Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6](=O)[C:7]([OH:9])=[O:8].[NH2:12][C@H:13]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH3:14].C([BH3-])#N.[Na+]>>[C:7]([CH:6]([NH:12][C@H:13]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])[CH3:14])[CH2:5][CH2:4][CH2:3][CH:2]([CH3:11])[CH3:1])([OH:9])=[O:8]
Reactant: CC(C)CCCC(=O)C(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)CCCC(N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Yield: 64.8 %

Procedure:
6-Methyl-2-oxoheptanoic acid (0.90 g) and L-alanyl-L-proline (0.21 g) were treated with sodium cyanoborohydride (0.21 g) as described above. A white fluffy solid, N-(1-carboxy-5-methylhexyl)-L-alanyl-L-proline (0.24 g) was obtained. After purification by chromatography the mass spectrum showed a peak at 472 (disilyl derivative). The nmr spectrum showed absorption centered at 4.5, 3.65, 2.0, 1.6, 1.3, and 0.85 ppm.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1.CN(C)C=O.[H-].[Na+]>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1oc(-n2ccnc2)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a mixed solution of methyl 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionate (3.0 g), imidazole (0.82 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.5 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into iced water, and the precipitated crystals were collected by filtration to give methyl 3-[4-(4-chlorophenyl)-2-(1H-imidazol-1-yl)-5-oxazolyl]propionate (1.6 g, yield 80%) as crystals. Recrystallization from methanol gave colorless prism crystals. melting point: 95–96° C.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11]([OH:16])=[CH:10][C:9]=2[O:8]1.[K].C(S([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][N:24]=1)(=O)=O)C>CS(C)=O.C1COCC1>[CH2:32]([S:29]([C:26]1[CH:27]=[CH:28][C:23]([O:16][C:11]2[CH:12]=[CH:13][C:14]3[O:15][CH2:7][O:8][C:9]=3[CH:10]=2)=[N:24][CH:25]=1)(=[O:30])=[O:31])[CH3:33]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc3c(c2)OCO3)nc1
Temperature: 0 °C
Yield: 80.8 %

Procedure:
Into a reaction flask was weighed 5.6 g of t-BuOK and then 50 ml of THF was added. In 50 ml of DMSO was dissolved 6.2 g of 3,4-methylenedioxyphenol which was then slowly added to the t-BuOK solution with stirring. To the resulting potassium phenate solution was added 10.5 g of 2,5-bis(ethylsulfonyl)pyridine and this mixture heated at 50°-55° C. for 3 hrs. After cooling, the reaction mixture was poured into 400 g of ice, stirred and then filtered. The solid which was recovered was dissolved in CH2Cl2, treated with charcoal, dried over MgSO4 and then filtered. The CH2Cl2 solution was concentrated to 50 ml, diluted with an equal volume of hexane and then chilled and a crystalline material recovered, which provided 9.9 g, (80% yield), of 5-(ethylsulfonyl)-2-(3,4-methylenedioxyphenoxy)pyridine, m.p. 97°-99° C.
Reaction SMILES: [C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21]CC(=O)[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2].F[C:24]([F:35])([F:34])[CH2:25]N(OS(=O)(=O)O)CC>C(Cl)(Cl)Cl>[C:1]([C@H:5]1[O:9][C:8](=[O:10])[C@@:7]([C@@H:17]2[CH2:21][CH2:25][C:24]([F:34])([F:35])[CH2:18]2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC(F)(F)F)OS(=O)(=O)O
Reactant: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(=O)C2)O1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)([C@@H]2CCC(F)(F)C2)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2.8 g of (2R,5R)-2-(t-butyl)-5-((1R)-3-oxocyclopentyl)-5-phenyl-1,3-dioxolan-4-one in 30 ml of chloroform, 4.89 ml of trifluorodiethylaminosulfuric acid was added under cooling with ice, followed by 20 hours' stirring at room temperature. The reaction liquid was diluted with chloroform, washed successively with water and with saturated brine, and dried over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the resulting residue was purified on silica gel column chromatography (eluent: hexane/ethyl acetate=20/1) to provide 2.4 g of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:10])[C@H:5]([CH3:9])[NH:6][CH2:7][CH3:8])C.[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:7]([N:6]([C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:5]([C:4]([OH:10])=[O:3])[CH3:9])[CH3:8]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCN[C@@H](C)C(=O)OCC
Product: CCCCCCCCCCCC(=O)N(CC)[C@@H](C)C(=O)O

