Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].C(O[C:12]([C:14]1[N:15]([N:24]=[CH:25]N(C)C)[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:18]=1)=[O:13])C.CC(O)=O>C1COCC1>[CH2:22]([O:21][C:19]([C:16]1[N:15]2[N:24]=[CH:25][C:6]([C:7]#[N:8])=[C:12]([OH:13])[C:14]2=[CH:18][CH:17]=1)=[O:20])[CH3:23]
Reactant: CCOC(=O)c1ccc(C(=O)OCC)n1N=CN(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(O)c(C#N)cnn12
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
To a solution of n-BuLi (1.6 M in hexanes) (290 μl, 0.465 mmol) in THF (1 ml) was added a solution of CH3CN (19.1 mg, 0.465 mmol) in THF (2 ml) dropwise at 0° C. The mixture was stirred for 20 min, then a solution of 406D (62 mg, 0.221 mmol) in THF (5 ml) was added. After the mixture was stirred for 40 min, the reaction temperature was lowered to −78° C., AcOH (38 μl, 0.663 mmol) was added. The reaction mixture was then stirred at rt overnight. Solvent was removed, 406E (26 mg, 50%) was obtained as a yellowish solid after preparative HPLC purification. LCMS Found: (M+H)+=232.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](Cl)(=[O:14])[CH3:13].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:1]1([C:7]2[CH:11]=[CH:10][S:9][C:8]=2[C:12](=[O:14])[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[S:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccsc2)cc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(-c2ccccc2)cs1
Product: CC(=O)c1sccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41 %
Yield: 29 %

Procedure:
A solution of 3-phenylthiophene (3.10 g, 19.3 mmol) and acetyl chloride (1.38 mL, 23.2 mmol) in dichloromethane (50 mL) was cooled to 0° C. Aluminium (III) chloride (2.58 g, 19.3 mmol) was added in several portions to control an otherwise vigorous exotherm. After addition was complete, the bath was removed and the reaction allowed to stir at ambient temperature for 2 h. The reaction mixture was then diluted with saturated aqueous NaHCO3 and the layers were separated. The organic phase was washed with another portion of NaHCO3 solution and brine. The resulting dichloromethane solution was concentrated in vacuo and the residue was purified by flash chromatography eluting with a gradient of 1-5% EtOAc/hexanes to afford 1.62 g (41% yield) of 1-(3-phenylthiophen-2-yl)ethanone and 1.13 g (29% yield) of 1-(4-phenylthiophen-2-yl)ethanone which were both spectroscpopically identical to literature compounds (See reference: Acta Chemica Scandinavica (1947-1973) 1970, 24, pp. 99-104.)
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][C:32](O)=[O:33]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[CH2:31][C@@H:27]5[CH2:28][CH2:29][CH2:30][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)C[C@@H]1CCCO1
Agent: Cl
Product: O=C(C[C@@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (40 mg, 72.9%), MS (ISP) m/z=443.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (50 mg, 0.124 mmol) and (S)-2-(tetrahydrofuran-2-yl)acetic acid
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C=O.[Cl:21][CH2:22]Cl>[Cl-].[Cl-].[Zn+2]>[Cl:21][CH2:22][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: O=C(N1CCC(c2ccccc2)CC1)C(F)(F)F
Reactant: ClCCl
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(N1CCC(c2ccc(CCl)cc2)CC1)C(F)(F)F
Temperature: 25 °C

Procedure:
A suspension of the product of step i) (18 g), paraformaldehyde (14 g) and zinc dichloride (14 g) in dichloromethane (700 mL) was stirred at room temperature. Hydrogen chloride gas was bubbled through the reaction for 30 minutes. The reaction was stirred at room temperature under a blanket of nitrogen for a further 18 hours. Water (150 mL) was added and the phases separated. The organic phase was dried using magnesium sulfate and concentrated in vacuo to give a green oil which was purified (SiO2 eluting with 30% i-hexane in dichloromethane) to give the sub-title compound (12 g).
Reaction SMILES: NC1C=CC(Cl)=CC=1C(C1C=CC(F)=CC=1)=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1.[F:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:28]=1[C:29](Cl)=[O:30]>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:29]([C:28]1[C:27]([F:26])=[CH:35][CH:34]=[CH:33][C:32]=1[F:36])=[O:30]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cc1ccc(N)cc1
Agent: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1
Product: Cc1ccc(N)c(C(=O)c2c(F)cccc2F)c1
Yield: 16 %

