Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=O)[CH2:9]1)([O:3][C:4](C)(C)C)=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:28]=[C:29]([C:31]1[C:32]([CH3:50])=[CH:33][C:34]([CH3:49])=[C:35]([NH:37][C:38]([C:40]2[N:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]3=[N:42][CH:41]=2)=[O:39])[CH:36]=1)[NH2:30].ClC(OC)=O>CN1C(=O)CCC1.C(O)(C(F)(F)F)=O.O>[N:42]1[CH:41]=[C:40]([C:38]([NH:37][C:35]2[C:34]([CH3:49])=[CH:33][C:32]([CH3:50])=[C:31]([C:29]3[N:28]=[C:12]([CH:10]4[CH2:9][N:8]([C:1]([O:3][CH3:4])=[O:2])[CH2:11]4)[O:14][N:30]=3)[CH:36]=2)=[O:39])[N:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=12
Reactant: Cc1cc(C)c(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Agent: COC(=O)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COC(=O)N1CC(c2nc(-c3cc(NC(=O)c4cnc5ccccn45)c(C)cc3C)no2)C1
Temperature: 125 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of Boc-azetidine-3-carboxylic acid (20 mg, 0.1 mmol) in anhydrous NMP (1 mL) was added CDI (16.3 mg, 0.1 mmol). The reaction was stirred for 10 minutes. Then, N-(5-(N′-hydroxycarbamimidoyl)-2,4-dimethylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (50c) (15 mg, 0.05 mmol) was added and the reaction was stirred for 15 minutes. The reaction was heated in the microwave at 125° C. for 15 minutes. The reaction mixture was added dropwise to water (20 mL) and extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered and concentrated to afford a residue which was dissolved in 0.5 mL of TFA and stirred for 10 minutes. Then TFA was removed under vacuum and the residue was dissolved in DCM (1 mL) followed by addition of TEA (15 mg, 0.15 mmol) and methyl chloroformate (6 mg, 0.06 mmol). The solvent was removed and the residue was purified by HPLC to give methyl 3-(3-(5-(imidazo[1,2-a]pyridine-3-carboxamido)-2,4-dimethylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F79). MS m/z 447.1 (M+1)+.
Reaction SMILES: [In].[NH2:2][C:3]1[N:8]=[C:7]([Cl:9])[C:6]([CH:10]=[O:11])=[C:5]([Cl:12])[N:4]=1.[I-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17]>[Zn].CN(C)C=O>[NH2:2][C:3]1[N:4]=[C:5]([Cl:12])[C:6]([CH:10]([OH:11])[CH2:17][CH:16]=[CH2:15])=[C:7]([Cl:9])[N:8]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: C=CCBr
Agent: [I-]
Agent: [In]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(O)c1c(Cl)nc(N)nc1Cl
Reaction time: 3 h

Procedure:
Indium powder (0.23 g) and zinc powder (1.31 g) were added to a mixture composed of commercially available 2-amino-4,6-dichloropyrimidine-5-carboaldehyde (1.92 g) and N,N-dimethylformamide (20 ml). Thereafter, sodium iodide (0.15 g) and allyl bromide (1.73 ml) were added to the mixture at room temperature. The resulting mixture was stirred for 3 hours. Thereafter, the reaction mixture was filtered through celite, and ethyl acetate was then added to the filtrate. The resulting mixture was successively washed with 1 N hydrochloric acid and a saturated saline in this order. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated. Thereafter, hexane was added to the residue, and a precipitate was then collected by filtration, so as to obtain the above title compound (1.75 g) as a solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[N:11]([CH2:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)[C:10]([SH:21])=[N:9][CH:8]=1)=[O:6].Cl>O>[F:20][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=1)[CH2:12][N:11]1[C:7]([C:5]([OH:6])=[O:4])=[CH:8][N:9]=[C:10]1[SH:21]
Reactant: COC(=O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc(S)n1Cc1cc(F)cc(F)c1
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (2.70 g, 0.674 mole) in water (110 ml) was added to 1-(3,5-difluorobenzyl)-2-mercaptoimidazole-5-carboxylic acid methyl ester prepared as above (6.39 g, 0.0225 mole) and the resulting solution was stirred for 2 hours. The solution was cooled in ice, acidified to pH 2 with 3N hydrochloric acid, and the product was filtered and dried. The product was recrystallized from ethanol-water and dried to give 1-(3,5-difluorobenzyl)-2-mercapto- imidazole-5-carboxylic acid, m.p.: 240°-241° C. (5.66 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH:26]([CH2:28]O)[CH2:25][C:24]3=[O:30])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH2:31]([N:33](CC)[CH2:34][CH3:35])[CH3:32].S(Cl)(C)(=O)=O.O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH:26]([CH2:28][N:33]4[CH2:34][CH2:35][CH2:32][CH2:31]4)[CH2:25][C:24]3=[O:30])=[CH:21][CH:22]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(CO)CC4=O)cc3)CC2)c(C)c1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(CN5CCCC5)CC4=O)cc3)CC2)c(C)c1
Temperature: 25 °C

Procedure:
1-{4-[4-(2,4-Dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-hydroxymethylpyrrolidin-2-one (150 mg) described in Example 338 was dissolved in dichloromethane (2 mL), triethylamine (0.16 mL) and mesyl chloride (0.06 mL) were added, and the mixture was stirred at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was dissolved in N,N-dimethylformamide (3 mL), pyrrolidine (0.15 mL) and potassium carbonate (51 mg) were added, and the mixture was stirred at 60° C.-70° C. for 9 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(pyrrolidin-1-ylmethyl)pyrrolidin-2-one. The obtained 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-4-(pyrrolidin-1-ylmethyl)pyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate (0.1 mL) was added, and the precipitate was collected by filtration to give the title compound (112 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:19]([CH2:20]O)=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:9]=[C:10]([Cl:12])[CH:11]=1>C(Cl)Cl>[Cl:3][CH2:20][C:19]1[C:14]([NH:13][C:8]2[CH:7]=[C:6]([Cl:5])[CH:11]=[C:10]([Cl:12])[CH:9]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: OCc1cccnc1Nc1cc(Cl)cc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccnc1Nc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (15 mL) was added slowly to a solution of 6.0 g of the above alcohol in 100 mL methylene chloride and the reaction stirred at room temperature for 18 hr. The reaction was concenterated, the residue dissolved in 150 mL methylene chloride and washed with 10% NaHCO3 solution. The organic layer was dried (Na2SO4) and concentrated to give 6.3 g of (3-chloromethylpyridin-2-yl) (3,5-dichlorophenyl)amine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]([OH:16])=O)=[O:10].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.O>ClCCl.CN(C)C=O>[C:22]1([CH2:21][O:20][C:19]2[CH:18]=[CH:17][C:13]([C:14]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:16])=[CH:12][C:11]=2[C:9]([O:8][CH3:7])=[O:10])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1OCc1ccccc1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C(=O)N2CCCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.61 ml, 6.99 mmol) was added dropwise to a stirred solution of 3-[(methyloxy)carbonyl]-4-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 49; 400 mg, 1.40 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 h. The solvent was removed, and the residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of pyrrolidine (497 mg, 6.99 mmol) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 2 h. Water (60 ml) was added, and the mixture was extracted with dichloromethane (3×60 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was loaded onto a silica gel column (200 g), and was eluted with dichloromethane/methanol=50:1 to yield the title compound as a colourless oil. 400 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.CCOCC>C(COC)OC.CO>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:34]([C:33]3[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:15]2(=[O:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=S(=O)(NC1CCN(Cc2ccccc2)CC1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CO
Solvent: COCCOC
Product: O=S1(=O)c2ccccc2C(c2ccc(F)cc2)N1C1CCN(Cc2ccccc2)CC1
Reaction time: 0.58 h
Yield: 46 %

Procedure:
A solution of N-(l-benzylpiperidin-4-yl)benzenesulfonamide from Example 1 above, (18.7 g, 56.5 mmol) and 210 ml dimethoxyethane was chilled at 0° C. under N2, followed by a slow addition over 25 minutes of 2.3 equivalent of n-butyl lithium (52 ml, 2.5 N/hexanes, 130 mmol) keeping the temperature below 15° C. After mechanically stirring for 35 minutes longer, 4-fluorobenzaldehyde (7.4 g, 59 mmol) in 50 ml dimethoxyethane was added at 5° C., and the reaction was stirred for 2 hours. Ether (400 ml) was added, and the reaction was washed with water and brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel eluting with CHCl3 to CHCl3 :5% MeOH to afford 11.85 g (46% yield) of the intermediate as a foam.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C[O-].[Na+].[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13]/[C:12]/2=[N:25]\[C:26]#[N:27]>CO>[NH2:27][C:26]1[N:3]([CH3:2])[O:4][C:12]2([C:11]3[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=3)[O:15][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[N:25]=1
Reactant: N#C/N=C1\CC(c2ccccc2)Oc2ccc(O)cc21
Reactant: CNO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1OC2(CC(c3ccccc3)Oc3ccc(O)cc32)N=C1N
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
To a solution of methylhydroxylamine HCl salt (28 mg, 0.326 mmol) in anhydrous MeOH (8 mL) was added NaOMe (25 wt. % in MeOH, 15.83 mg, 0.294 mmol), followed by (E)-N-(6-hydroxy-2-phenylchroman-4-ylidene)cyanamide (86 mg, 0.326 mmol). After stirred 10 minutes, the solvent was removed in vacuum. The residue was dissolved in DCM (15 mL) and filtered, and the solvent was removed in vacuum to give the crude product, which was purified by preparative TLC to give 3′-amino-2′-methyl-2-phenyl-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-6-ol (20 mg, 20%). 1HNMR (CDCl3): 7.30-7.51 (m, 5H), 6.95 (s, 1H), 6.69 (m, 2H), 5.15 (t, 3H), 2.98 (s, 3H), 2.28 (d, 2H), 1.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].Br[C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:21]1[CH:22]=[CH:23][C:24]([N:27]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:25][CH:26]=1
Reactant: Brc1ccc(N(Cc2cccnc2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2cccnc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 74.7 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (1060.0 mg) was reacted with N-(4-bromophenyl)-N-((pyridin-3-yl)methyl)pyrimidin-2-amine (120.0 mg) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(pyridin-3-ylmethyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (147.8 mg). Column chromatography (silica gel, eluent: chloroform→chloroform/ethyl acetate=1/1) and thin layer chromatography (chloroform/ethyl acetate=1/1) were used for purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[NH2:10][C:11]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:10][C:11]1[C:16]([O:17][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1ncccc1O
Reactant: ClCc1ccccc1Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ncccc1OCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
A mixture of 2-chlorobenzyl chloride (47.6 g, 0.296 mol) and 2-amino-3-hydroxypyridine (29.6 g, 0.269 mol) in 40% aqueous sodium hydroxide solution (200 ml) and dichloromethane (200 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. A further 200 ml of water was added and the product extracted into dichloromethane, dried, the solvent evaporated and the residue triturated with petroleum ether to obtain the product (32 g, 46%), m.p. 95°-100° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[OH:20])[C:15](=[O:28])[N:14]2[C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[CH:9][CH:8]=1)(=O)=O.[N+:38]([C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1)([O-:40])=[O:39].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:14]2[C@H:13]([C:10]3[CH:9]=[CH:8][C:7]([C:45]4[CH:44]=[CH:43][CH:42]=[C:41]([N+:38]([O-:40])=[O:39])[CH:46]=4)=[CH:12][CH:11]=3)[C@@H:16]([CH2:17][CH2:18][C@@H:19]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[OH:20])[C:15]2=[O:28])=[CH:34][CH:33]=1
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)N1c1ccc(F)cc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc([N+](=O)[O-])c3)cc2)N1c1ccc(F)cc1
Reaction time: 2 h
Yield: 95.1 %

Procedure:
4-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenyl trifluoromethanesulfonate (50.0 mg, 0.092 mmol) and 3-nitrophenylboronic acid (21.6 mg, 0.129 mmol) were dissolved in 1:1 toluene:ethanol (2 mL). 2.0 M aqueous potassium carbonate (0.092 mL) was added and the solution degassed. Tetrakis(triphenylphosphine)palladium(0) (5.7 mg, 0.005 mmol) was added and the reaction stirred vigorously for 2 h at refluxing temperature under a nitrogen atmosphere. The cooled reaction was diluted into dichloromethane (15 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (2×5 mL). The combined extracts were dried over sodium sulfate, filtered, concentrated and purified by chromatography (12 g silica gel, 5% to 50% ethyl acetate-hexane) to afford (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-nitrobiphenyl-4-yl)azetidin-2-one (45.0 mg, 95% yield) as a clear film; Rf 0.33 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ ?8.42 (m, 1H), 8.21 (ddd, J=8.1, 2.4, 1.2 Hz, 1H), 7.89 (ddd, J=7.9, 1.5, 1.2 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.33-7.22 (m, 4H), 7.04-6.92 (m, 4H), 4.76 (t, J=6.0 Hz, 1H), 4.71 (d, J=2.1 Hz, 1H), 3.14 (m, 1H), 1.91-2.11 (m, 4H) ppm; MS [M−OH] 497.5.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[CH2:20]OS(C)(=O)=O)(=[O:4])=[O:3].[Na+].[I-].[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH2:11]([S:10][CH2:20][C@@H:6]1[CH2:7][C@@H:8]([S:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:9][N:5]1[S:2]([CH3:1])(=[O:3])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc(CS[C@@H]2C[C@@H](COS(C)(=O)=O)N(S(C)(=O)=O)C2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CS[C@@H]2C[C@@H](CSCc3ccccc3)N(S(C)(=O)=O)C2)cc1
Yield: 98.9 %

Procedure:
A slurry of 300 mg (0.73 mmol) (2S,4R)-methanesulfonic acid 1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidin-2-ylmethyl ester and 109 mg (0.73 mmol) of NaI in 3 ml DMF at 0° C. was treated with 0.35 ml (2.93 mmol) benzylmercaptane and 96 mg (2.2 mmol) 55% NaH. The reaction was warmed up during 2 h to room temperature and worked up with aqueous saturated NH4Cl solution/EtOAc (3×). The organic phase was dried over Na2SO4, evaporated and purified by crystallization (Et2O) to give 158 mg (49%) of (2S,4R)-2-benzylsulfanylmethyl-1-methanesulfonyl-4-(4-methoxy-benzylsulfanyl)-pyrrolidine, mp 69–71° C., MS: 438 (MH+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:18]([N:8]1[CH2:9][CH:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH:6]([CH2:4][OH:3])[CH2:7]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CN(Cc2ccccc2)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3SR,4RS) 1-Benzyl-4-(4-fluoro-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (CAS RN: 874990-58-6) (20 g, 0.061 mol) were dissolved in THF (600 mL). At 0° C. LiAlH4 (2.8 g, 0.073 mol) was added portion wise. After stirring at 0° C. for 4 h water (15 mL), then 5N NaOH (15 mL) and additional water (25 mL) was added. After stirring at ambient temperature for 1 h the mixture was extracted with ethyl acetate (3×50 mL), the combined organic phases were dried on sodium sulfate, filtered and evaporated. The crude title product was obtained as a light yellow oil (14.95 g, 86%) and directly used in the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:10]1=[O:26].CI.Cl[CH2:30]CCl>C(Cl)Cl.[Ag]=O>[CH3:30][O:1][CH2:2][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)[C:10]1=[O:26]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(CO)C(=O)OC1)C2=O
Agent: O=[Ag]
Solvent: CI
Solvent: ClCCl
Product: COCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 25 °C

Procedure:
tert-butyl 2-(4-(hydroxymethyl)-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.42 g, 1.15 mmol), silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were taken up in DCM (5 mL) and stirred over night at room temperature under nitrogen. Additional silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were added to the mixture with DCE (8 mL) and the resulting mixture was heated at 54° C. overnight. The reaction mixture was filtered through CELITE® to remove silver oxide, concentrated, and purified by silica gel column chromatography (40 g RediSep Gold column) using (20-80) % EtOAc/DCM as mobile phase to afford the title compound.
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:32])[CH2:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH:28]=[CH:29][C:25]=3[CH:24]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:33]([O:35][CH2:36][C:37](O)=[O:38])[CH3:34].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:33]([O:35][CH2:36][C:37]([O:11][CH2:10][C@H:8]1[O:9][C@@H:1]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=2[C:20](=[O:32])[CH2:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH:28]=[CH:29][C:25]=3[CH:24]=2)[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@@H:6]1[OH:7])=[O:38])[CH3:34]
Reactant: CCOCC(=O)O
Reactant: O=C(CCc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOCC(=O)OC[C@H]1O[C@@H](Oc2cccc(O)c2C(=O)CCc2ccc3occc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 35.5 %

Procedure:
To a solution of 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (889 mg) and ethoxyacetic acid (250 mg) in pyridine (25 ml) is added N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (1527 mg) under ice-cooling, and the mixture is stirred at room temperature for 19 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and chloroform, and the mixture is stirred. The organic layer is collected, washed with water, dried, and evaporated to remove the solvent. The residue is dissolved in a mixture of methanol (10 ml) and tetrahydrofuran (10 ml), and thereto is added triethylamine (202 mg). The mixture is stirred at 50° C. for 40 minutes, and evaporated to remove the solvent. The residue is dissolved in ethyl acetate, and the mixture is washed with water, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform/methanol) to give 2'-(6-O-ethoxyacetyl-β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)propiophenone (377 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][N:14](C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.O.[NH2:20]N>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][NH:14][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CCN(C)C)cc1OC
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNCC2)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 1-(3,4-dimethoxy-phenyl)-3-dimethylamino-propan-1-one.HCl, (1.4 g, 5 mmol) EtOH, (20 mL) and hydrazine monohydrate, (0.3 mL, 6 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained 1030 mg, 5 mmol, 100% yield. LC-MS (ESI) m/e 207 (M+H). Step 3