Procedure:
Example 1A was repeated, replacing starting materials with N-ethyl alanine ethyl ester and dodecanoyl chloride and followed by hydrolysis to give N-Ethyl-N-(1-oxododecyl)alanine.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH2:18]([OH:23])[C:19]([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>O>[CH2:18]([O:23][C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)CO
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc([N+](=O)[O-])cc1C#N
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a dimethylformamide solution (364 ml) containing 2-chloro-5-nitrobenzonitrile (91 g) and neopentyl alcohol (52 g) was added sodium hydride (60% contained, 27.8 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give 2-neopentyloxy-5-nitrobenzonitrile (105 g). Subsequently, ammonium chloride (10 g) and iron powder (75 g) were added to a mixed solvent of water (286 ml) and ethanol (753 ml) and the mixture was heated to 65° C. 2-Neopentyloxy-5-nitrobenzonitrile (80.5 g) was added by portions over 20 min and the mixture was stirred at the refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. An aqueous sodium hydroxide solution was added and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization and the crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (70 g). melting point: 55-56° C.
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][NH2:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([S:20][C:21](Cl)=[O:22])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:18]([S:20][C:21](=[O:22])[NH:15][CH2:14][CH2:13][O:12][C:11]1[CH:16]=[CH:17][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1)[CH3:19]
Reactant: CCSC(=O)Cl
Reactant: NCCOc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCSC(=O)NCCOc1ccc(Oc2ccccc2)cc1
Yield: 45.1 %

Procedure:
4 g of 2-[(p-phenoxy)phenoxy]ethylamine and 11.2 g of chlorothioformic acid S-ethyl ester are dissolved in 150 ml of acetone. 14.5 g of potassium carbonate are added to the solution. This mixture is heated under reflux for 6 hours and then filtered. The residue is washed with acetone and the filtrate is evaporated in vacuo. The crystalline residue is suspended in cyclohexane and filtered to yield 2.5 g (53%) of 2-[(p-phenoxy)phenoxy]ethylthiocarbamic acid S-ethyl ester, m.p.--56°-58° C.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[C:10]([N+:17]([O-])=O)=[CH:11][C:12]([CH3:16])=[C:13]([CH:15]=1)[NH2:14].[OH-].[Na+]>C1(O)C2C(=CC=CC=2)C(O)=CC=1.O>[Cl:8][C:9]1[CH:15]=[C:13]([NH2:14])[C:12]([CH3:16])=[CH:11][C:10]=1[NH2:17]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1N
Agent: Oc1ccc(O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(N)c(Cl)cc1N
Yield: 93.9 %

Procedure:
A reaction vessel was charged with 60 g of toluene, 50 g of water, 37.3 g of 5-chloro-2-methyl-p-nitroaniline, 6 g of sodium hydroxide and 0.3 g of 1,4-naphthalenediol, and then the same procedure as in Example 1 was followed, to obtain 29.4 g of 2-chloro-5-methyl-p-phenylenediamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:9][CH:10]=O)=[CH:4][CH:3]=1.[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[CH2:22]([O:21][C:19](=[O:20])/[CH:24]=[CH:10]/[CH:9]=[C:8]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)/C=C/C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
As in Example 99, 3,3-bis(4-chlorophenyl)-2-propenal (11.08) was reacted with (carbethoxymethylene)triphenylphosphorane (14.3 g) in ethanol (30 ml) for 30 minutes at ambient temperature. The mixture of esters obtained from the usual work up was purified by crystallization from ether-hexane to give 8.1 g of (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid ethyl ester, mp 98°-100° C. A portion of the (E)-isomer was crystallized from hexane to yield the pure ester (E)-5,5-bis(4-chlorophenyl)-2,4-pentadienoic acid ethyl ester mp 98.5°-100° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[CH:32]1([CH:35]([C:37]2[CH:42]=[C:41]([F:43])[C:40](B3OC(C)(C)C(C)(C)O3)=[C:39]([F:53])[CH:38]=2)[OH:36])[CH2:34][CH2:33]1>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:40]3[C:39]([F:53])=[CH:38][C:37]([CH:35]([CH:32]4[CH2:34][CH2:33]4)[OH:36])=[CH:42][C:41]=3[F:43])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: CC1(C)OB(c2c(F)cc(C(O)C3CC3)cc2F)OC1(C)C
Product: Cn1ncc(NC(=O)c2csc(-c3c(F)cc(C(O)C4CC4)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with cyclopropyl(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (Intermediate 140) gave 275, which was isolated as a mixture of diastereomers. LCMS (ES+) m/z 522 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C:5](Br)([F:7])[F:6])[CH3:2].[C:10]([NH:17][C@H:18]([CH:23]=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>O1CCCC1.C(OCC)(=O)C.[Zn]>[CH2:1]([O:3][C:4](=[O:9])[C:5]([F:7])([F:6])[C@H:23]([OH:24])[C@H:18]([CH2:19][CH:20]([CH3:21])[CH3:22])[NH:17][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH3:2]
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1.45 g zinc powder are suspended in 30 ml tetrahydrofuran and heated to reflux temperature. 4.4 g ethylbromodifluoroacetate are added at once and as soon as a vigorous reaction is initiated 2 g of N--BOC--L--leucinal dissolved in 5 ml tetrahydrofuran are added dropwise. After 30 minutes the reaction mixture is allowed to cool, then taken up in ethyl acetate and washed with 2N tartaric acid. The organic phase is dried over magnesium sulfate, evaporated to dryness and chromatographed over silicagel using ether/hexane 2:8 as an eluent. N--BOC--(4S,3R)-2,2-difluorostatine ethyl ester is obtained ([α]D20 =-12.2°, c=0.29 in ethanol).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:16]1([CH3:26])[C:17]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1.[Na+].[Cl-]>O.C1(C)C=CC=CC=1>[C:16]1([CH3:26])[C:17]([S:22]([O:13][C@H:10]2[CH2:11][CH2:12][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)(=[O:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O[C@H]1CCN(Cc2ccccc2)C1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)O[C@H]1CCN(Cc2ccccc2)C1

