Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][C:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:34](O)=[O:35])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].P(Cl)(Cl)(Cl)=O>CN(C)C1C=CN=CC=1.C(#N)C>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][C:34]([C:31]3([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:32][CH2:33][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:29][CH2:30]3)=[O:35])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CN(C)c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2nonc2-c2noc(=O)n2-c2ccc(F)c(Br)c2)(c2ccccc2)CC1
Temperature: 100 °C

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (0.15 g, 0.44 mmol), 1-(tert-butoxycarbonyl)-4-phenylpiperidine-4-carboxylic acid (0.4 g, 1.3 mmol), and 4-dimethylaminopyridine (32 mg, 0.26 mmol) in acetonitrile (2 mL) was treated with phosphoryl chloride (0.13 mL, 1.4 mmol) and heated in the microwave at 100° C. for 10 min. The reaction mixture was concentrated and the residue was diluted with ethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL), dried with sodium sulfate, filtered, and concentrated to a crude residue which was purified by silica gel to give the coupled product, tert-butyl 4-[({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)carbonyl]-4-phenylpiperidine-1-carboxylate. This material was diluted with dichloromethane (5 mL) and treated with 4.0 M HCl in 1,4-dioxane (3 mL) and stirred for 45 min. The reaction mixture was concentrated and the crude residue was purified by preparative LCMS to give the desired product (10 mg, 4%). LCMS for C22H19BrFN6O4 (M+H)+: m/z=529.0, 531.0.
Reaction SMILES: [C-:1]#[N:2].[Na+].FC(F)(F)C(O)=O.Br[CH2:12][C:13]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].O>CS(C)=O>[C:1]([CH2:12][C:13]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1CC#N
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a suspension of sodium cyanide (6.3 g) in DMSO (200 ml) was added trifluoroacetic acid (6.6 ml) under water-cooling, methyl 2-(bromomethyl)-4-nitrobenzoate (J. Med. Chem., 42, 3510-3519 (1999)) (11.8 g) synthesized separately was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (ethyl acetate/hexane=1/10 to 1/3) to give a crude product of the title compound as a pale-yellow powder (2.52 g, 27%). The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:24][C:25](Br)=[O:26].[NH2:28][CH:29]1[CH2:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:24][C:25]([NH:28][CH:29]2[CH2:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30]2)=[O:26])=[CH:21][CH:22]=1
Reactant: O=C(Br)CBr
Reactant: NC1Cc2ccccc2C1
Reactant: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)NCC2
Product: COc1cc2c(cc1OC)C(Cc1ccc(Cl)cc1)N(CC(=O)NC1Cc3ccccc3C1)CC2

Procedure:
prepared by reaction of 1-(4-Chloro-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-amino-indane
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=O.[CH3:11]N1CCOCC1.Cl[C:19]([O:21][CH2:22][CH:23]([CH3:25])C)=[O:20]>ClCCl>[CH3:11][CH:22]([O:21][C:19]([O:9][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2](=[O:1])[CH3:10])=[O:20])[CH2:23][CH3:25]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(=O)CCCCC(=O)O
Reactant: CN1CCOCC1
Solvent: ClCCl
Product: CCC(C)OC(=O)OCCCCCC(C)=O
Reaction time: 1 h

Procedure:
11.2 g (0.07 mole) of 6-ketoheptanoic acid was dissolved in 100 ml of dichloromethane and 10 g of N-methylmorpholine was added. The reaction mixture was cooled in an ice bath, stirred and kept under a nitrogen atmosphere. 11.6 g (0.085 mole) of isobutyl chloroformate dissolved in 25 ml of dichloromethane was slowly added over a period of 15 minutes. The reaction mixture was allowed to proceed for one hour. The reaction mixture was evaporated to an oily solid and used in subsequent reactions.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.ClC[CH:12]([O:15]C(CCl)CCl)CCl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH:12]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)=[O:15]
Reactant: ClCC(CCl)OC(CCl)CCl
Reactant: c1ccc2c(c1)CCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 9.4 ml (83.4 mmole) 2,3-dihydrobenzofuran in 250 ml methylene dichloride was cooled under nitrogen to 0° to -5° C. and 18 ml (167 mmole)titanium tetrachloride was added dropwise at 0° C. The resulting brown mixture was stirred 10 minutes and 8.3 ml (91.6 mmole) 1,1-dichloromethyl methylether was then added dropwise at 0° C. During this addition the reaction mixture became dark red. The mixture was allowed to warm to room temperature, stirred for two hours and poured slowly into a 2 liter beaker containing 700 ml saturated aqueous sodium bicarbonate solution. The resulting mixture was filtered through diatomaceous earth and the solids washed with methylene dichloride. The separated organic layer was dried (Na2SO4) and the solvent evaporated to afford a residual oil, log (81%) of which appeared homogeneous on silica gel TLC, eluting with an ethyl acetate/hexane/5% acetic acid 1:5:5 by volume. Mass spectrum (m/e): 148 (M+), 147, 119.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8][CH2:9][C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[NH:22][CH2:21][CH2:20][CH2:19]2.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:8][CH2:9][C:10]([N:22]2[C:23]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:13])[CH2:19][CH2:20][CH2:21]2)=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CSc1ncccc1Cl
Reactant: Cc1cccc2c1NCCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc2c1N(C(=O)CSc1ncccc1Cl)CCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 33 %

