypropoxy)-1-p-toluenesulfonylindole (24 parts) in 29% yield. This showed the same physical characteristics with an authentic sample.