Procedure:
In a manner similar to that described above for compound 1t, p-toluidine and 2,6-difluorobenzoyl chloride were converted to 1aj (16% yield) MS m/z=248 (M+H).
Reaction SMILES: C1([C:4](Cl)=[O:5])CC1.[F:7][C:8]1[CH:9]=[C:10]([N:22]2[CH2:26][C@H:25]([CH2:27][NH2:28])[O:24][C:23]2=[O:29])[CH:11]=[CH:12][C:13]=1[CH:14]1[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]1.CO.[CH:32]([Cl:35])(Cl)[Cl:33]>>[Cl:33][CH:32]([Cl:35])[C:4]([NH:28][CH2:27][C@@H:25]1[O:24][C:23](=[O:29])[N:22]([C:10]2[CH:11]=[CH:12][C:13]([CH:14]3[CH2:15][CH2:16][S:17](=[O:20])(=[O:21])[CH2:18][CH2:19]3)=[C:8]([F:7])[CH:9]=2)[CH2:26]1)=[O:5]
Reactant: ClC(Cl)Cl
Reactant: O=C(Cl)C1CC1
Reactant: NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: O=C(NC[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(Cl)Cl

Procedure:
Following the general procedure of EXAMPLE 3, and making non-critical variations but substituting dichloroacetyl chloride for cyclopropanecarbonyl chloride and (5S)-(-)-3-[3-fluoro-4-(tetrahydro-1,1-dioxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone (EXAMPLE 5, Step 1) for (5S)-3-[3-fluoro-4-(cis-tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-5-aminomethyl-2-oxazolidinone and chromatographing the crude product with methanol/chloroform (2/98), the title compound is obtained, mp 136-137° C. (dec.).
Reaction SMILES: C([C:3]1[N:13]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)C.Br[C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[C:39]#[N:40].O1CCO[CH2:47][CH2:46]1>>[CH2:46]([C:3]1[N:13]([CH:14]2[C:22]3[C:17](=[CH:18][C:19]([C:37]4[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=4[C:39]#[N:40])=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:47]
Reactant: N#Cc1ccccc1Br
Reactant: C1COCCO1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2c(c1)CCC2n1c(CC)nc2c(C)cc(C)nc21
Product: CCc1nc2c(C)cc(C)nc2n1C1CCc2cc(-c3ccccc3C#N)ccc21
Temperature: 23 °C

Procedure:
To a solution of 2-ethyl-5,7-dimethyl-3-(5-tributylstannanyl-indan-1-yl)-3H-imidazo[4,5-b]pyridine (264 mg, 0.48 mmol) in anhydrous dioxane (1.5 mL) was added 2-bromobenzonitrile (109 mg, 0.6 mmol) and PdCl2 (PPh3)2 (34 mg, 0.048 mmol). The reaction mixture was heated under reflux for 17 hours, cooled to 23° C. and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 30% ethyl acetate/hexanes to give 100 mg of the desired product. 1H NMR (250 MHz, CDCl3): d 7.75 (1H, m), 7.64 (1H, m), 7.55 (m, 2 H), 7.35 (t, 1 H), 7.00 (d, 1 H), 6.9 (s, 1 H), 6.6 (m, 1 H), 3.4 (m, 2 H), 2.95 (m, 1 H), 2.65 (s, 3 H), 2.58 (s, 3 H), 1.3 (t, 3 H).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24](OC)=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][CH2:32][C@@H:33]([OH:35])[CH3:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24]([O:35][C@@H:33]([CH3:34])[CH2:32][O:31][CH3:30])=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)O
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COC[C@H](C)OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
A solution of (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (prepared as in Example 1, 35 mg, 0.09 mmol) in a hydrochloric acid (gas) saturated acetic acid (5 mL) solution was heated in a sealed tube at 75° C. for 2 h. After that, the reaction mixture was cooled to room temperature, and concentrated. The residue was added to (S)-1-methoxy-propan-2-ol (162 mg, 1.76 mmol), and toluene-4-sulfonic acid hydrate (10 mg). The mixture was heated to 90° C., for 18 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was purified using reverse phase HPLC (Biosystems MDS-SCIEX LC/MS, Pursuit C-18 2×10 mm, water/acetonitrile 0.05% trifluoroacetic acid) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-((S)-2-methoxy-1-methyl-ethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide (3 mg, 9%) as a white foam: LR-ES-MS m/z calculated for C23H36N4O5 [M]+ 448, observed [M+H]+ 449; 1H NMR (300 MHz, CDCl3) δ ppm 1.08-1.25 (m, 2H) 1.16 (s, 6H) 1.32 (d, J=6.3 Hz, 3H) 1.43-2.07 (m, 9H) 3.40 (s, 3H) 3.44-3.59 (m, 2H) 3.66 (br. s., 1H) 3.90-4.00 (d, J=17.8 Hz, 1H) 3.95 (s, 2H) 4.08 (d, J=17.8 Hz, 1H) 4.34-4.47 (m, 1H) 4.80 (dd, J=8.9, 6.5 Hz, 1H) 5.12 (s, 1H) 6.67 (d, J=2.0 Hz, 1H) 7.30 (d, J=2.0 Hz, 1H) 8.85 (br. s., 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH2:12]([OH:14])[CH3:13]>CO>[CH2:12]([O:14][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[CH2:2][Cl:1])[CH3:13]
Reactant: CCO
Reactant: O=C(Cl)c1ccccc1CCl
Solvent: CO
Product: CCOC(=O)c1ccccc1CCl
Reaction time: 10 h
Yield: 90 %

