Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH2:9])[CH:5]=[C:4]([N:10]2[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]2)[N:3]=1.C(Cl)Cl.[CH2:19]([O:23][C:24](Cl)=[O:25])[CH2:20][CH2:21][CH3:22]>C(N(CC)CC)C>[N:10]1([C:4]2[N:3]=[C:2]([NH:1][C:24]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])=[O:25])[N+:7]([O-:8])=[C:6]([NH:9][C:24]([O:23][CH2:19][CH2:20][CH2:21][CH3:22])=[O:25])[CH:5]=2)[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]1
Reactant: Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)Nc1cc(N2CC=CCC2)nc(NC(=O)OCCCC)[n+]1[O-]
Temperature: 5 °C

Procedure:
20 G. of 2,4-diamino-6-[3,6-dihydro-1(2H)-pyridyl]pyrimidine-3-oxide are mixed with 250 ml. of methylene chloride and 35 ml. of triethylamine, stirred and cooled to 5° C. The mixture is treated with 45 ml. of chloroformic acid butyl ester and stirred at room temperature for 6 hours. The mixture obtained is washed with water, extracted with methylene chloride and evaporated under reduced pressure. The residue is recystallized from ethanol, there being obtained dibutyl 6-[3,6-dihydro-1(2H)-pyridyl]-2,4-pyrimidine-dicarbamate-3-oxide, having a melting point of 131°-132° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C1(C[C@H](N2CC(OC)=CC2=O)C(NC2C=CN(CC(OC)(C)C)N=2)=O)CCCC1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([NH:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])([CH3:28])[CH3:30])[N:22]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)OC)n2)C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1

Procedure:
A solution of (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (138 mg, 0.52 mmol), 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 98 mg, 0.63 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (326 mg, 0.75 mmol), N,N-diisopropylethylamine (200 mg, 1.54 mmol) in dichloromethane (10 mL) was stirred for 18 h under nitrogen at 23° C. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g silica gel; 0% to 10% methanol/dichloromethane) to afford, (S)-3-cyclopentyl-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (123 mg, 59%) as a white foam, LR-ES-MS m/z calculated for C21H32N4O4 [M]+ 404, observed [M+H]+ 405; 1H NMR (300 MHz, CDCl3) δ ppm 0.78-1.31 (m, 7H) 1.15 (s, 6H) 1.55-1.77 (m, 5H) 1.77-1.95 (m, 2H) 3.82 (s, 3H) 3.87 (d, J=17.8 Hz, 1H) 3.94 (s, 2H) 4.05 (d, J=17.8 Hz, 1H) 4.92 (dd, J=9.5, 5.9 Hz, 1H) 5.14 (s, 1H) 6.67 (d, J=2.1 Hz, 1H) 7.28 (d, J=2.1 Hz, 1H) 8.72 (br. s., 1H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:16][CH2:17][CH:18]1[CH2:22][C:21]2[C:23]([CH3:37])=[C:24]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]([CH3:28])=[C:26]([CH3:27])[C:20]=2[O:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]1(=[O:67])[NH:61][C:60](=[O:62])[C:59]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:58]12>O1CCCC1>[CH2:30]([O:29][C:24]1[C:25]([CH3:28])=[C:26]([CH3:27])[C:20]2[O:19][CH:18]([CH2:17][CH2:16][N:61]3[C:57](=[O:67])[C:58]4=[CH:66][CH:65]=[CH:64][CH:63]=[C:59]4[C:60]3=[O:62])[CH2:22][C:21]=2[C:23]=1[CH3:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCO)O2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCN1C(=O)c3ccccc3C1=O)O2
Reaction time: 2 h
Yield: 94.3 %

