Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([CH:8]=1)[NH2:7].Cl>C(O)C.[Zn]>[Cl:1][C:2]1[CH:8]=[C:6]([NH2:7])[C:5]([NH2:9])=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1
Reactant: Nc1cc(Cl)c(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(Cl)c(-c2ccc(F)cc2)cc1N
Temperature: 85 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5 g, 16.75 mmol) in dioxane (200 ml) was added (4-fluorophenyl)boronic acid (4.7 g, 33.59 mmol), water (20 ml), K3PO4 (7 g, 32.98 mmol), Pd(PPh3)4 (924 mg, 0.80 mmol) with an inert atmosphere of nitrogen. The resulting solution was stirred for 8 h at 95° C. and then concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 5% to 20% ethyl acetate in petroleum ether to produce 5-chloro-4-(4-fluorophenyl)-2-nitroaniline as a yellow solid (4.1 g, 91%). Next, a solution of 5-chloro-4-(4-fluorophenyl)-2-nitroaniline (4.1 g, 15.38 mmol) in ethanol (100 ml) was added to hydrogen chloride (4 ml, 48 mmol, conc) and Zn (6 g, 460 mmol) at room temperature. The resulting solution was stirred for 3 h at 85° C. The resulting mixture was concentrated under vacuum and dissolved in water (200 ml), adjusted pH to 8 with aqueous sodium bicarbonate and extracted with dichloromethane (3×200 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a silica gel column with 5% to 10% ethyl acetate in petroleum ether to produce 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine as a brown oil (2.5 g, 70%). Finally, a solution of 4-chloro-5-(4-fluorophenyl)benzene-1,2-diamine (100 mg, 0.42 mmol) in hydrogen chloride (1 ml) and trifluoroacetic acid (5 ml) was stirred overnight at 80° C. The reaction was quenched by the addition of water (50 ml) and the pH value of the solution adjusted to 7 with aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3×50 ml) and the organic layers combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by Pre-TLC with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)-1H-1,3-benzodiazole as a white solid (50.7 mg, 38%).
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][C:20]=1[OH:21])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])(=[O:4])[CH:2]=[CH2:3].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.CC(C)=O>[CH:22]1([NH:28][C:29](=[O:30])[O:21][C:20]2[CH:19]=[CH:18][C:9]([C:10](=[O:11])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][C:7]=2[CH2:6][NH:5][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C=CC(=O)NCc1cc(C(=O)c2ccccc2)ccc1O
Reactant: O=C=NC1CCCCC1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=CC(=O)NCc1cc(C(=O)c2ccccc2)ccc1OC(=O)NC1CCCCC1
Yield: 31 %

