Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)([C:14]#[N:15])[CH3:13])[N:10]=[C:4]2[CH:3]=1.[Br:30]N1C(=O)CCC1=O>C(#N)C>[Br:30][C:8]1[N:9]([CH2:11][C:12]([NH:16][C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)([C:14]#[N:15])[CH3:13])[N:10]=[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[N:6][C:5]=12
Reactant: CC(C#N)(Cn1cc2ncc(Cl)cc2n1)NC(=O)c1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C#N)(Cn1nc2cc(Cl)cnc2c1Br)NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 60 °C
Yield: 78.6 %

Procedure:
A mixture of N-[2-(6-Chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-4-trifluoromethoxybenzamide (134 mg described in Example 155) and N-bromosuccinimide (68 mg) in acetonitrile (3.5 mL) was heated to 60° C. overnight. The mixture was concentrated under reduced pressure to yield a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (125 mg, 80%). MS (ES): M/Z [M+H]=502. 1H NMR: (400 MHz, DMSO-d6): 1.78 (s, 3H), 5.10-5.22 (m, 2H), 7.52 (d, J=8.2 Hz, 2H), 7.98 (d, J=8.7 Hz, 2H), 8.43 (d, J=2.0 Hz, 1H), 8.58 (d, J=1.9 Hz, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −57.1 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:15][CH:14]3[N:16]([CH3:17])[CH:10]([CH2:11][CH2:12][CH2:13]3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][CH2:28]Br>C(O)C>[NH3:1].[N:1]1([C:2]2[CH:3]=[C:4]([C:8]3[CH2:9][CH:10]4[N:16]([CH3:17])[CH:14]([CH2:13][CH2:12][CH2:11]4)[CH:15]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: BrCCCCBr
Reactant: CN1C2C=C(c3cccc(N)c3)CC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1C2C=C(c3cccc(N4CCCC4)c3)CC1CCC2
Product: N

Procedure:
A mixture of (±)-3-(3-aminophenyl)-9-methyl-9-azabicyclo[3.3.1]non-2-ene (0.50 g, 2.2 mmol), potassium carbonate (0.61 g, 4.4 mmol), 1.4-dibromobutane (0.52 g, 2.4 mmol) and ethanol (15 ml) was stirred at reflux overnight. The mixture was evaporated and water (25 ml) was added followed by extraction two times with ethyl acetate (25 ml). Chromatography on silica gel with dichloromethane, methanol and conc. ammonia (89:10:1) gave the title compound as an oil. Yield 0.12 g, 19%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:26][CH2:27][CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:42][C:43](O)=[O:44].C(Cl)Cl>CCCCCCC.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:29])[CH:10]([O:26][CH2:27][CH3:28])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:43](=[O:44])[CH2:42][C:32]2[N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:35][C:31]=2[CH3:30])=[C:14]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccccc2)nc1CC(=O)O
Reactant: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(Cc1ccc(OC(=O)Cc2nc(-c3ccccc3)oc2C)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid benzyl ester (45 mg, 0.11 mol) and (5-methyl-2-phenyl-oxazol-4-yl)-acetic acid (25 mg, 0.11 mmol) in dry DCM (2.0 mL) first DMAP (2.8 mg, 0.02 mmol) and then EDCxHCl (26.5 mg, 0.13 mmol) was added and the mixture was stirred under nitrogen atmosphere at room temperature for 17 h. The solvent was removed under vacuo and the product was isolated out of the remaining oil by column chromatography using n-heptane/EtOAc (4:1) as the eluent. The title compound was obtained as an oil (56.1 mg, 82.6%). 1H NMR (400 MHz, CDCl3): δ 7.95 (m, 2H), 7.40 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 6.98-67.20 (m, 10H), 5.08, (d, 2H), 3.97 (t, 1H), 3.85 (s, 2H), 3.70 (s, 2H), 3.55 (m, 1H), 3.28 (m, 1H), 2.93 (d, 2H), 2.32 (s, 3H), 1.1 (t, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[CH:18]=2)=[C:6]([CH3:8])[N:7]=1.[BrH:19].[NH+]1C=CC=CC=1.O.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.O1CCCC1>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]3[C:18]=2[Br:19])=[C:6]([CH3:8])[N:7]=1
Reactant: CNc1nc(C)c(-c2cn3ccc(C)cc3n2)s1
Reactant: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CNc1nc(C)c(-c2nc3cc(C)ccn3c2Br)s1

