Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].[CH3:18][NH2:19]>CO>[CH3:1][C:2]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:19][CH3:18])=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)(c1ccccc1)c1ccc(C=O)cc1
Reactant: CN
Solvent: CO
Product: CNCc1ccc(C(C)(C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
4-(1-Methyl-1-phenylethyl)benzaldehyde (3.61 g; 16.1 mmol) and molecular sieves (4 angstroms: about five granules) were added to 40% methylamine in methanol (40 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was taken up in ether (100 ml), and the organic layer was washed with saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (25 ml). Sodium borohydride (0.70 g) was added to the solution, and the thus-obtained mixture was heated for 1 hour at 50° C. The solvent was evaporated under reduced pressure, and the residue was taken up in ether (100 ml). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethanol (10 ml). Excess amount of 4N hydrochloric acid—ethyl acetate was added to the solution, and the solvent was evaporated under reduced pressure. The residue was taken up in isopropyl ether (100 ml), and white crystals that precipitated were collected by filtration. The crystals were converted into their free forms by use of aqueous sodium hydroxide solution, followed by extraction with ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, to thereby yield 2.49 g of the target compound as orange oily matter (yield: 64.6%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)oc1C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
At −78° C., to a stirred solution of commercial 2,3-dimethylfuran (50 g, 0.520 mol) in THF (2.6 L) was add dropwise 1.6M n-BuLi/hexanes (325 mL, 0.520 mol). After the addition was complete, the dry ice/acetone bath was removed and the reaction was stirred for 1 h. At −78° C., to the reaction was added dropwise commercial benzyl bromide (62 mL, 0.520 mol). After the addition was complete the reaction was stirred at −78° C. for 6 h, the dry ice/acetone bath was removed and the reaction was stirred for 7 days. The reaction was concentrated in vacuo and purified on silica gel eluting with hexane to give 75.70 g (78%) of the title compound as a clear oil; 1H NMR (DMSO-d6) δ 1.83 (s, 3H), 2.08 (s, 3H), 3.83 (s, 2H), 5.83 (s, 1H), 7.16-7.30 (m, 5H). mass spectrum (EI), m/z 186 (M+).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH2:10](Br)[C:11]#[CH:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][CH2:12][CH:11]=[CH2:10]
Reactant: C#CCBr
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccccc1OC
Temperature: 25 °C
Reaction time: 34 h
Yield: 98.3 %

Procedure:
To a well stirred solution of guaiacol (10.0 g, 80.55 mmol) and propargyl bromide (11.5 g, 96.66 mmol) in DMF (100 mL) was added anhydrous K2CO3 (22.0 g, 161.2 mmol) and the mixture was stirred at room temperature for 34 hours. The mixture was then filtered to remove inorganic material. Filtrate was concentrated under vacuo and diluted with water (250 mL). It was then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave the product (13.0 g) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11](Cl)(=[O:13])=[O:12].[NH3:15]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[C:10]=1[S:11]([NH2:15])(=[O:13])=[O:12]
Reactant: N
Reactant: O=S(=O)(Cl)c1c(Cl)nc2ccccn12
Solvent: CC#N
Product: NS(=O)(=O)c1c(Cl)nc2ccccn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.6 g of 2-chloroimidazo[1,2-a]pyridine- 3-sulfonyl chloride in 60 ml of acetonitrile is added to 60 ml of aqueous ammonia under cooling and the mixture is stirred at room temperature for 2 hours. The acetonitrile is distilled off under reduced pressure and the resulting crystals are collected by filtration and washed with water to give 3.8 g of the title compound. Recrystallization from dilute ethanol gives colorless needles.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13]C)=[O:11])=[O:2].Cl.[C:19]([BH3-])#N.[Na+].O>CO>[CH3:19][O:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)CCCOc1cccc(C=O)c1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1cccc(OCCCC(=O)OC)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.8 %

Procedure:
A solution of 4-(3-formylphenoxy)butyric acid, ethyl ester (4.72 g) in methanol (25 ml) containing hydrogen chloride (0.35 g) was stirred for 12 hr. at room temperature, then cooled to 0°. Sodium cyanoborohydride (1.26 g) was added and after 30 min., iced water (200 ml) was added and the mixture extracted with ether (2×150 ml). Evaporation of the dried (MgSO4) ethereal extracts gave a pale yellow oil which was distilled (165°/0.8 mm) to give the title compound (3.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:21](=[N:1][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(N=Cc2ccccc2)c2c(c1)ncn2-c1ccccc1