Procedure:
To a solution of (3-chloro-pyridin-2-ylsulfanyl)-acetic acid (19, 0.27 g, 1.3 mmol) in 12 mL of dry THF at 0° C. was added neat 8-methyl-1,2,3,4-tetrahydroquinolin (0.20 g, 1.3 mmol) followed by addition of DMAP (0.19 g, 1.6 mmol) and EDCI (0.31 g, 1.6 mmol). The reaction was stirred for 20 h at room temperature under N2. The reaction mixture was diluted with 50 mL of CH2Cl2, washed with H2O, 10% citric acid, NaHCO3 (saturated), brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography (hexanes/EtOAc) to give 0.15 g (33% yield) of the target 20 as an off-white solid. MS (APCI) m/z: 333.1 (100%, [M+H]+, 186.0 (35%, [M−147+H]+; HPLC purity: 100%; Anal. Calcd. for C17H17ClN2OS: C, 61.34; H, 5.15; N, 8.42; Cl, 10.65; S, 9.63. Found: C, 61.04; H, 5.28; N, 8.36; Cl, 10.78; S, 9.68.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=O.[N:11]([CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[C:12]=[O:13].Cl.[NH2:24][OH:25].C(OC)(OC)OC>C1COCC1.N1C=CC=CC=1>[OH:25][N:24]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:12]([NH:11][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[O:13])=[CH:6][CH:5]=1)[CH3:1]
Reactant: NO
Reactant: CC(=O)c1ccc(N)cc1
Reactant: COC(=O)C(N=C=O)C(=O)OC
Agent: Cl
Solvent: C1CCOC1
Solvent: COC(OC)OC
Solvent: c1ccncc1
Product: COC(=O)C(NC(=O)Nc1ccc(C(C)=NO)cc1)C(=O)OC
Reaction time: 3 h

Procedure:
A solution of 0.02 mol 4-aminoacetophenone in 40 mL THF is added dropwise to a solution of 0.02 mol of dimethyl isocyanatomalonate and 5 mL pyridine in 40 mL THF, and the reaction mixture is stirred for 3 hours. The solvent is then removed by rotary evaporator. The residue is dispersed in 50 mL CH3OH, and 0.022 mol hydroxylamine hydrochloride and 0.06 mol trimethyl orthoformate are added. The reaction mixture is heated to reflux for 10 hours. The solvent is removed by rotary evaporator. Addition of water to the residue results in precipitation of N-[4-(1-hydroxyiminoethyl)phenyl]-N'-bis(methoxycarbonyl)methylurea, which is isolated by filtration and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:43]([C:45]1[CH:54]=[CH:53][C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:46]=1)[CH3:44])(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH:43]([C:45]4[CH:54]=[CH:53][C:52]5[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=5)[N:46]=4)[CH3:44])=[CH:13][CH:14]=3)[C:9]([S:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:8]2[CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=1
Reactant: CC(OS(C)(=O)=O)c1ccc2ccccc2n1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC(C)c3ccc4ccccc4n3)ccc2n1Cc1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-hydroxy-indol-2-yl]-2,2-dimethylpropanoate (EP 419,049, Example 1, Step C) (460 mg) in acetonitrile (5 mL) was added solid cesium carbonate (652 mg). To this mixture was added a solution of mesylate from Step B (326 mg) in acetonitrile (3 mL) and stirred at 70° C. for 1 hr. The reaction mixture was poured into 25% NH4OAc (50 mL), extracted with ethyl acetate (2×50 mL), washed with brine (50 mL), and dried (MgSO4). The solution was evaporated to dryness and the residue was chromatographed on flash silica gel using ethyl acetate:hexane (1:4) as eluant to give the title compound identical to the one obtained from Method 1, Step A.
Reaction SMILES: [C:1]([N:11]1[CH2:14][C:13]([CH3:30])([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@@H:24]([CH2:26][NH2:27])[O:23][C:22]3=[O:28])=[CH:17][C:16]=2[F:29])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[N:31]1C=CC=[CH:33][CH:32]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[F:29][C:16]1[CH:17]=[C:18]([N:21]2[CH2:25][C@H:24]([CH2:26][NH:27][C:37](=[O:39])[CH3:38])[O:23][C:22]2=[O:28])[CH:19]=[CH:20][C:15]=1[C:13]1([CH3:30])[CH2:14][N:11]([C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:12]1.[C:32]([NH2:31])(=[O:2])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: CC1(c2ccc(N3C[C@@H](CN)OC3=O)cc2F)CN(C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3(C)CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Product: CC(N)=O
Temperature: 0 °C

Procedure:
The title compound was prepared as followed: (R)-(-)-N-carbobenzyloxy-3-methyl-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine was diluted with 220 mL dichloromethane, cooled to 0° C., and successively treated with 3.7 mL pyridine (46 mmol) and 1.8 mL acetic anhydride (19 mmol) with no observable change. The cooling bath was removed and the reaction mixture was warmed to room temperature for 16 hours. The visually unchanged solution was concentrated to a yellow foam, rediluted with 50 mL dichloromethane, and filtered to remove the remaining insoluble precipitate. The filtrate was purified by LC on 340 g (230-400) silica gel eluting with 2.5% methanol/ethyl acetate to afford 5.85 g (84%) of (S)-N-[[3-[3-fluoro-4-[1-(carbobenzyloxy)-3-methyl)-3-azetidinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide as a colorless glass. Rf 0.24 (2.5% methanol/ethyl acetate); [α]D -19° (c 0.9971, methanol); IR (mull) 1754, 1706, 1676, 1516, 1430, 1415, 1357, 1227, 1194, 1075 cm-1 ; 1H NMR (300 MHz, CDCl3) δ7.42 (dd, 1H, J=2.1 Hz, J=12.9 Hz, aromatic), 7.33 (m, 5H, aromatic), 7.13 (dd, 1H, J=2.2 Hz, J=8.5 Hz, aromatic), 7.04 (t, 1H, J=8.5 Hz, aromatic), 6.56 (bt, 1H, J=6.2 Hz, NH), 5.10 (s, 2H, Ph--CH2), 4.79 (m, 1H, methine), 4.30 (d, 2H, J=8.2 Hz, Ph--C--CH2a s), 4.01 (m, 3H, Ph--C--CH2b s, Ph--N--CH2a), 3.78 (dd, 1H, J=6.7 Hz, J=9.1 Hz, Ph--N--CH2b), 3.64 (m, 2H, NH--CH2 s), 2.02 (s, 3H, O=C--CH3), 1.60, (s, 3H, Ph--C--CH3); 13C NMR (75 MHz, CDCl3) 171.2, 160.3 (d, JCF =246 Hz), 156.6, 154.2, 137.9 (d, JCF =11 Hz), 136.5, 128.9 (d, JCF =14 Hz), 128.4, 127.9, 127.2 (d, JCF =7 Hz), 113.2 (d, JCF =2 Hz), 106.4 (d, JCF =28 Hz), 72.0, 66.6, 60.7, 60.3, 47.3, 41.7, 36.1, 28.1, 22.9; Anal. Calcd for C24H26N3O5F1 : C, 63.29; H, 5.75; N, 9.23. Found: C, 62.98; H, 5.96; N, 8.98.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[SH:7].C[Si](C)(C)N[Si](C)(C)C.[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18].CN1C=CN=C1S[Si](C)(C)C>C(OCC)(=O)C.S1(C2C(=CC=CC=2)C(=O)N1)(=O)=O.CN(C)P(=O)(N(C)C)N(C)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1
Reactant: Cn1ccnc1S
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cn1ccnc1S[Si](C)(C)C
Agent: O=C1NS(=O)(=O)c2ccccc21
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1ccnc1SCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A mixture consisting of 2.85 g (25 mmoles) of 1-methyl-2-mercaptoimidazole, 22 mg (0.12 mmoles) of saccharin, 20 ml of toluene and 5.2 ml (25 mmoles) of hexamethyldisilazane was refluxed for 1 hour and after cooling to room temperature, 5.40 g (25 mmoles) of 4-nitrobenzyl bromide and then 5 ml of hexamethylphosphoric triamide were added to the mixture which contained 1-methyl-2-(trimethylsilylthio)-imidazole. After stirring for 2 hours at room temperature, the mixture was diluted to 150 ml with ethyl acetate and the solution thus obtained was washed three times with 50 ml of a saturated sodium bicarbonate solution and then twice with 20 ml of water. The organic layer was dried, filtered and evaporated to dryness and the crystalline residue was washed with 100 ml of petroleum ether (boiling range 60°-80° C.) and then vacuum dried to obtain 5.54 g (89% yield) of 1-methyl-2-(4-nitrobenzylthio)-imidazole melting to 74°-77° C. Crystallization of a sample from ethanol raised the melting point to 77.5°-78.0° C.
Reaction SMILES: [CH3:1][C@@H:2]1[NH2+:6][C@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.[CH3:12][O:13][C:14]([NH:16][C@@H:17]([CH:21]([CH3:23])[CH3:22])[C:18](O)=[O:19])=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:12][O:13][C:14]([NH:16][C@@H:17]([CH:21]([CH3:23])[CH3:22])[C:18]([N:6]1[C@@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:19])=[O:15]
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)[NH2+]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Reaction time: 20 h
Yield: 73 %

Procedure:
To a cold (0-4° C.) stirred solution of ethyl (2S,5S)-5-methylpyrrolidin-1-ium-2-carboxylate (7 g, 24.4 mmol) (J. Med. Chem. 2006, 49, 3520-3535), (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (4.5 g, 25.6 mmol), and HATU (9.7 g, 25.6 mmol) in DMF (66 ml) is added DIPEA (12.7 ml, 73.3 mmol). The resultant mixture is slowly warmed up to rt and stirred for 20 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with sodium bicarbonate, brine, dried (Na2SO4) and concentrated. The residue is purified by flash column chromatography on silica gel using ethyl acetate-hexanes (3:7 to 4:6) as eluent to afford ethyl (2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidine-2-carboxylate (5.6 g, 73%) as a white solid.
Reaction SMILES: C(N1CCCC1)C1C=CC=CC=1.[CH2:13]([N:20]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCCCCCCC.CCCCCCCCCC>CCCCCC>[CH2:13]([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: c1ccc(CN2CCCC2)cc1
Solvent: CCCCCC
Solvent: CCCCCCCCCC
Solvent: CCCCCCCC
Product: O[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
It has been found that alkane-degrading microorganisms are excellent biocatalysts for the hydroxylation of N-benzylpyrrolidine to optically active N-benzyl-3-hydroxy-pyrrolidine. Examples are bacteria degrading n-alkane containing 4 or more C-atoms. By screening with a microtiter plate, 25 of a set of 70 strains degrading n-hexane, n-octane, n-decane, or n-dodedane, were found to be able to catalyse this hydroxylation (example 5). The enantioselectivity and relative activity of 14 selected alkane-degrading strains are shown in table 3 (example 6). Hydroxylation of N-benzylpyrrolidine with Pseudomonas putida P1 gave (R)-N-benzyl-3-hydroxypyrrolidine in 62% e.e.; hydroxylation of N-benzylpyrrolidine with the isolate HXN-1100 gave (R)-N-benzyl-3-hydroxypyrrolidine in 70% e.e.; surprisingly, hydroxylation of N-benzylpyrrolidine with the isolate HXN-200 gave (S)-N-benzyl-3-hydroxypyrrolidine in 53% e.e. (Pseudomonas putida P1 was isolated with n-octane as carbon source by van Beilen, J., ETH Zurich; the isolates HXN-1100 and HXN-200 were isolated with n-hexane as carbon source by Engesser, K.-H. and Plaggemeier, Th., University of Stuttgart; all these strains are in the strain collection of institute of Biotechnology, ETH Zurich).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([C:19]#[N:20])=[C:12]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=1.C(N(CC)C(C)C)(C)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.C(=O)(O)[O-].[Na+]>C1COCC1>[Cl:29][C:24]1[CH:23]=[C:22]([NH:21][C:12]2[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([NH:8][C:5](=[O:6])[CH:4]=[CH:3][CH2:2][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH:10]=3)[N:15]=[CH:14][C:13]=2[C:19]#[N:20])[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: O=C(Cl)C=CCBr
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: N#Cc1cnc2ccc(NC(=O)C=CCN3CCOCC3)cc2c1Nc1ccc(F)c(Cl)c1
Reaction time: 3 h
Yield: 35.7 %

Procedure:
Added 500 μl (4.80 mmol) 4-bromo-but-2-enoyl chloride to a solution of 1.50 g (4.80 mmol) 6-amino-4-[(3-chloro-4-fluorophenyl)amino]-3-quinolinecarbonitrile and 836 μl (4.80 mmol) N,N-diisopropylethylamine in 50 ml THF at 0° C. under N2. At 1 hour added the mixture dropwise to 2.09 ml (24 mmol) morpholine in 10 ml THF at 0° C. Removed ice bath upon complete addition and at 3 hours, poured reaction onto a mixture of ice and saturated sodium bicarbonate. Extracted with ethyl acetate, dried organic layer with brine and sodium sulfate, and stripped solvent. Loaded compound onto a column of silica gel, eluted with 12% methanol/ethyl acetate, stripped solvent from desired fractions, and dried in vacuo, giving 798 mg of yellow solid: mass spectrum (electrospray m/e): M+H=466.4, 468.4.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:19]([O:21][C:22](=[O:32])[CH2:23][NH:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:20].C(OCC)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:19]([O:21][C:22](=[O:32])[CH2:23][N:24]([C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=1)[CH3:20]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNc1ncccc1C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)c1ncccc1C
Temperature: 25 °C

Procedure:
CBZ-L-Valine (15.4 g, 0.0612 mol) was dissolved in CH2Cl2 (300 mL) and the following reagents were added in equal molar amounts in the stated order; 4-dimethylaminopyridine (DMAP), ethyl-N-(3-methylpyridinyl)glycinate and WSCDI. The reaction mixture was allowed to stir at room temperature over night. Evaporation of the solvent yielded a viscous semisolid which was treated with ethyl acetate and then with water and separated. The organic extract was washed with water followed by 5% aqueous Na2CO3 and saturated aqueous NaCl-solution. After drying over MgSO4, filtration and evaporation under reduced pressure yielded an oil (11.1 g) which was purified over silica gel using CH2Cl2 : CH3OH 97.3 as eluent. Isolated 9.2 g of an amber oil.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:11][OH:12])=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>ClCCl>[CH3:27][S:24]([O:12][CH2:11][CH:10]([C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH2:13][CH2:14][CH2:15][CH3:16])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCC(CO)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(COS(C)(=O)=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 10.2 g (46 mmol) of 2-(3,4-methylenedioxyphenyl) hexyl alcohol, were added 50 ml of dichloromethane and 7.7 ml (55 mmol) of triethylamine, and further added dropwise under cooling with ice 4.3 ml (55 mmol) of mesyl chloride. After stirring for one hour at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate and dried over anhydrous magnesium sulfate. By evaporating off the solvent, 2-(3,4-methylenedioxyphenyl)hexyl methanesulfonate was obtained in an almost quantitative yield.
Reaction SMILES: [C:1]([C:3]1[C:8](F)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:10][S-:11].[Na+]>CN(C=O)C.O>[C:1]([C:3]1[C:8]([S:11][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: C[S-]
Reactant: N#Cc1ncccc1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cccnc1C#N
Reaction time: 0.08 h

Procedure:
A stirred solution of 1.00 g (8.19 mmol) of 2-cyano-3-fluoropyridine and 0.631 g (9.01 mmol) of sodium thiomethoxide in 8 mL of DMF was stirred at room temperature for 1 h. The reaction mixture was diluted with water (80 mL) and stirred for 5 min. The resulting solid was filtered and dried on a high vacuum line to give the product as an off-white solid: 1H NMR (CDCl3) δ8.46 (d,1H, 4.6 Hz), 7.66 (d, 1H, 8.3 Hz), 7.44 (dd, 1H, 4.6, 8.3 Hz), 2.58 (s, 3H).