Procedure:
To a solution of 2-(2-methylamino-4-methylthiazol-5-yl)-7-methylimidazo[1,2-a]pyridine (1.92 g) in a mixture of acetic acid (14 ml) and tetrahydrofuran (10 ml) was added pyridinium hydrobromide perbromide (2.6 g) at ambient temperature and the mixture was stirred for an hour. The reaction mixture was poured into water and the resultant aqueous solution was adjusted to pH 7.5 with saturated potassium carbonate. The product was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of methylene chloride and diethyl ether to give 2-(2-methylamino-4-methylthiazol-5-yl)-3-bromo-7-methylimidazo[1,2-a]-pyridine (2.2 g).
Reaction SMILES: [H-].[Na+].O1[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:8][C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([S:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])[NH:15][C:11]=2[CH:10]=1.Cl[C:30]1[CH:37]=CC(Cl)=[CH:34][C:31]=1[CH2:32]Cl>O>[CH3:4][C:5]1[CH:37]=[CH:30][C:31]([CH3:34])=[CH:32][C:6]=1[CH2:7][N:15]1[C:11]2[CH:10]=[C:9]([CH3:8])[C:27]([CH3:28])=[CH:26][C:12]=2[N:13]=[C:14]1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[N:25]
Reactant: Cc1cc2nc(SCc3ccccc3C#N)[nH]c2cc1C
Reactant: ClCc1cc(Cl)ccc1Cl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C)c(Cn2c(SCc3ccccc3C#N)nc3cc(C)c(C)cc32)c1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 37 %

Procedure:
Sodium hydride (178 mg, 4.90 mmol) and tetrahydrofuran (30 ml) were added to a previously dried reaction vessel. To the mixture were added 2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzenecarbonitrile (719 mg, 2.45 mmol) and 2,5-dichlorobenzyl chloride (543 μl, 4.90 mmol), and the mixture was stirred at 60° C. for 40 minutes. Water was added thereto, followed by extraction with ethyl acetate. After the ethyl acetate phase was dried with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 2-((1-((2,5-dimethylphenyl)methyl)-5,6-dimethylbenzimidazole-2-ylthio)methyl)benzenecarbonitrile (370 mg, yield 37%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:17]O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:30])(=O)=O.O>ClCCl>[Cl:30][CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:9]=[CH:10]2
Reactant: OCc1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Fc1ccc(-n2ccc3cc(CCl)ccc32)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 118.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-hydoxymethyl-1H-indole (10a) (21.5 g) and triethyl amine (21.5 mL) in dichloromethane a solution of methanesulfonyl chloride (15.3 g) in dichloromethane was added at 0-5° C. After stirring at 0-5° C. for 2 h, water (600 mL) was added the phases were separated and the aqueous phase was extracted with dichloromethane (500 mL). The combined organic phases were dried (MgSO4) and the solvents evaporated affording 5-chloromethyl-1-(4-fluorophenyl)-1H-indole as an oil (27.5 g). A solution of the crude chloromethyl derivative in dimethyl sulfoxide was added to a solution of sodium cyanide in dimethyl sulfoxide at 80° C. After heating of the reaction mixture at 80° C. for further 40 minutes, the reaction mixture was cooled to room temperature and water (900 ml) was added. The resulting mixture was extracted with diethyl ether (2×1.5 L) and the combined organic phases were washed with brine (2×1.5 L). Drying of the combined organic phases (Na2SO4), evaporation of the solvents and purification by column chromatography on silica gel (ethyl acetate/heptane 1:3) afforded pure 5-cyanomethyl-1-(4-fluorophenyl)-1H-indole as an oil (8.2 g): 1H NMR (CDCl3) δ 3.80 (s, 2H), 6.60 (d, 1H), 7.05-7.25 (m, 3H), 7.25 (d, 1H), 7.35-7.45 (m, 3H), 7.60 (broad s, 1H).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:16][CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
Boc-Val-OH (8.69 g, 40.0 mmol) and Gly-OBzl.HCl (8.07 g, 40.0 mmol) were dissolved in methylene chloride (100 ml), and the solution was maintained at 0° C. Triethylamine (6.13 ml, 44.0 mmol), HOBt (1-hydroxybenzotriazole, 6.74 g, 44.0 mmol), and WSC.HCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 8.44 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml× twice), saturated brine (50 ml), 5% sodium hydrogencarbonate aqueous solution (50 ml× twice), and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, then the magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain white crystals of Boc-Val-Gly-OBzl (13.2 g, 36.2 mmol).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[C:3]=1[Cl:13].[CH3:14][O-:15].[Na+].[Cl-].[NH4+]>CO>[Cl:13][C:3]1[C:4]([CH3:12])=[N:5][CH:6]=[C:7]([C:2]=1[O:15][CH3:14])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cnc(C)c(Cl)c1Cl
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(C)c(Cl)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.4 %

Procedure:
Crude methyl 4,5-dichloro-6-methylnicotinate (380 mg) was dissolved in 3 ml of methanol and, in a nitrogen stream, sodium methoxide (120 mg) was then added to the solution under cooling on ice. The temperature of the reaction solution was gradually raised to room temperature, and it was stirred for 18 hours. After the disappearance of the materials had been confirmed, a saturated ammonium chloride aqueous solution was added to the reaction solution under cooling on ice, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled away. The residue was purified by silica gel chromatography (ethyl acetate-hexane), so as to obtain the title compound (210 mg) as a solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:33]=[C:34]([CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:35]=3)[C:10]([C:13]3[CH:32]=[CH:31][C:16]([C:17]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([O:26]C(C)(C)C)=[O:25])=[O:18])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[C:48]([OH:54])([C:50]([F:53])([F:52])[F:51])=[O:49].C(Cl)Cl>>[F:51][C:50]([F:53])([F:52])[C:48]([OH:54])=[O:49].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([CH:33]=[C:34]([CH2:36][CH2:37][C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)[N:35]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([N:19]4[CH2:23][CH2:22][CH2:21][C@H:20]4[C:24]([OH:26])=[O:25])=[O:18])=[CH:31][CH:32]=3)=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H]1CCCN1C(=O)c1ccc(-c2cnc(N3CCOCC3)c3nc(CCc4ccc5ccccc5n4)cn23)cc1
Yield: 30 %