Procedure:
(S)-1-Benzyl-3-pyrrolidinol (44.32 g), 132.88 g of toluene and 166.95 g of a 30% aqueous solution of NaOH were respectively weighed and placed in a 500-mL four-necked flask. While the mixture was stirred, the flask inside temperature was lowered to 6.0° C. Then, 104.94 g of toluenesulfonyl chloride was added in divided portions at an interval of about 5 g/10 minutes over 3 hours and 10 minutes at a flask inside temperature of 5 to 10° C. Water (37 mL) was added to dissolve the NaCl which had precipitated out in the aqueous phase, and the mixture was separated into the toluene phase and aqueous phase. A toluene solution of (S)-1-benzyl-3-pyrrolidinol toluenesulfonate was thus obtained in a yield of 85.5 mole percent.
Reaction SMILES: CN(C)CCNC.C([Li])CCC.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[O:22][CH3:23].[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:24][C:16]1[C:15]([O:22][CH3:23])=[C:14]([F:13])[CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: COc1cc(C=O)ccc1F
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1c(F)ccc(C=O)c1Cl
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
A solution of N,N,N′-trimethylethylenediamine (20.3 mL, 156 mmol) in 75 mL of THF was cooled to −50° C. and a 2.5M solution of n-butyllithium in hexanes (62.5 mL, 156 mmol) was added dropwise with stirring during 15 minutes, keeping the internal temperature below −35° C. The temperature was maintained at 40° C. for 30 minutes, and then the reaction mixture was cooled to −70° C. A solution of 4-fluoro-3-methoxybenzaldehyde (24.09 g, 156.3 mmol) in 75 mL of THF was added dropwise during 15 minutes, keeping the reaction temperature below −50° C. When the addition was complete, the reaction was allowed to warm to −40° C. and held there for 25 minutes. The reaction was then re-cooled to −70° C. and a 2.5M solution of n-butyllithium in hexanes (62.5 mL, 156 mmol) was added dropwise. When the addition was complete, the reaction was allowed to warm to −20° C. and kept at that temperature overnight (12 hours). The reaction mixture was then cooled to −30° C. and the cold solution was added via cannula during 30 minutes to a room temperature solution of hexachloroethane (111 g, 469 mmol) in 200 mL of THF. After stirring at room temperature for 4 hours, the reaction mixture was poured into 500 mL of ice cold 4N HCl. Most of the THF was removed by rotary evaporation under reduced pressure and the residual mixture was extracted twice with 1:1 ethyl ether/hexanes. The organic layers were combined and washed successively with 1N NaOH, 1N HCl, water, and brine. After drying over sodium sulfate, removal of the solvent under vacuum gave a yellow solid. Flash chromatography on silica gel eluting with hexanes/dichloroethane (2:1 to 1:1) gave 2-chloro-4-fluoro-3-methoxybenzaldehyde as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[CH2:26](Br)[CH:27]=[CH2:28].C(OCC)(=O)C>CN(C)C=O>[CH2:28]([O:19][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:20])[CH:27]=[CH2:26]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reaction time: 6.5 h
Yield: 14 %