Procedure:
A mixture of 30 g (0.107 mole) of 3-acrylamidomethyl-4-hydroxybenzophenone, 13.5 g (0.108 mole) of cyclohexyl isocyanate, 0.2 g of 2,6-di-tert-butyl-p-cresol, 1.5 g of triethylamine and 180 ml of acetone was refluxed for 3 hours and then left to stand. The crystals formed were filtered off, and 26.3 g of the desired product having a melting point of 142°-144° C. were obtained in this manner. A further 13.5 g of the desired carbamate were obtained by evaporating down the mother liquor.
Reaction SMILES: CS(O[C@H:6]([CH3:23])[CH2:7][N:8]([CH2:19][C@@H:20]([NH2:22])[CH3:21])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])(=O)=O>CO>[CH3:23][C@H:6]1[NH:22][C@H:20]([CH3:21])[CH2:19][N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7]1
Reactant: C[C@H](N)CN(C[C@@H](C)OS(C)(=O)=O)C(=O)OCc1ccccc1
Solvent: CO
Product: C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H](C)N1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
(R)-1-(((S)-2-aminopropyl)(benzyloxycarbonyl)amino)propan-2-yl methanesulfonate (1.8 g, 5.15 mmol) dissolved in anhydrous MeOH (120 mL) was heated up to 60° C. for 4 hours. Reaction was complete as determined by TLC. After overnight stirring at room temperature solvent was evaporated to afford (3R,5R)-benzyl 3,5-dimethylpiperazine-1-carboxylate [L31285-103-1] in quantitative yield (1.28 g) as gummy off white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH:28][C@@H:29]([CH2:42][NH2:43])[CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1>>[OH:28][C@H:29]([CH2:30][O:31][C:32]1[C:40]2[NH:39][C:38](=[O:41])[NH:37][C:36]=2[CH:35]=[CH:34][CH:33]=1)[CH2:42][NH:43][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=3)(=[O:16])=[O:17])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.60-1.80 (m, 2H), 2.00-2.15 (m, 2H), 2.06 (s, 3H), 2.50-2.70 (m, 2H), 2.90-3.20 (m, 3H), 3.60-3.75 (m, 2H), 4.15-4.25 (m, 1H), 5.70 (brs, 1H), 6.61 (t, J=8.7 Hz, 1H), 6.80-6.92 (m, 5H), 7.60 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 9.72 (brs, 1H), 10.42 (s, 1H), 10.65 (s, 1H), 10.80 (s, 1); MS (ES) m/z: 595.2 (MH+); HRMS Calcd. for C29H35N6O6S(MH+): 595.2339. Found: 595.2332.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]OS(C4C=CC(C)=CC=4)(=O)=O)=[CH:20][CH:19]=2)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][N:42]4[CH2:43][CH2:44][CH:39]([CH2:38][NH2:37])[CH2:40][CH2:41]4)=[CH:20][CH:19]=2)=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(OC(=O)c3c4ccccc4nc4ccccc34)cc2)cc1
Reactant: NCc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCC1CCN(CCc2ccc(OC(=O)c3c4ccccc4nc4ccccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.1 %

Procedure:
In 30 ml of DMF, 2.9 g of the compound (3) obtained in Example 3 were dissolved, followed by the addition of 0.59 g of 4-aminomethylpyridine. The resultant mixture was stirred at room temperature, to which 0.60 g of t-BuOK was added under ice cooling. The thus-obtained mixture was stirred at room temperature for 5 hours. The DMF was distilled off under reduced pressure, and the residue was dissolved in CHCl3. The solution so obtained was washed with water and then dried over anhydrous magnesium sulfate (MgSO4). The solvent was distilled off under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (eluent: CHCl3/MeOH=7/3), whereby 0.41 g of the compound (4) was obtained (yield: 18%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]2=[O:30])=[N:21][C:20]=1[CH3:31])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([NH:16][C:17]([C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C:26](=[CH:1][C:2]3[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=3)[C:25]2=[O:30])=[N:21][C:20]=1[CH3:31])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(N2CCCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: O=Cc1cccnc1
Product: Cc1nc(N2CCCC(=Cc3cccnc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 17 %

Procedure:
Following the procedure as described in Example 10, making variations as required to use nicotinaldehyde in place of benzaldehyde to react with N-benzyl-4-methyl-2-(2-oxopiperidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 17% yield: mp 206-208° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.69 (br s, 1H), 8.54 (br s, 1H), 7.91 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.39-7.21 (m, 6H), 6.26 (t, J=5.5 Hz, 1H), 4.57 (d, J=5.5 Hz, 2H), 4.32-4.22 (m, 2H), 2.93-2.82 (m, 2H), 2.64 (s, 3H), 2.09-1.96 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 163.8, 162.6, 157.3, 152.3, 150.7, 149.4, 138.0, 136.8, 135.5, 130.5, 128.8, 127.9, 127.6, 123.5, 120.1, 47.4, 44.0, 25.9, 22.2, 17.4; MS (ES+) m/z 419.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>CCO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cc1Cl
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCOCC2)cc1Cl
Yield: 38 %

Procedure:
A solution of 4-(3-chloro-4-nitrophenyl)morpholine (Preparation 112, 450 mg, 1.854 mmol) in EtOH/EtOAc (1:1, 30 mL) was passed through a 10% Pd/C cartridge using an H-cube (atmospheric H2, room temperature, 1 mL/min). The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography eluting with 0-20% MeCN in water to afford the title compound (150 mg, 38%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[C@H:22]12[CH2:30][NH:29][CH2:28][C@@H:27]1[NH:26][CH2:25][CH2:24][O:23]2.C(N(CC)CC)C>C(#N)C>[C:12]([C:11]1[C:2]([C@:22]23[CH2:30][NH:29][CH2:28][C@@H:27]2[NH:26][CH2:25][CH2:24][O:23]3)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C1CO[C@H]2CNC[C@@H]2N1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1c([C@]23CNC[C@@H]2NCCO3)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
1.00 g (3.26 mmol) of 7-chloro-8-cyano-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid are stirred under argon at 40-45° C. for 25 hours with 501 mg (3.91 mmol) of (1S,6S)-2-oxa-5,8-diazabicyclo[4.3.0]nonane and 0.9 ml of triethylamine in 30 ml of acetonitrile. All volatile components are removed in vacuo and the residue is recrystallized from ethanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[C:10]([C:14]1[C:15]([Cl:22])=[CH:16][C:17]([I:21])=[C:18]([OH:20])[CH:19]=1)([CH3:13])([CH3:12])[CH3:11]>CC(=O)CC>[C:10]([C:14]1[C:15]([Cl:22])=[CH:16][C:17]([I:21])=[C:18]([O:20][CH2:8][CH3:9])[CH:19]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)c1cc(O)c(I)cc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOc1cc(C(C)(C)C)c(Cl)cc1I
Temperature: 80 °C
Yield: 80.2 %

Procedure:
Potassium carbonate (8.0 g, 58.0 mmol) and iodoethane (3.0 mL, 37.7 mmol) were added to a stirred solution of 5-t-butyl-4-chloro-2-iodophenol (2.4 g, 8.1 mmol; prepared according to Fukata et al. Bull. Chem. Soc. Jpn. 1994, 67, 592-594) in 2-butanone (50 mL). The resulting mixture was heated in an oil bath (80° C.) for 16 h and then allowed to cool. The solution was concentrated and redisolved in methylene chloride. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated to give 4-tert-butyl-5-chloro-2-ethoxy-1-iodobenzene (2.2 g, 85%) as a yellow oil.
Reaction SMILES: O.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[OH-].[K+]>CC1C=CC(C(C)C)=CC=1>[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]([OH:18])=[O:17]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C1CCCCO1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccc(C(C)C)cc1
Product: O=C(O)CCCCc1c[nH]c2ccc(F)cc12
Reaction time: 80 h
Yield: 21.8 %

Procedure:
In a water separator, 5-fluoroindole (5.0 g, 37 mmol.), δ-valerolactone (3.83 ml, 42 mmol.), potassium hydroxide (3.09 g, 55 mmol.) in p-cymene (120 ml) were heated to boiling, with stirring. The water separation was stopped after 80 h. For working up, water (50 ml) was added to the mixture at RT and stirring was carried out for 30 min. The phases were then separated in a separating funnel. The aqueous phase was washed with ether (3×20 ml), adjusted to pH 1 with 2M HCl and extracted with ether (5×25 ml). The combined extracts were washed with water (5×10 ml), dried, filtered and concentrated. The residue was purified by flash chromatography on silica gel (375 g) (eluant: 2700 ml of cyclohexane/EE 4:1 followed by 1500 ml of cyclohexane/EE 1:1 and 650 ml of EE). 1.9 g of 5-(5-fluoro-1H-indol-3-yl)pentanoic acid were obtained (beige solid, m.p. 86–92° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH2:21][CH2:20]2)=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:38](=[O:40])[N:9]([CH2:10][C@H:11]3[CH2:12][CH2:13][C@H:14]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([C:25]([CH:27]5[CH2:29][CH2:28]5)=[O:26])[CH2:21][CH2:20]4)=[O:18])[CH2:15][CH2:16]3)[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1NC[C@H]1CC[C@H](C(=O)N2CCN(C(=O)C3CC3)CC2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C1CC1)N1CCN(C(=O)[C@H]2CC[C@H](Cn3c(=O)[nH]c4ccc(Cl)cc43)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of {trans-4-[(2-Amino-5-chloro-phenylamino)-methyl]-cyclohexyl}-(4-cyclopropane carbonyl-piperazin-1-yl)-methanone (448 mg, 1.07 mmol), triethylamine (0.45 mL, 3.22 mmol) in DCM (10 mL) was cooled at 0° C. Triphosgene (104 mg, 0.35 mmol) was added and the reaction was allowed to warm up to room temperature and left stirring for 18 hours. The reaction was diluted with 0.4 M Na2CO3 solution, the organic phase collected and the solvent removed under reduced pressure. The crude product was purified by SiO2 column eluting with ethylacectate-methanol (9:1), affording 230 mg of the pure product (49% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C:12](=[O:14])[CH2:11][CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[O:14]=[C:12]1[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(=O)CCC1C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CCC(=O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 23 h
Yield: 114.4 %

Procedure:
1-(tert-Butoxycarbonyl)-5-oxopiperidine-2-carboxylic acid (2.0 g, 8.22 mmol) was dissolved in DMF (20 mL) under nitrogen and potassium carbonate (1.7 g, 12.33 mmol) was added, followed by iodomethane (620 μL, 9.95 mmol). The reaction mixture was stirred at room temperature under nitrogen for 23 h. Additional methyl iodide (256 μL, 4.11 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2×25 mL) and brine (2×25 mL), then dried over sodium sulfate and concentrated to dryness. The crude residue was purified by flash column chromatography (Biotage), eluting with 0 to 100% ethyl acetate in heptanes, to afford the title compound (2.42 g, 53%) as a pale yellow oil. δH (250 MHz, CDCl3) 4.70 (dt, J 59.4, 6.3 Hz, 1H), 4.35 (dd, J 27.3, 19.0 Hz, 1H), 3.90 (dd, J 19.0, 12.4 Hz, 1H), 3.77 (s, 3H), 2.56-1.95 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)=[CH:18][C:17]=1[CH3:28]>C1(C)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:28][C:17]1[CH:18]=[C:19]([C:22]2[O:23][C:24]([CH3:27])=[N:25][N:26]=2)[CH:20]=[CH:21][C:16]=1[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]=1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: COC(=O)c1ccc([Sn](C)(C)C)nc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(-c3nnc(C)o3)cc2C)nc1
Reaction time: 2 h
Yield: 54.3 %

Procedure:
Methyl 6-(trimethylstannyl)nicotinate (D11, 0.300 g, 1.00 mmol) was dissolved in dry toluene (15 ml) and was treated with 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole (EP 0533268A1) (0.211 g, 0.834 mmol). The mixture was flushed with argon and bis(triphenyl phosphine)pallalladium (II) chloride (0.029 g, 0.042 mmol) was added. The mixture was then heated to reflux under argon. After 2 h, further methyl 6-(trimethylstannyl)nicotinate (0.030 g, 0.100 mmol) in toluene (2 ml) and bis(triphenylphosphine) palladium (II) chloride (0.010 g, 0.014 mmol) was added. Reflux was continued for a further 2 h before the reaction mixture was allowed to cool. The reaction mixture was then filtered through kieselguhr. The kieselguhr was washed with toluene (2×20 ml) and the filtrate was evaporated under reduced pressure to give a yellow/brown solid which was dried in vacuo (0.450 g). The solid was then purified by silica-gel chromatography (1:1 Petrol 60-80: EtOAc as eluant) to give the title compound as a cream coloured solid (0.140 g, 54%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Clc1ccc(Cl)c(CBr)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:14]1CCN2C(=NCCC2)CC1>C(=O)(OC)OC.CC(=O)OCC>[CH3:14][O:9][C:6]1[CH:7]=[CH:8][C:3]([S:2]([F:10])([F:11])([F:12])([F:13])[F:1])=[CH:4][CH:5]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Oc1ccc(S(F)(F)(F)(F)F)cc1
Solvent: COC(=O)OC
Solvent: CCOC(C)=O
Product: COc1ccc(S(F)(F)(F)(F)F)cc1
Yield: 41.4 %

Procedure:
5.00 g of 4-pentafluorosulfanylphenol were dissolved in 50.00 g of dimethyl carbonate and 3.46 g of DBU were added. The mixture was boiled under reflux for 10 hours, then allowed to cool and diluted with 200 ml of EA. Subsequently, the mixture was washed twice with 100 ml each time of a 5% aqueous HCl solution, then with 100 ml of a 5% aqueous NaOH solution. Drying was effected over MgSO4 and the solvent was removed under reduced pressure. Chromatography on silica gel using 1:1 DIP/HEP afforded 2.2 g of a colorless oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15]([O:19][C:20]([N:22]1[C@@H:26]([C@@H:27]([OH:39])[C@@H:28]([NH2:38])[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)[CH2:25][O:24][C:23]1([CH3:41])[CH3:40])=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(#N)C.C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[C@@H:26]([C@@H:27]([OH:39])[C@@H:28]([N:38]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:29][C:30]2[CH:31]=[C:32]([F:37])[CH:33]=[C:34]([F:36])[CH:35]=2)[CH2:25][O:24][C:23]1([CH3:41])[CH3:40])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)COC1(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Temperature: 25 °C
Yield: 86.9 %

Procedure:
Add benzyl bromide (75 mL, 630.55 mmol) to a suspension of potassium carbonate (85 g, 615.006 mmol) and (R)-4-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (80 g, 207.25 mmol) in acetonitrile (900 mL). Heat to reflux for 16 hours, cool to room temperature, and dilute with ethyl acetate (2 L). Wash with ammonium chloride (1.5 L), saturated aqueous sodium chloride (1.5 L), dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 5:95 to 20:80 ethyl acetate:hexanes) to give the desired compound as a white solid (102.1 g, 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([NH2:11])=O)([O-:3])=[O:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:9]([C:5]1[S:6][CH:7]=[CH:8][C:4]=1[N+:1]([O-:3])=[O:2])#[N:11]
Reactant: NC(=O)c1sccc1[N+](=O)[O-]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1sccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
The amide 30 (15.5 g, 90 mmol), prepared as described above, was dissolved in dichloromethane (700 ml). Triethylamine (27.2 g, 37.6 ml, 270 mmol) was added and the solution cooled to 0° C. After dropwise addition of neat trifluoroacetic anhydride (24.6 g, 16.5 ml, 117 mmol), the reaction was allowed to warm to room temperature and stirred for 1 h. The solution was concentrated in vacuo, the residue taken into ethyl acetate and then washed successively with hydrochloric acid (1N, 2×), water (1×), saturated aqueous sodium hydrogencarbonate (2×) and brine. Drying over sodium sulfate and removal of solvent gave a dark solid, which was purified by flash chromatography (400 g of silica gel, petroleum ether:ethyl acetate 7:3+1% MeOH as eluent) yielding 2-cyano-3-nitrothiophene 31 (13.4 g, 96.5%). 1H NMR (CDCl3): δ 7.75 (1H, d, J 5.5), 7.68 (1H, d, J 5.5). An analytical sample was obtained by recrystallization from dichloromethane/n-pentane, m.p. 87–88° C.; elemental analysis, calc. for C5H2N2O2S: C, 38.96; H, 1.31; N, 18.17; S, 20.80. Found: C, 38.92; H, 1.20; N, 18.03; S, 21.31.