Procedure:
To a double-neck 500 ml flask equipped with cooler, thermometer and dropping funnel was added 180 g of o-(chloromethyl)benzoic acid chloride, and then 60 ml of ethanol was further added dropwise, while maintaining the internal temperature of reactor at 40˜50° C. After all amounts of methanol were infused, the reacting mixture was stirred for 10 hours, while maintaining the internal temperature of a reactor at 40˜50° C. After a distiller was equipped immediately, the residue was subjected to fractional distillation under reduced pressure to afford 179 g of desired compound (yield 90%) as oil.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:14][C@@H:15]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[NH:28][CH:29]=[C:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:34][CH:33]=3)[N:31]=2)=[CH:23][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:14][C@@H:15]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[NH:28][CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:36][CH:37]=4)[N:31]=3)=[CH:25][CH:26]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCOc1ccc(-c2c[nH]c(-c3ccc(C[C@H](N)C(=O)OC)cc3)n2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2c[nH]c(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.1 %

Procedure:
To a solution of 4-(tert-butyl)benzoic acid (25 mg, 0.14 mmol), (S)-methyl 2-amino-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate (55 mg, 0.13 mmol), and TEA (53 μl, 0.38 mmol) in DMF (1 mL) was added HATU (53 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted in DCM, and washed aq. NaHCO3. The organic layer was dried, concentrated and purified by chromatography (EA/hexane) to provide 14 mg (17%) of methyl (S)-2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)-1H-imidazol-2-yl)phenyl)propanoate. LCMS-ESI (m/z) calculated for C37H45N3O4: 595.8. found 596.4 [M+H]+, tR=2.33 min. (Method 8).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.N1C=CN=C1.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25].CCOC(C)=O>CN(C=O)C.O>[Si:27]([O:8][CH:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:5]1)([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC1CC(c2ccncc2[N+](=O)[O-])=CC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 18 h

Procedure:
To a solution of 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 equiv.) in DMF (0.5 M) was added imidazole (4.0 equiv.) and TBDMSCl (2.5 equiv.). After stirring for 18 hours the solution was portioned between EtOAc and H2O and separated. After washing further with H2O (3×) and NaCl(sat.), drying over MgSO4, filtering and removal of solvents, 4-(3-(tert-butyldimethylsilyloxy)-5-methylcyclohex-1-enyl)-3-nitropyridine was obtained (85%). LC/MS=349.2 (M+H), LC=5.99 min.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:3]1.C(N(C(C)C)CC)(C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)([O-])O.[Na+]>ClCCl>[CH3:29][S:30]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)=[CH:11][CH:10]=2)[CH2:3]1)(=[O:32])=[O:31]
Reactant: O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)O[C@H]1CCN(CCc2ccc(N3CCCC3)cc2)C1
Reaction time: 4 h

Procedure:
(S)-3-Hydroxy-1-(4-pyrrolidinophenethyl)pyrrolidine (6.30 g, 23.4 mmol) was dissolved in 100 ml of dichloromethane. Diisopropylethylamine (5.28 ml, 30.0 mmol) and methanesulfonyl chloride (2.34 ml, 30.0 mmol) were added to the obtained solution at 0° C. and they were stirred for 4 hours. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with dichloromethane and methanol (10:1), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(4-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow oily substance (7.50 g, 49%).
Reaction SMILES: [CH2:1]1CCN2C(=NCCC2)CC1.[C:12]1([CH2:18][C:19]([OH:21])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl.O>[C:12]1([CH2:18][C:19]([O:21][CH3:1])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccccc1
Temperature: 90 °C

Procedure:
DBU (3.35 g, 22.0 mmol) was added to a mixture of phenylacetic acid (3.0 g, 22.0 mmol) in DMC (30 mL) and the resulting mixture was heated to reflux (90° C.) for 24 hours. The reaction mixture was cooled to ambient temperature and diluted with CH2Cl2 (50 mL) and water (40 mL). The organic layer was separated and washed in sequence with 2 M HCl (2×40 mL), saturated aqueous NaHCO3 (40 mL) and water (2×40 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl phenylacetate as an oil.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([C:8]([OH:10])=O)=[C:5]([CH3:11])[CH:4]=1)=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>CN(C=O)C.C(OCC)(=O)C>[CH3:11][C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[C:8]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[O:10]
Reactant: Cc1cc(C=O)[nH]c1C(=O)O
Reactant: C1COCCN1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C=O)[nH]c1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of 5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid (306.3 mg, 2 mmol) in DMF (5 mL) was added HOBt (324.3 mg, 2.4 mmol), EDC (460.1 mg, 2.4 mmol) and then morpholine (0.21 mL, 2.4 mmol). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was diluted with ethyl acetate and washed with sodium bicarbonate. The aqueous layer was extracted several times with ethyl acetate. The combined organic layer was washed with brine, dried, concentrated and column chromatographed (MeOH/DCM) to give 395 mg (89%) of 4-methyl-5-(morpholine-4-carbonyl)-1H-pyrrole-2-carbaldehyde as a light yellow foam solid. 1H NMR (360 MHz, DMSO-d6) δ 12.18 (br s, 1H, NH), 9.46 (s, 1H, CHO), 6.79 (s, 1H), 3.43 (m, 4H, 2×CH2), 2.29 (m, 4H, 2×CH2), 2.17 (s, 3H, CH3), 2.01 (s, 3H, CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[C:17]([F:18])=[C:16]([F:19])[CH:15]=[CH:14][C:13]=2[F:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Li][CH2:22][CH2:23][CH2:24][CH3:25].[C:26]1(C)[CH:31]=C[C:29]([S:32]([N:35]2CC2)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C1COCC1.CN(CCN(C)C)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:12]2[C:13]([F:20])=[CH:14][CH:15]=[C:16]([F:19])[C:17]=2[F:18])[CH2:25][CH2:24][C:23]2[CH:22]=[C:26]([CH3:31])[CH:27]=[CH:28][C:29]=2[S:32]([NH2:35])(=[O:34])=[O:33])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: O=S(=O)(Cc1c(F)ccc(F)c1F)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)N2CC2)cc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(N)(=O)=O)c(CCC(c2c(F)ccc(F)c2F)S(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.1 %

Procedure:
A solution of 2-(4-chloro-benzenesulfonylmethyl)-1,3,4-trifluoro-benzene (5.6 g, 17.5 mmol) in THF/TMEDA (5:1, 180 mL) at −78° C. was treated with n-BuLi (12 mL, 17.5 mmol, 1.5 M in hexanes). After 15 min, a solution of N-p-toluenesulfonyl aziridine (3.5 g, 17.5 mmol, prepared as described in Eur. J. Org. Chem. 2002, 3004) in THF (10 mL) was added, and the reaction mixture warmed slowly to ambient temperature. After 4 h, the reaction mixture was quenched with 1N HCl and extracted with EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over MgSO4 and concentrated in vacuo. Flash chromatography (25→50% EtOAc/Hex) provided the title compound (4.9 g, 54%): 1H NMR (CDCl3 400 MHz) δ 7.64 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.1 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 7.14 (m, 1H), 6.75 (m, 1H), 4.81 (m, 1H), 3.17 (ddd, J=7.1, 7.1, 5.6 Hz, 1H), 2.96 (m, 1H), 2.64 (m, 1H), 2.47 (m, 1H), 2.41 (s, 3H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[N:6][CH:7]=[C:8]([CH:10]=O)[CH:9]=1.[C:25]([O:28][CH2:29][CH3:30])([CH3:27])=[O:26].O>C1COCC1>[Cl:3][C:4]1[C:5]([NH:12][C@@H:13]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]2)=[N:6][CH:7]=[C:8](/[CH:10]=[CH:27]/[C:25]([O:28][CH2:29][CH3:30])=[O:26])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ncc(C=O)cc2Cl)C1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Temperature: 15 °C