Procedure:
46 mg of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in N,N-dimethylformamide (0.5 mL), and 21 mg of sodium hydrogen carbonate and 30 μL of allyl bromide were added, followed by stirring for 6.5 hours. Ethyl acetate was added to the reaction solution, followed by sequential washing with water and saturated brine and drying over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to afford 7.5 mg of the title compound as a colorless solid (yield 14%). The resulting solid was recrystallized from ethyl acetate-hexane, the generated precipitate was filtered off, the wet crystal was washed with hexane, and subsequently dried under reduced pressure at room temperature to afford the title compound as a colorless crystalline powder. Enantiomeric excess: 999% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 8.0 minutes).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([C:9]2([C:31]([F:34])([F:33])[F:32])[CH2:13][CH2:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([CH2:18][NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])=[C:16]([C:27]([F:30])([F:29])[F:28])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N+]([O-])([O-])=[O:37].[NH4+].[Ce].COC(C)(C)C>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C:9]2([C:31]([F:34])([F:32])[F:33])[CH2:13][CH2:12][N:11]([C:14]3[CH:26]=[CH:25][C:17]([CH2:18][NH:19][C:20]([CH:22]4[CH2:23][CH2:24]4)=[O:21])=[C:16]([C:27]([F:28])([F:29])[F:30])[CH:15]=3)[CH:10]2[OH:37])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3F)(C(F)(F)F)C2)cc1C(F)(F)F)C1CC1
Agent: [Ce]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(N2CCC(c3cc(Cl)cc(Cl)c3F)(C(F)(F)F)C2O)cc1C(F)(F)F)C1CC1

Procedure:
N-{4-[3-(3,5-dichloro-2-fluorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(trifluoro-methyl)benzyl}cyclopropanecarboxamide (0.18 g) was dissolved in N,N-dimethylformamide (5 ml), cooled by using an ice bath, and then stirred. To the solution, a 1 M aqueous solution of cerium ammonium nitrate (IV) (0.72 ml) was added dropwise and stirred in an ice bath for 2 minutes. After that, t-butyl methyl ether was added for dilution and the organic layer was washed with water, an aqueous solution of sodium thiosulfate and saturated brine in that order. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure, and the residue obtained was purified by column chromatography to obtain N-{4-[3-(3,5-dichloro-2-fluorophenyl)-2-hydroxy-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(trifluoromethyl)benzyl}cyclopropanecarboxamide (0.08 g).
Reaction SMILES: [OH-].[K+].[CH2:3]([SH:5])[CH3:4].[CH3:6][O:7][C:8](=[O:26])[CH:9](Cl)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1.C(OCC)C>CO>[CH3:6][O:7][C:8](=[O:26])[CH:9]([S:5][CH2:3][CH3:4])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: CCS
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CCSC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC
Temperature: 25 °C
Yield: 86.7 %

Procedure:
Potassium hydroxide (0.092 g; 1.64 mmole) was dissolved in methanol. Ethanethiol (0.133 g; 2.14 mmole) and 3-(4-benzyloxyphenyl)-2-chloropropanoic acid methyl ester (0.5 g; 1.64 mmole) were added. The reaction mixture was stirred at room temperature over night. Diethyl ether (15 ml) was added. The mixture was filtered and evaporated. The residue was purified by adding active charcoal in methanol. The mixture was stirred for 15 minutes and the active charcoal was filtered off. Evaporation of the solvent gave 0.47 g (86.7% yield) of 3-(4-benzyloxyphenyl)-2-ethylsulfanyl propanoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1O>>[OH:48][CH2:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCCc1ccccc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCO)cc1

Procedure:
Analogously to Method G, 5.00 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.99 g of 2-(2-hydroxyethyl)phenol are reacted. The title compound is obtained as a colourless oil. Rf=0.08 (1:2 EtOAc-heptane); Rt=5.81.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[C:22]([OH:24])=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([CH3:25])([CH3:26])[C:22]([O:24][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:23])=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(=O)O
Reactant: OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CC(C)(CCCCOc1ccc(OCCCCCn2ccnc2)cc1)C(=O)OCc1ccccc1
Reaction time: 120 h

Procedure:
To a mixture of 0.90 g 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoic acid, 10 ml dichloromethane, 0.24 ml benzyl alcohol and 30 mg dimethylaminopyridine, was added with stirring 0.46 g dicyclohexylcarbodiimide at room temperature, and stirring was continued for five days. The urea which separated out was filtered off, and the filtrate was washed with 0.1N caustic soda solution and then with water. After dehydration, the solvents were distilled off, and the residue was purified by silical gel column chromatography, affording 1.05 g of benzyl 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoate.