Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10](=[O:12])[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[C:25]1([SH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[C:25]1([S:31][CH2:2][C:3]2[CH:4]=[CH:5][C:6]3[O:11][C:10](=[O:12])[C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=3[CH:18]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cc2cc(CCl)ccc2oc1=O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(CSc3ccccc3)ccc2oc1=O

Procedure:
A mixture of 1 g of ethyl 6-chloromethyl-2-oxo-2H-1-benzopyran-3-carboxylate (3.75 mmol), 0.57 g of potassium carbonate (4.13 mmol), 2.07 g of thiophenol (18.75 mmol) and 10 ml of absolute ethanol is reflux for 3 h. After removal of the solvent by distillation under reduced pressure, the residue is taken up in chloroform. The organic phase is washed with water and then dried over MgSO4. The solvent is removed by distillation under reduced pressure and the residue is washed with hexane to remove the excess thiophenol. The title product is recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[OH:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH2:16])[CH:12]=[CH:11][C:10]=1[N:17]1[S:21](=[O:23])(=[O:22])[NH:20][C:19](=[O:24])[CH2:18]1
Reactant: C=Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2-benzyloxy-4-vinylphenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (73 mg, 0.21 mmol) in CH2Cl2 (4 mL) at 0° C. is added dropwise 1M BBr3 (0.32 mL, 0.32 mmol) in CH2Cl2 and the reaction is stirred at 0° C. for 30 min. The mixture is quenched with water (1 mL) followed by washing with Et2O. The aqueous layer is concentrated under reduced pressure and the crude residue is purified by chromatography on a C18 column using a gradient of 0-15% EtOH/water as eluent to give the title compound: (M−H)−=253; 1H NMR (MeOD) δ 7.32 (d, J=8.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.79 (dd, J=8, 2 Hz, 1H), 4.69 (q, J=6.48 Hz, 1H), 4.26 (s, 2H), 2.63 (s, 1H), 1.34 (d, J=6.57 Hz, 3H).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12](Cl)[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[C:12]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH3:26])[N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1B(O)O
Reactant: C[C@H](Nc1nc(Cl)cc(-n2cnc3ccccc32)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1cc(-n2cnc3ccccc32)nc(N[C@@H](C)c2ccccc2)n1
Yield: 48.9 %

Procedure:
To a solution of 2-[(S)-1-phenylethylamino]-4-[benzimidazol-1-yl]-6-chloropyrimidine (30 mg) and 2-methylphenyboronic acid (18 mg) in 10:1 toluene:EtOH was added 1M Na2CO3 (0.215 mL) and Pd(PPh3)4 (5 mg). The resulting mixture was heated and maintained at reflux for 9 h, then cooled and filtered through MgSO4. The filtrate was concentrated under reduced pressure and purified by preparative thin layer chromatography (1:50 EtOAc:CH2Cl2) to give 17 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.58 (br s, 1H); 7.85-7.3 (m, 13H); 6.9 (s, 1H); 5.9 (br s, 1H); 5.25 (br s, 1H); 2.45 (br s, 3H); 1.7 (d, J=7.1 Hz, 3H). Mass spectrum (CI) 406.3 (M+1).
Reaction SMILES: [C:1]([C:3]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][N:8](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:7][CH2:6]1)#[N:2].C1(O)C=CC=CC=1.[OH-].[Na+]>Br>[C:1]([C:3]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(CC(C#N)(c3ccccc3)c3ccccc3)CC2)cc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: N#CC(CC1CCNCC1)(c1ccccc1)c1ccccc1
Yield: 76.5 %

Procedure:
A mixture of 4-(2-cyano-2,2-diphenylethyl)-1-(4-methylphenylsulphonyl)piperidine (20 g, 45 mmol--see Preparation 14) and phenol (20 g) in 48% aqueous hydrobromic acid (200 ml) was heated under reflux for 2 hours, basified with 2M aqueous sodium hydroxide (100 g) cautiously with ice-cooling and extracted into dichloromethane. The organic layer was dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (10.0 g, 77%) as a colourless powder which was characterised by its 1H-NMR spectrum.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([OH:29])=[CH:28][C:22]=2[S:21](=[O:31])(=[O:30])[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]([NH2:42])=[O:41]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([NH:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([O:29][CH2:39][C:40]([NH2:42])=[O:41])=[CH:28][C:22]=2[S:21](=[O:30])(=[O:31])[N:20]=1
Reactant: CC(C)CCNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Reactant: NC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)CCNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCC(N)=O)ccc3N2)c(O)c2ccccc21
Temperature: 165 °C
Yield: 70.2 %

Procedure:
The product of Example 323C (0.025 g, 0.057 mmol) was reacted with cesium carbonate (0.055 g, 0.17 mmol), 2-bromoacetamide (0.012 g, 0.087 mmol) and a catalytic amount of tetrabuylammonium iodide in N,N-dimethylformamide (3 mL) at 25° C. for 2 hours. The reaction was concentrated to half the volume under a stream of nitrogen warmed through a manifold heated to 165° C. The resulting solution was diluted with water and the precipitate was collected by filtration and dried to give the title compound (0.020 g, 72%). MS (ESI−) m/z 498 (M−H)−. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (m, 3H) 1.33 (m, 6 H) 1.54 (m, 2 H) 4.49 (s, 2 H) 5.90 (m, 1 H) 7.06 (m, 1 H) 7.21 (m, 2 H) 7.40 (m, 1 H) 7.55 (m, 2 H) 8.07 (dd, J=8.27, 1.29 Hz, 1 H) 16.23 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C=O>O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1nnc(SCc2ccccc2)s1

Procedure:
A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (39.9 g), potassium carbonate (41.4 g), α-chlorotoluene (38.0 g), and N,N-dimethylformamide (180 ml) is heated for 1.5 hours on a steam bath. The reaction mixture is drowned into water (1,000 ml) and the product collected by filtration and air dried. The crude product is recrystallized from ethanol and melts at 154°-156° C.
Reaction SMILES: [OH-].[Na+].[CH:3]1[CH2:7][CH:6]=[CH:5][CH:4]=1.[CH3:8][CH:9](Br)[CH2:10][CH3:11]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH3:8][CH:9]([C:4]1[C:3]([CH:3]([CH2:4][CH3:5])[CH3:7])=[C:7]([CH:9]([CH2:10][CH3:11])[CH3:8])[CH2:6][CH:5]=1)[CH2:10][CH3:11]
Reactant: CCC(C)Br
Reactant: C1=CCC=C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCC(C)C1=CCC(C(C)CC)=C1C(C)CC
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A double-walled reactor having a volume of 1 L, provided with baffles, condenser, top stirrer, thermometer and dropping funnel, was charged with 400 g of clear 50% strength NaOH (5 mol). Then 9.6 g of Aliquat 336 (24 mmol) and 15.2 g (0.23 mol) of freshly cracked cyclopentadiene were added. The reaction mixture was stirred vigorously for a few minutes, then 99.8 g of 2-butyl bromide (0.73 mol) were added over a period of half an hour, while the reaction mixture was cooled with circulating water at 10° C. After half an hour's stirring at room temperature, the reaction mixture was heated to 70° C., followed by a further three hours of stirring. Stirring was stopped and phase separation was performed. The aqueous layer was drawn off and 400 g (5.0 mol) of fresh 50% strength NaOH were added, followed by a further two hours of stirring at 70° C. GC was used to show that more than 90% of the mixture of di-, tri- and tetra(2-butyl)cyclopentadiene was trisubstituted cyclopentadiene. The product was distilled at 1 mbar and 91° C. After distillation, 40.9 g of tri(2-butyl)cyclopentadiene were obtained, which was characterized with GC, GC-MS, 13C- and 1H-NMR.
Reaction SMILES: [CH3:1]N1C2=NC=C(C3C=CN=CC=3)C=C2C(N)=N1.[CH2:18]([NH:20][C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:28]=2)[N:23]([CH3:36])[N:22]=1)[CH3:19]>>[CH2:18]([N:20]([CH3:1])[C:21]1[C:29]2[C:24](=[N:25][CH:26]=[C:27]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[CH:28]=2)[N:23]([CH3:36])[N:22]=1)[CH3:19]
Reactant: Cn1nc(N)c2cc(-c3ccncc3)cnc21
Reactant: CCNc1nn(C)c2ncc(-c3ccncc3)cc12
Product: CCN(C)c1nn(C)c2ncc(-c3ccncc3)cc12

Procedure:
E-56. Following the procedure described in Example E-1 but using in place of 1-methyl-5-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-3-amine a molar equivalent quantity of N-ethyl-1-methyl-5-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-3-amine, it is contemplated that there can be obtained N-ethyl-N,1-dimethyl-5-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-3-amine.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:1]([N:4]([C:17](=[O:19])[CH3:18])[C:5]1[N:6]=[C:7]([Br:10])[S:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1csc(Br)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(C(C)=O)c1csc(Br)n1
Yield: 10.7 %

Procedure:
A solution of 4-acetylamino-2-bromothiazole 10 g, prepared as described in Example 1, in acetic anhydride (100 ml) and pyridine (35 ml) was stirred at 100° C. for 24 hours. The reaction mixture was cooled and the excess acetic anhydride and pyridine removed in vacuo, and the residue was re-evaporated three times with toluene. The residue was purified by column chromatography using silica gel and eluting with chloroform, and recrystallised from hexane to give the title compound (1.2 g) m.p. 63°-65° C. (Found: C, 32.1; H, 2.8; N, 10.6 C7H7BrN2O2S requires C, 32.0; H, 2.7; N, 10.7%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C(N(C(C)C)CC)(C)C.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1,5-Dichloro-2-methyl-4-nitrobenzene (2.42 mmol, 500 mg) was dissolved in dry dimethylformamide (5 ml) and diisopropylethylamine (1 eq., 2.42 mmol, 0.413 ml), 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (1 eq., 2.42 mmol, 484 mg) were added at room temperature and the mixture was stirred at 100° C. overnight. The crude mixture was then cooled to room temperature and water was added; the aqueous solution was extracted with ethyl acetate (3×); organics were alternatively washed with brine and water. The organics were combined, dried over Na2SO4, filtered and the solvent was evaporated to afford the crude compound that was purified by chromatography (ethyl acetate/hexane) to yield the title compound, 98 mg, 11%, bright orange solid.
Reaction SMILES: C([N:5]1[C:9]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([CH2:18][N:19]3[CH2:24][C@@H:23]4[CH2:25][C@H:20]3[CH2:21][N:22]4[C:26](=[O:35])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=3[F:34])[N:12]=2)=[CH:8][CH:7]=[N:6]1)(C)(C)C>C(O)=O>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:26]([N:22]1[CH2:21][C@@H:20]2[CH2:25][C@H:23]1[CH2:24][N:19]2[CH2:18][C:13]1[N:12]=[C:11]([NH:10][C:9]2[CH:8]=[CH:7][NH:6][N:5]=2)[CH:16]=[C:15]([CH3:17])[N:14]=1)=[O:35]
Reactant: Cc1cc(Nc2ccnn2C(C)(C)C)nc(CN2C[C@@H]3C[C@H]2CN3C(=O)c2cccc(Cl)c2F)n1
Solvent: O=CO
Product: Cc1cc(Nc2cc[nH]n2)nc(CN2C[C@@H]3C[C@H]2CN3C(=O)c2cccc(Cl)c2F)n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
101 mg of N-(1-tert-butyl-1H-pyrazol-5-yl)-2-(((1S,4S)-5-(3-chloro-2-fluorobenzoyl) -2,5-diazabicyclo[2.2.1]hept-2-yl)methyl)-6-methylpyrimidine-4-amine was dissolved in 1 ml of formic acid followed by stirring at 100° C. for 3 hours. The reaction solution was concentrated in vacuo, diluted with ethyl acetate, and then washed with saturated sodium bicarbonate, water and saturated brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a reversed phase preparative liquid chromatography to give the title compound.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][C:8]=1[N+:15]([O-:17])=[O:16]>CCOCC>[Br:2][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH3:5])=[C:8]([N+:15]([O-:17])=[O:16])[CH:9]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc(CO)cc1[N+](=O)[O-]
Solvent: CCOCC
Product: COc1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 137.6 %

Procedure:
Under an argon atmosphere and cooling with ice, phosphorus tribromide (2.36 mL, 24.7 mmol) was added dropwise to a solution of (4-methoxy-3-nitrophenyl)methanol (12.2 g, 66.6 mmol) in anhydrous ether (350 mL) under stirring, and the mixture was stirred for 3.5 hours. Ice water (300 mL) was added to the reaction mixture. The organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was purified by means of silica gel column chromatography (eluent: n-hexane:ethyl acetate=2:1→1:1 v/v) to afford 8.36 g (51%) of the title compound as pale yellow crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.O[CH:12]([N:26]1[C@H:29]([CH2:30][C:31]([S:33][C@H:34]2[CH2:38][CH2:37][N:36]([C:39](=[N:41][C:42]([O:44][CH2:45][C:46]3[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][CH:47]=3)=[O:43])[CH3:40])[CH2:35]2)=[O:32])[C@H:28]([C@H:55]([O:57][C:58]([O:60][CH2:61][C:62]2[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=2)=[O:59])[CH3:56])[C:27]1=[O:71])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=O.C(N(CC)CC)C.P([O-])([O-])([O-])=O>C(Cl)Cl>[N+:52]([C:49]1[CH:50]=[CH:51][C:46]([CH2:45][O:44][C:42]([N:41]=[C:39]([N:36]2[CH2:37][CH2:38][C@H:34]([S:33][C:31]([CH2:30][C@H:29]3[N:26]([CH2:12][CH2:13][O:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=4)[C:27](=[O:71])[C@@H:28]3[C@H:55]([O:57][C:58]([O:60][CH2:61][C:62]3[CH:67]=[CH:66][C:65]([N+:68]([O-:70])=[O:69])=[CH:64][CH:63]=3)=[O:59])[CH3:56])=[O:32])[CH2:35]2)[CH3:40])=[O:43])=[CH:47][CH:48]=1)([O-:54])=[O:53]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2C(O)C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](SC(=O)C[C@@H]2[C@@H]([C@@H](C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)N2CCOCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.17 h
Yield: 72.5 %

Procedure:
110 mg (0.87 mmole) of oxalyl chloride were dissolved in 5 ml of methylene chloride. To the solution was added 137 mg (1.75 mmole) of dimethyl sulphoxide under a stream of a nitrogen gas at -780° C. The mixture was then stirred for 10 minutes, after which a solution of 500 mg (0.577 mmole) of (3R, 4R)-1-[1-hydroxy-1-(p-nitrobenzyloxycarbonyl)methyl]-4-([(S)-1-[N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-azetidinone was added to the mixture over 2 minutes. The mixture was stirred for 5 minutes and then 250 mg (2.48 mmole) of triethylamine were added thereto and the mixture was stirred for 15 minutes. About 30 ml of a 0.1M phosphate buffer solution (pH 7.1) was added to the mixture, which was then stirred and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulphate and the solvent was distilled off. The residue was quickly subjected to column chromatography through 10 g of silica gel eluted with 2:1 to 1:1 by volume mixtures of benzene and ethyl acetate, to afford 350 mg (yield 70%) of the title product as an oily substance. Infra-red and nuclear magnetic resonance spectra of the product agreed with those of the product obtained as described in Example 16(a)(iii).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:14].[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>CC(O)=O.O>[O:19]=[C:18]1[C:17]2[C:16](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15](=[O:20])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:12])[CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[OH:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CN(C)S(=O)(=O)c1ccc(N)c(O)c1
Solvent: O
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1ccc(N2C(=O)c3ccccc3C2=O)c(O)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A suspension of 4-amino-3-hydroxy-N,N-dimethylbenzenesulfonamide (120 mg, 0.555 mmol) and phthalic anhydride (82 mg, 0.555 mmol) in AcOH (3 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction was cooled and diluted with water to afford a suspension. The precipitate was filtered, washed with water and dried under high vacuum to afford the title compound as a pink solid (142 mg, 74%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].C(OCC)(=O)C.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[S:19])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COCC(c2cccc(Br)c2)(C(F)F)N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: FC(F)C1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
5-(3-Bromo-phenyl)-5-difluoromethyl-morpholin-3-one (6.10 g, 19.93 mmol) was dissolved in 63 ml dry pyridine, and P2S5 (5.32 g, 23.91 mmol) was added. The mixture was heated to 80° V for 2 hrs. After completion, the mixture was put between ethyl acetate and 1H HCl solution. Phases were separated and the organic phase was washed with 1 N HCl, saturated NaHCO3 solution and brine. The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 8.60 (s, 1H, NH), 7.80-7.35 (m, 4H), 6.54 (t, 1H, CHF2), 4.45 (m, 2H), 4.28 (d, 1H), 4.12 (d, 1H); MS: 322 [(M+H)+].
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13]C(C)(C)C)[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:11])[CH3:13]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-alanine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.16 (d, J=7.4, 1H), 7.57 (d, J=8.6, 2H), 6.62 (d, J=8.7, 2H), 4.36 (dd, J=13.0, 6.9, 1H), 3.53 (dd, J=10.2, 3.4, 1H), 3.39-3.33 (m, 1H), 3.29 (q, J=6.9, 1H), 3.22 (dd, J=9.7, 8.1, 1H), 3.01 (dd, J=9.9, 4.0, 1H), 2.77-2.63 (m, 2H), 2.42 (s, 3H), 2.20-2.13 (bs, 1H), 2.12-2.03 (m, 1H), 1.99-1.86 (m, 1H), 1.64 (dq, J=12.7, 7.9, 1H), 1.41 (d, J=6.8, 3H), 1.39-1.32 (m, 1H); MS (ESI+) m/z 356 (M+H)+.
Reaction SMILES: [NH:1]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C@H:2]([C:15]([O:17][CH3:18])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.O.[NH2:30][NH2:31].C([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl>C(O)C>[CH2:22]([O:21][C:19](=[O:20])[NH:1][CH:2]([C:15]1[O:17][CH:18]=[N:30][N:31]=1)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NN
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Agent: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(CC(NC(=O)OCc2ccccc2)c2nnco2)ccc1O
Reaction time: 8 h
Yield: 32.6 %

Procedure:
To a solution of Z-Tyr(3-tBu)-OMe (4.0 g, 10.39 mmol) in ethanol (100 ml), hydrazine monohydrate (6.4 ml, 103.9 mmol) was added at room temperature. The mixture was stirred overnight and evaporated under reduced pressure to remove the solvent. The thus obtained residue was mixed with ethyl orthoformate (100 ml) and p-toluenesulfonic acid monohydrate (198 mg, 1.04 mmol) at room temperature. The mixture was stirred for 1.5 hours and mixed with 1N HCl (100 ml). The mixture was stirred for 20 min., and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (1.34 g, 33%).