Procedure:
To a solution of 7-amino-1-phenyl-5-trifluoromethylbenzimidazole (0.50 g, 1.81 mmol) in anhydrous toluene (10 ml) was added benzaldehyde, p-toluenesulphonic acid (10 mg) and molecular sieves. The resultant mixture was stirred at reflux for 1.5 hours. The molecular sieves were removed by filtration and the filtrate was concentrated under reduced pressure. The concentrate was partitioned between aqueous sodium carbonate (2M) and ethyl acetate. The organic phase was dried and concentrated, and the concentrate was eluted through silica gel with a mixture of ethyl acetate and ligroin (1:1 v/v). Removal of solvent from the eluate left the desired product as a yellow solid (0.37 g, 56%) m/z, 366.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cccc(COC(=O)Cl)c1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Product: Cc1cccc(COC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c1

Procedure:
3-Methylbenzyl (1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexylcarbamate was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 3-methylbenzyl carbonochloridate (63.5 mg, 0.22 mmol) according to General Procedure H to give 30 mg (33.4%) of white solid. Anal. Calcd. for C27H34N4O2 m/z 446.3, found: 447.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.45 (d, J=8.8 Hz, 2H), 7.19 (m, 1H), 7.12 (m, 2H), 6.97 (dd, J=8.8 Hz, J=2.8 Hz, 2H), 4.98 (m, 2H), 3.71 (m, 1H), 3.59 (m, 1H), 3.28 (m, 1H), 2.97 (m, 1H), 2.74 (m, 1H), 2.66 (m, 1H), 2.50 (m, 1H), 2.31 (s, 3H), 2.04 (m, 1H), 1.92 (m, 2H), 1.78 (m, 3H), 1.62 (m, 1H), 1.28 (m, 5H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:7]2[CH2:8][CH2:9][NH:10][C:11]3([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.CCN(CC)CC.[CH3:33][N:34]=[C:35]=[O:36]>C1COCC1>[CH3:33][NH:34][C:35]([N:10]1[C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:13][CH2:12]2)[C:6]2=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[N:7]2[CH2:8][CH2:9]1)=[O:36]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NCCn1c(C(F)(F)F)ccc12
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)N1CCn2c(C(F)(F)F)ccc2C12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To tert-butyl 6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (600 mg, 1.67 mmol), THF (3 mL) and Et3N (698 μL, 5.01 mmol) was added methyl isocyanate (199 μL, 3.34 mmol). The mixture was allowed to stir at room temperature for 2 h. The mixture was charged with additional Et3N (698 μL, 5.01 mmol) and methyl isocyanate (199 μL, 3.34 mmol), and the reaction was stirred at room temperature for 3 d. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (40 mL) and washed with water (3×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield tert-butyl 2-(methylcarbamoyl)-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (680 mg, 97%). ESI-MS m/z calc. 416.2, found 417.4 (M+1)+; Retention time: 1.73 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.14 (q, J=4.3 Hz, 1H), 6.56 (d, J=3.4 Hz, 1H), 6.03 (d, J=3.9 Hz, 1H), 3.88 (t, J=5.4 Hz, 2H), 3.73 (t, J=5.4 Hz, 2H), 3.69-3.55 (m, 2H), 3.23-3.03 (m, 2H), 2.78-2.62 (m, 2H), 2.56 (d, J=4.4 Hz, 3H), 1.76-1.60 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [C:1]([O:4][CH:5](Cl)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O-:27])=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15].[K+].[I-].[Na+]>CN(C=O)C>[C:14]([NH:17][C:18]1[C:19]([I:34])=[C:20]([N:29]([C:31](=[O:33])[CH3:32])[CH3:30])[C:21]([I:28])=[C:22]([C:25]([O:27][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:26])[C:23]=1[I:24])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(Cl)Cc1ccccc1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(Cc2ccccc2)OC(C)=O)c(I)c(N(C)C(C)=O)c1I
Reaction time: 21 h

Procedure:
1-Chloro-2-phenylethyl acetate (Intermediate 9) (4.20 g, 21.1 mmol) in dry DMF (25 ml) is added dropwise at 50° C. to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (15.5 g, 23.2 mmol) and sodium iodide (158 mg, 1.0 mmol) in dry DMF (300 ml). The precipitate is removed by filtration after stirring for 21 hours and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (200 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[O:14])[N:10]=2)[CH2:3]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:26][S:27]([O:1][CH:2]1[CH2:3][N:4]([C:6]2[S:7][CH:8]=[C:9]([CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)=[O:14])[N:10]=2)[CH2:5]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCc1csc(N2CC(O)C2)n1)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 3-hydroxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (457 mg, 1.25 mmol) (obtained as described in Reference Example 62(3)) in methylene chloride (25 ml) were added methanesulfonyl chloride (0.29 ml, 3.75 mmol) and triethylamine (0.53 ml, 3.80 mmol) in an ice bath. After stirring the mixture for 10 minutes in the ice bath, the resulting mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (1:1) as the eluant to afford 3-methanesulfonyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl)azetidine (499.4 mg, yield 90%) as a yellow solid.
Reaction SMILES: [NH2-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].[CH3:10][O:11][CH2:12][C:13](OC)=[O:14].O>C(O)(=O)C>[CH3:10][O:11][CH2:12][C:13](=[O:14])[CH2:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[CH3:3]
Reactant: COCC(=O)OC
Reactant: CC(=O)C(C)(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COCC(=O)CC(=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 9.74 g (250 mmol) of sodium amide, and the flask was purged with argon. Then, 80 mL of toluene was placed in the flask. Subsequently, 25.0 g (249.6 mmol) of 3,3-dimethyl-2-butanone was slowly dropped into the flask, and the resulting mixture was stirred for 15 minutes. Into the flask was further dropped 10.4 g (99.9 mmol) of methyl methoxyacetate, and the mixture was stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 50 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, neutralized with acetic acid, and subjected to extraction with ether. The ether extract was washed with water, dried over hydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (65° C., 426 Pa) to give 5.90 g (yield: 34%) of 1-methoxy-5,5-dimethyl-2,4-hexanedione as colorless liquid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:32][CH2:33][CH:34]([OH:66])[CH2:35][O:36][C:37]1[C:42]([CH3:43])=[CH:41][C:40]([C:44]2[O:45][C:46]3[N:47]=[C:48]([CH2:57][C:58]4[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=4)[N:49]=[C:50]([O:53][CH2:54][CH2:55][CH3:56])[C:51]=3[N:52]=2)=[CH:39][C:38]=1[CH3:65].C(N(C(C)C)C(C)C)C>CN(C)C=O>[Cl:64][C:61]1[CH:60]=[CH:59][C:58]([CH2:57][C:48]2[N:49]=[C:50]([O:53][CH2:54][CH2:55][CH3:56])[C:51]3[N:52]=[C:44]([C:40]4[CH:39]=[C:38]([CH3:65])[C:37]([O:36][CH2:35][CH:34]([OH:66])[CH2:33][NH:32][C:1](=[O:9])[C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[C:42]([CH3:43])[CH:41]=4)[O:45][C:46]=3[N:47]=2)=[CH:63][CH:62]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CN)c(C)c3)nc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(O)CNC(=O)c4ccccc4)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.1 %

Procedure:
A mixture of 37 mg of benzoic acid, 110 mg of [(benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium tetrafluoroborate (TBTU), 100 mg of 1-amino-3-{4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (example 20) and 104 mg of ethyldiisopropylamine in 2 ml of dimethylformamide was stirred for 16 h at room temperature. After removal of the solvent the product was isolated via preparative HPLC (method HPLC2) to yield 11 mg of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][N:7]=[C:6]([CH2:9][CH2:10][CH3:11])[C:5]=1[CH2:12][OH:13].Cl[C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][N:16]=1.O>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][C:15]([O:13][CH2:12][C:5]2[C:6]([CH2:9][CH2:10][CH3:11])=[N:7][O:8][C:4]=2[CH3:3])=[N:16][CH:17]=1
Reactant: CCCc1noc(C)c1CO
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To a stirred suspension of sodium hydride (2.78 g of a 60% dispersion in mineral oil, 64 mmol) in THF (40 mL) at 0° C. and under argon was added solution of (5-methyl-3-propyl-isoxazol-4-yl)-methanol (7.60 g, 49 mmol) in tetrahydrofuran (40 mL) dropwise. The mixture was warmed to ambient temperature, stirred for 30 min, then cooled to 0° C. and a solution of methyl 6-chloronicotinate (8.40 g, 49 mmol) in THF (40 mL) was added dropwise. The reaction mixture was warmed to room temperature. After 2 h, water was added then the resulting mixture extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, 0 to 20% ethyl acetate in heptane) gave the title compound (8.4 g, 50%) as a light yellow oil. MS: m/e=413.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C([Li])CCC.[CH3:34][N:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1>C(OCC)C>[CH2:1]([C:8]1[C:13]([C:38]2([OH:41])[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: CN1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CO[C@@H]1CN(c2ccc(C3(O)CCN(C)CC3)c(Cc3ccccc3)n2)C[C@H]1O
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a mixture of 500 mg of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1) and 10 ml of diethyl ether was added dropwise 1.99 ml of a 2.45 M hexane solution of n-butyllithium at −78° C. After stirring at the same temperature for 30 minutes, a solution of 552 mg of 1-methyl-4-piperidone in 3 ml of diethyl ether was added dropwise thereto. After stirring at the same temperature for 30 minutes, the temperature was elevated to room temperature. The organic layer was separated by adding water and ethyl acetate to the reaction mixture, and then it was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was purified by NH-silica gel column chromatography with 5% methanol/ethyl acetate, to give 125 mg of the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:16]([OH:18])=[O:17].O[CH2:20][CH2:21][O:22][C:23](=[O:27])[C:24]([CH3:26])=[CH2:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)C1C=CN=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:23]([O:22][CH2:21][CH2:20][O:17][C:16]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13](=[O:15])[C:14]=2[CH:1]=1)=[O:18])(=[O:27])[C:24]([CH3:26])=[CH2:25]
Reactant: O=C(O)c1ccc2sc3ccccc3c(=O)c2c1
Reactant: C=C(C)C(=O)OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCOC(=O)c1ccc2sc3ccccc3c(=O)c2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 6.9 %

Procedure:
A mixture of thioxanthen-9-one-2-carboxylic acid (3.8 g, 19.8 mmol), 2-hydroxyethylmethacrylate (7.7 g, 59.3mmol), 4-dimethylamino-pyridine p-toluenesulfonic acid salt (2.3 g, 7.9mmol), and anhydrous dichloromethane (31 mL) is cooled to 0° C. under nitrogen and treated with 1,3-dicyclohexyl-carbodiimide (2.1 g, 10.1 mmol). After 15 min, the reaction mixture was warmed to ambient and stirred for 12 h. The precipitated urea by product was filtered, and the filtrate was washed successively with 10% aqueous HCl, 10% aqueous NaHCO3, water, and brine. The solution was dried (Na2SO4)and concentrated to deposit yellow oil. The product was purified by column chromatography to provide 500 mg of a pale yellow solid (17% of theory). 1H (CDCl3): δ 1.99 (s, 3H), 4.60 (dd, 4H), 5.60 (s, 1H), 6.20 (s, 1H), 7.60 (m, 4H), 8.20 (d, 1H), 8.70 (d, 1H), 9.30 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23]([OH:25])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[CH3:55][NH:56][O:57][CH3:58]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23](=[O:25])[N:56]([O:57][CH3:58])[CH3:55])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNOC
Reactant: COc1ccc(CS[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CS[C@@H]2C[C@@H](C(=O)N(C)OC)N(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
A solution of 5 g (13.6 mmol) (2S,4R)-4-(4-Methoxy-benzylsulfanyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 20-5620 in 150 ml CH2Cl2 was treated with 10.5 ml (95.2 mmol) N-methylmorpholine, 0.37 g (2.72 mmol) 1-hydroxybenzotriazole, 6.26 g (32.64 mmol) EDCI and 2.92 g (29.92 mmol) N,O-dimethylhydroxylamine hydrochloride. The reaction was stirred over night at room temperature and partitioned between aqueous 10% KHSO4/EtOAc (3×). The organic phases were washed with aqueous saturated NaCl and dried over Na2SO4. Purification by flash-chromatography on silica gel (Hexane/EtOAc 1:1) gave 3.6 g (62%) of (2S,4R)-4-(4-methoxy-benzylsulfanyl)-2-(methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, MS: 411 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[CH2:18])[N:12]=1.C(O)(=O)C>CO>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:18][CH2:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([CH3:10])[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=Cc1cccc(C)n1
Reactant: CC(=O)N1CCNCC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=O)N1CCN(CCc2cccc(C)n2)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a stirring solution of N-acetylpiperazine (2.50 g, 20 mmol) in methanol (40 mL) at 0° C. under nitrogen was added 2-methyl-6-vinyl-pyridine (2.39 g, 20 mmol) and acetic acid (1.28 mL). The mixture was stirred for 24 hours at 80° C. and was then concentrated. The residue was partitioned between 10% aqueous K2CO3 /CH2Cl2. The organic phase was dried and concentrated to afford 3.60 g (73%) of 1-acetyl-4-[2-(6-methyl-2-pyridyl)ethyl]piperazine as a brown solid which was used directly in the next step: 1H NMR (CDCl3): δ7.48 (m, 1H), 7.0 (d, 1H), 3.63 (t, 2H), 3.45 (t, 2H), 2.95-2.60 (m, 4H), 2.50 (m, s, 9H), 2.08 (s, 3H).