Procedure:
5.7 ml of diisopropyl azodicarboxylate is added, dropwise, to a mixture of 6.0 g of 2-(RS)-(2-hydroxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane cold to 0° C., 7.6 g of triphenylphosphine and 3.1 g of phthalimide in 35 ml of anhydrous tetrahydrofurane. After these additions, the mixture is brought to room temperature and stirred for 2 hours. After the solvent has been evaporated, the residue is purified with chromatography column (SiO2), which produces 8.0 g of N-[2-(2,3-dihydro-5-benzyloxy-4,6,7-trimethyl-2-benzofuranyl)ethyl]phthalimide m.p. 108°-110° C.: IR(KBr): 1772, 1716 cm-1 (νO=CNC=O). The phthalimide thus obtained is solubilized in a mixture of 50 ml of tetrahydrofurane and 20 ml of absolute ethanol. 3.2 ml of hydrated hydrazine are added dropwise and the mixture is kept under reflux with stirring for 2 hours. After the mixture has been brought to room temperature the formed phthalhydrazine is filtered out, and the filtrate is concentrated to a volume of about 20 ml. The additional phthalhydrazine which forms is filtered out. After the solvent is evaporated from the filtrate, the residue is treated with ethylic ether saturated with HCL to obtain the precipitate of the hydrochloride of the product. The precipitate is filtered under a vacuum, which gives 4.0 g of a white solid. m.p. 192°-193° C.; IR (KBr): 3032 cm-1 (νNH3 +); 1H-NMR (CD3OD): δ7.5-7.2 (5H,m), 4.7 (2H,s), 3.4-2.7 (4H,m), 2.4-2.2 (2H,m), 2.2 (6H,s), 2.1 (3H,s).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH2:5][C:6](Cl)([Cl:8])[Cl:7])[CH:3]1[C:10]([O:12][CH3:13])=[O:11].N1CCCC1>CN(C)C=O>[Cl:7][C:6]([Cl:8])=[CH:5][CH:4]1[CH:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:1])[CH3:14]
Reactant: COC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: COC(=O)C1C(C=C(Cl)Cl)C1(C)C

Procedure:
A mixture of 2.6 g (0.01 mol) of methyl 2,2-dimethyl-3-(2,2,2-trichloroethyl)cyclopropane-1-carboxylate (compound Z, C/T=80/20), 1.0 ml of pyrrolidine, and 20 ml of dimethylformamide was heated at 100° for 20 hours to give, by glpc analysis, 68.5% cis and 24.0% trans (C/T=74/26) methyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane-1-carboxylate, compound C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH3:8])[C:4]([C:9]([F:12])([F:11])[F:10])=[N:3]1.[OH-].[K+].Cl[CH:16]([F:18])[F:17].O>CC(O)C>[F:17][CH:16]([F:18])[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([C:9]([F:11])([F:10])[F:12])[C:5]=1[CH3:8]
Reactant: FC(F)Cl
Reactant: Cc1c(C(F)(F)F)nn(C)c1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Reaction time: 2 h
Yield: 88.5 %

Procedure:
Into 78.6 g (436.4 mmol) of 1,4-dimethyl-5-hydroxy-3-trifluoromethyl-1H-pyrazole in 500 ml of 2-propanol was added 153.1 g (2728.6 mmol) of powdery potassium hydroxide at room temperature, followed by stirring. Furthermore, an excess amount of chlorodifluoromethane was introduced into the reaction solution under stirring. Thereafter, the reaction temperature once rose to 70° C. by exothermic heat and then returned to room temperature after 2 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was distilled to obtain 88.9 g (yield: 88.5%) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:17]([CH2:19][CH2:20][CH2:21][CH3:22])[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCc1nc(Br)sc1C(=O)OCC
Reactant: CC(C)(C)OC(=O)NC1CNC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nc(N2CC(NC(=O)OC(C)(C)C)C2)sc1C(=O)OCC
Yield: 74.4 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (212 mg, 1.23 mmol), ethyl 2-bromo-4-n-butyl-1,3-thiazole-5-carboxylate obtained in Example (220b) (300 mg, 1.03 mmol) and diisopropylethylamine (0.36 mL, 2.06 mmol), to obtain 294 mg of the title compound as a white solid (74%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)#[N:6]>O.CN(C=O)C.C1(C)C=CC=CC=1>[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]=[N+:2]=[N-:3])=[CH:9][CH:8]=1)#[N:6]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CN=[N+]=[N-])cc1

Procedure:
A solution of 20.23 g (0.31 mol) sodium azide in 50 ml water was added to 49.15 g (251 mmol) 4-cyanobenzyl bromide in 200 ml DMF at ambient temperature. An exothermic reaction took place and after 1.5 h the reaction mixture was diluted with 200 ml toluene(caution: In order to avoid separation of potentially explosive azide compounds it is adviceable to add the toluene to the rection mixture before addition of the water) and 500 ml water. The aqueous phase was extracted with an additional 2×50 ml toluene. The combined organic extracts were washed with 2×50 ml water and brine and finally dried (MgSO4) and filtered. The solution was used as such in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4](F)[C:3]=1[F:20].[N:21]1([C@H:26]2[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27]2)[CH:25]=[CH:24][CH:23]=[N:22]1.C(N(C(C)C)CC)(C)C>CS(C)=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]([C:17]#[N:18])=[CH:12][N:7]3[C@@H:8]([CH3:11])[CH2:9][O:10][C:5]([C:6]=23)=[C:4]([NH:31][C@H:28]2[CH2:29][CH2:30][C@H:26]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)[CH2:27]2)[C:3]=1[F:20]
Reactant: C[C@H]1COc2c(F)c(F)c(N)c3c(=O)c(C#N)cn1c23
Reactant: N[C@H]1CC[C@H](n2cccn2)C1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COc2c(N[C@H]3CC[C@H](n4cccn4)C3)c(F)c(N)c3c(=O)c(C#N)cn1c23
Temperature: 100 °C
Reaction time: 7 h
Yield: 14.6 %

Procedure:
A mixture of (3S)-8-amino-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (580 mg, 2.09 mmol), trans-3-(1H-pyrazol-1-yl)cyclopentylamine (380 mg, 2.51 mmol) and di-isopropylethylamine (0.80 mL, 4.59 mmol) in anhydrous DMSO (12 mL) was stirred at 100° C. for 7 h. After cooling, the reaction mixture was poured into ice-water and then extracted with CH2Cl2-MeOH. The organic layer was washed with water and brine, and dried over anhyd Na2SO4 followed by the removal of solvent. The crude product was purified by column chromatography (EtOAc) to yield (3S)-8-amino-9-fluoro-2,3-dihydro-3-methyl-7-oxo-10-[trans-3-(1H-pyrazol-1-yl)cyclopentylamino]-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carbonitrile (125 mg, 15%) as a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH2:7][CH2:6]2.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>C(Cl)CCl>[Cl-:15].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N+:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]=2)=[CH:18][CH:17]=1
Reactant: COc1cc2c(cc1OC)CCN=C2
Reactant: ClCc1ccc(Cl)cc1
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)CC[N+](Cc1ccc(Cl)cc1)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 6,7-dimethoxy-3,4-dihydroisoquinoline and 4-chlorobenzyl chloride in ethylene chloride. Melting point: 182°-184° C. (Decomp.)
Reaction SMILES: OC(C(F)(F)F)=O.[C@H:8]12[CH2:14][C@H:11]([NH:12][CH2:13]1)[CH2:10][N:9]2[C:15]([C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][C:34]=1[F:35])[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[NH:23][N:22]=1)=[O:16].[O:36]1[CH:40]=[CH:39][CH:38]=[C:37]1[C:41](=[O:45])[C:42](O)=[O:43].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:34]1[CH:33]=[CH:32][C:19]([CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24](=[O:31])[NH:23][N:22]=2)=[CH:18][C:17]=1[C:15]([N:9]1[CH2:10][C@@H:11]2[CH2:14][C@H:8]1[CH2:13][N:12]2[C:42](=[O:43])[C:41]([C:37]1[O:36][CH:40]=[CH:39][CH:38]=1)=[O:45])=[O:16]
Reactant: O=C(O)C(=O)c1ccco1
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1C[C@@H]2C[C@H]1CN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)c1ccco1
Temperature: 25 °C
Reaction time: 60 h
Yield: 51.7 %

Procedure:
4-(3-((1S,4S)-2,5-diazabicyclo[2,2,1]heptane-2-carbonyl)-4-fluorobenzyl)phthalazin-1 (2H)-one TFA salt (200 mg, 0.41 mmol), 2-(furan-2-yl)-2-oxoacetic acid (352 mg, 2.52 mmol), DIPEA (0.63 ml, 3.78 mmol), and HATU (320 mg, 0.84 mmol) were mixed in DMF (30 ml). After the resulting reaction mixture was stirred at room temperature for 60 h, the reaction mixture was partition between DCM and water (100 ml each). The aqueous phase was extracted with DCM (100 ml), and the combined organic phase was washed with water, sat. aqueous sodium bicarbonate, and brine, dried over sodium sulphate, filtered, and concentrated to yield the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford the desired product (106 mg, 50.5%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])=[O:10])[CH:7]=1.[H-].[Na+].[C:33]([CH:37]1[CH2:39][O:38]1)([CH3:36])([CH3:35])[CH3:34].O>CN(C=O)C>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([C:25]3[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=3)[CH:20]=2)=[CH:4][C:5]([F:17])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH2:39][CH:37]([OH:38])[C:33]([CH3:36])([CH3:35])[CH3:34])[C:12]2=[O:16])=[O:10])[CH:7]=1
Reactant: CC(C)(C)C1CO1
Reactant: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCNC4=O)cc3Cl)ccn2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)N4CCN(CC(O)C(C)(C)C)C4=O)cc3Cl)ccn2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
A 0° C. solution of Example C9 (0.30 g, 0.696 mmol) in DMF (3 mL) was treated with NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred at RT for 0.5 h, treated drop-wise with 2-(tert-butyl)oxirane (0.139 g, 1.393 mmol), stirred at RT for 1 h, then heated at 60° C. overnight. Additional 2-(tert-butyl)oxirane (0.1 mL) was added, the mixture heated at 60° C. for 7 h, cooled to RT, treated with additional NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred for 20 min, treated with -(tert-butyl)oxirane (0.139 g, 1.393 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, treated with water, extracted with EtOAc (3×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc, MeOH/DCM) to afford N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide (29 mg, 7.5%). 1H NMR (400 MHz, DMSO-d6): δ 10.95 (d, J=2.7 Hz, 1 H), 8.41 (d, J=8.1 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 7.97 (s, 1 H), 7.57 (d, J=11.3 Hz, 1 H), 7.20 (d, J=2.5 Hz, 1 H), 6.64 (dd, J=5.7, 2.5 Hz, 1 H), 4.84 (d, J=5.5 Hz, 1 H), 3.84 (s, 3 H), 3.80 (m, 2 H), 3.58 (m, 2 H), 3.31 (m, 2 H), 3.05 (m, 1 H), 0.87 (s, 9H); MS (ESI) m/z: (M+H+): 531.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Br:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[S:21](Cl)(=[O:23])=[O:22])=[CH:15][CH:14]=1>>[Br:12][C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22])=[CH:15][CH:14]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Br)nc1
Reactant: Nc1ccccc1S(N)(=O)=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccc(Br)nc1
Yield: 69 %