Procedure:
A solution of diethylphosphonoacetcacid ethyl ester (980 mg), in THF (5 ml) was added dropwise to admixture of 60% sodium hydride in oil (187 mg) in THF (30 mL) with stirring at 10-20° C. under atmospheric pressure of nitrogen, and the reaction mixture was stirred at ambient temperature for 30 minutes. A solution of tert-butyl (3R)-3-[(3-chloro-5-formyl-2-pyridinyl)amino]-1-pyrrolidinecarboxylate (0.95 g) in THF (10 ml) solution was added the above mixture and resultant mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-n-hexane (6:4). The eluted fractions containing the desired product were collected and evaporated in vacuo to give tert-butyl (3R)-3-({3-chloro-5-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (0.98 g)
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([N:17]2[CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][C:32]([CH2:35][CH3:36])=[CH:31][CH:30]=4)=[C:23]([O:37][CH3:38])[CH:22]=3)[CH2:18]2)=[O:16])[CH:10]=1)(=O)=O.[NH:39]1[CH2:44][CH2:43][NH:42][CH2:41][C:40]1=[O:45]>C(O)CC>[CH2:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH:19]3[CH2:20][N:17]([C:15]([C:11]4[CH:10]=[C:9]([O:8][CH2:7][CH2:6][N:42]5[CH2:43][CH2:44][NH:39][C:40](=[O:45])[CH2:41]5)[CH:14]=[CH:13][N:12]=4)=[O:16])[CH2:18]3)=[CH:22][C:23]=2[O:37][CH3:38])=[CH:34][CH:33]=1)[CH3:36]
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCOS(C)(=O)=O)ccn4)C3)cc2OC)cc1
Reactant: O=C1CNCCN1
Solvent: CCCO
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCN5CCNC(=O)C5)ccn4)C3)cc2OC)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 74.4 %

Procedure:
To a solution of 2-(2-{3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}-pyridin-4-yloxy)ethyl methanesulfonate (0.4 g) prepared in Example 6 (1) in 1-propanol (5.0 mL) was added 2-piperazinone (0.22 g). The reaction mixture was stirred at 100° C. for 18 hr. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=8/1 to 7/1) to give the title compound (0.3 g, 76%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:37])[NH:19][C:20]2[CH:24]=[C:23]([C:25](=[O:32])[NH:26][CH2:27][CH2:28][C:29](=[NH:31])[NH2:30])[N:22]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:21]=2)=[CH:14][CH:13]=1)(C)(C)C.CCOCC>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:19][C:20]2[CH:24]=[C:23]([C:25](=[O:32])[NH:26][CH2:27][CH2:28][C:29](=[NH:30])[NH2:31])[N:22]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:21]=2)=[O:37])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(C(=O)Nc2cc(C(=O)NCCC(=N)N)n(CC3CC3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: COc1ccccc1
Product: N=C(N)CCNC(=O)c1cc(NC(=O)c2ccc(C(=O)NCCN)cc2)cn1CC1CC1
Reaction time: 0.5 h
Yield: 156 %

Procedure:
310 mg (0.55 mmol) 98 was dissolved in a mixture of 1 mL anisol and 4 mL trifluoroacetic acid and was agitated occasionally by swirling for 30 minutes at ambient temperature. 40 mL of cold ether was added, the precipitate was centrifuged, the ether phase was discarded, and the precipitate washed with ether (1×) then was re-precipitated from 5 mL methanol with 40 mL ether and dried to give 377 mg (96%) 99 as bis-TFA salt. MS: 220.61 (M+2H+).