Procedure:
The title compound was synthesized as described for Example 178 in 69% yield, starting from 2-aminobenzenesulfonamide and (E)-2-(6-bromopyridin-3-yl)ethenesulfonyl chloride. Purification by column chromatography, using ammonium hydroxide/methanol/chloroform (1:10:89) as the eluent.
Reaction SMILES: [C:1]([N:4]([CH2:26][C@@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:44][CH2:43][S:42](=[O:46])(=[O:45])[CH2:41][CH2:40]3)=[C:35]([F:47])[CH:34]=2)[CH2:28]1)[C:5]([O:7][CH:8]([O:10][C:11](=[O:25])[C@@H:12]([NH:17]C(OC(C)(C)C)=O)[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH3:9])=[O:6])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.C1COCC1.[ClH:61]>C(OCC)C>[ClH:61].[C:1]([N:4]([CH2:26][C@@H:27]1[O:31][C:30](=[O:32])[N:29]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]3[CH2:40][CH2:41][S:42](=[O:45])(=[O:46])[CH2:43][CH2:44]3)=[C:35]([F:47])[CH:34]=2)[CH2:28]1)[C:5]([O:7][CH:8]([O:10][C:11](=[O:25])[C@@H:12]([NH2:17])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)OC(C)OC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
2(S)-tert-butoxycarbonylamino-3(S)-methyl-pentanoic acid 1-(acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamoyloxy)-ethyl ester (12j) (1.00 g, 1.46 mmol), anisole (0.24 g, 2.188 mmol) and THF (30 mL) are cooled in an ice bath. Hydrochloric acid (4 N in dioxane, 10.94 mL) is added dropwise. The solution is stirred in an ice bath for 30 min and then at RT for 4 h. The reaction mixture is re-cooled to 0° C. and ethyl ether is added. The resulting solids are collected by filtration and washed with a cold ethyl ether/ethyl acetate mixture to afford the title compound. Isolated yield: 64%. 1H NMR (400 MHz, DMSO-d6): δ 8.46 (br s, 3H), 7.43-7.39 (m, 1H), 7.36 (t, 1H), 7.22 (d, 1H), 6.85-6.79 (m, 1H), 4.77-4.71 (m, 1H), 4.13-4.00 (m, 2H), 3.96 (dd, 1H),3.88-3.84 (m, 1H), 3.80-3.74 (m, 1H), 3.51-3.28 (m, partially obscured by water, 2H), 3.18-3.12 (m, 1H), 3.04 (d, 2H), 2.40 (d, 3H), 2.08 (q, 2H), 1.97-1.93 (m, 2H), 1.90-1.84 (br m, 1H), 1.50 (dd, 3H), 1.44-1.36 (m, 1H), 1.26-1.14 (m, 1H), 0.88 (dd, 3H), 0.84-0.79 (m, 3H).
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6]>C(O)(=O)C.O.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[O:1]=[C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH:11]([CH3:13])[CH2:10][CH2:9][CH:8]1[CH:14]([CH3:16])[CH3:15])=[O:6]
Reactant: CC1CCC(C(C)C)C(C(=O)NCC(O)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1CCC(C(C)C)C(C(=O)NCC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
A 20 mL round bottom flask equipped with a stir bar was charge with 2-Isopropyl-5-methyl-cyclohexanecarboxylic acid (2-hydroxy-2-phenyl-ethyl)-amide (100 mg, 0.33 mmol) and acetic acid (1 mL). A solution of CrO3 (36 mg, 0.363 mmoles, 1.1 eq) in acetic acid (500 μl) and water (100 μl) was slowly added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 15 min and diluted with ethyl acetate (30 mL) and saturated NaHCO3 (aq.) (30 mL). The heterogeneous mixture was transferred to a reparatory funnel where the aqueous phase was separated and re-extracted with ethyl acetate (2×10 mL). The organic phases were combined and washed with sat NaHCO3 (3×10 mL), H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% to 50% ethyl acetate/hexane for elution) provided the title compounds as white solid (92 mg, 93%).
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(N1C=CN=C1)=[O:2].[CH3:13]NN(CC)NC.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:23][CH:22]=1>O1CCCC1>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([S:27][CH:28]2[CH2:32][CH2:31][N:30]([C:1]([NH:8][CH2:12][CH2:11][N:10]([CH3:9])[CH3:13])=[O:2])[CH2:29]2)=[CH:25][CH:26]=1
Reactant: CCN(NC)NC
Reactant: Clc1ccc(SC2CCNC2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCC(Sc2ccc(Cl)cc2)C1
Yield: 69.7 %

Procedure:
A solution of 5.20 g (0.032 mole) of 1,1'-carbonyldiimidazole and 2.73 g (0.031 mole) of N,N-dimethylaminoethylamine in 200 ml of tetrahydrofuran was stirred at room temperature for 50 min. A solution of 5.63 g (0.0264 mole) of 3-[(4-chlorophenyl)thio]pyrrolidine (free base) in tetrahydrofuran was added and the solution was refluxed for about 66 hr. The solvent was removed in vacuo and the resulting oil was dissolved in methylene chloride. The methylene chloride solution was extracted with several portions of water and was dried over magnesium sulfate. The solvent was removed in vacuo and the resulting solid was recrystallized from methylene chloride-diethyl ether-hexane to give 6.03 g (69.7%) of white crystals, m.p. 97°-98.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21]O)=[CH:16][CH:15]=1)#[N:13].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OCCc2ccc(C#N)cc2)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
4-Methyl-3-nitrophenol (0.765 g; 5.0 mmol), 2-(4-cyanophenyl)ethanol (0.735 g; 5.0 mmol) and diethylazodicarboxylate (0.87 g; 5.0 mmol) were dissolved in THF (20 mL). Triphenylphosphine (1.31 g; 5.0 mmol), dissolved in THF (5 mL), was added and the solution stirred overnight. Evaporation in vacuo and the addition of diethyl ether afforded a yellow solid that was recrystallized from water:acetone (9:1), affording the sub-title compound as yellowish crystals. Yield: 1.04 g (74%).