Procedure:
A solution of compound 17b (350 mg, 0.550 mmol) in TFA/DCM (10 mL, 1:4 v/v) was stirred at rt for 3 h. Solvent was evaporated and Et2O (30 mL) was added. The resulting solids were collected by filtration and washed with Et2O to obtain the title compound 35 as a yellow solid (142 mg, 30% yield). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 9.01 (d, J=8.8 Hz, 1H), 8.31 (d, J=8.0 Hz, 1H), 8.16-8.09 (m, 2H), 8.02 (d, J=8.8 Hz, 1H), 7.94-7.90 (m, 1H), 7.80 (s, 1H), 7.72-7.53 (m, 4H), 7.38-7.34 (m, 1H), 4.44-4.35 (m, 1H), 3.81-3.73 (m, 4H), 3.61-3.50 (m, 4H), 3.45-3.31 (m, 6H), 2.43-2.28 (m, 1H), 1.90-1.78 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H32N6O4: 577.2 (M+H). Found 577.1.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][OH:6].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:6][CH2:5][CH2:4][CH:3]([C:2]([F:11])([F:12])[F:1])[CH2:7][CH2:8][CH2:9][CH3:10])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: CCCCC(CCO)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reaction time: 2 h
Yield: 92 %

Procedure:
0.48 g of 3-trifluoromethyl-1-heptanol was dissolved in 0.79 g of pyridine, and the solution was cooled with ice, followed by addition of 0.5 g of p-toluenesulfonyl chloride, stirring for 2 hours under cooling with ice and stirring for 2 hours at room temperature. After the reaction, the product was acidified with 2N-hydrochloric acid and extracted with methylene chloride. The resultant methylene chloride solution was washed with water and dried with magnesium sulfate, and the solvent was distilled off, whereby 3-trifluoromethylheptyl p-toluenesulfonate was obtained in an amount of 0.82 g (yield: 92%) and showed: [α]D23 +0.5, [α]D23 +2.2 (c 2, methylene chloride).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C.C(Cl)CCl>CN(C)C1C=CN=CC=1>[CH3:18][O:17][N:16]([CH3:15])[C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: CNOC
Reactant: Cc1ccccc1CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2-methylphenyl)acetic acid in dry methylene chloride (16.7 g, 108.4 mmol) under nitrogen atmosphere was added N,O-dimethylhydroxylamine (13.8 g, 141.5 mmol), triethylamine (20 mL, 143.8 mmol), 4-dimethylaminopyridine (DMAP, 14.2 g, 119.3 mmol) and EDC (27 g, 140.6 mmol). The reaction mixture was stirred at RT for 2 hr then transferred to a separation funnel. The mixture was washed consecutively with 2 N aq. HCl, brine, saturated aq. NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and the solvent evaporated under vacuum to give 21 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.20 (4H, m), 3.80 (2H, s), 3.65 (2H, s), 3.65 (3H, s), 2.34 (3H, m).
Reaction SMILES: I[CH2:2][C:3]([NH2:5])=[O:4].[Cl:6]([O-])(=O)(=O)=O.[Al+3].Cl([O-])(=O)(=O)=O.Cl([O-])(=O)(=O)=O.[CH2:22]([O:25][C:26]([N:28]1[C@H:32]([CH2:33][C:34]2[S:38][C:37]3=[CH:39][N:40]=[C:41]([Cl:42])[N:36]3[CH:35]=2)[CH2:31][C@H:30]([S:43][C:44]2[C@H:45]([CH3:61])[C@@H:46]3[C@@H:56]([C@H:57]([OH:59])[CH3:58])[C:55](=[O:60])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][CH:53]=[CH2:54])=[O:50])[CH2:29]1)=[O:27])[CH:23]=[CH2:24]>C(#N)C>[Cl-:6].[CH2:22]([O:25][C:26]([N:28]1[C@H:32]([CH2:33][C:34]2[S:38][C:37]3=[CH:39][N:40]([CH2:2][C:3](=[O:4])[NH2:5])[C:41]([Cl:42])=[N+:36]3[CH:35]=2)[CH2:31][C@H:30]([S:43][C:44]2[C@H:45]([CH3:61])[C@@H:46]3[C@@H:56]([C@H:57]([OH:59])[CH3:58])[C:55](=[O:60])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][CH:53]=[CH2:54])=[O:50])[CH2:29]1)=[O:27])[CH:23]=[CH2:24]
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3cn4c(Cl)ncc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: NC(=O)CI
Agent: [Al+3]
Solvent: CC#N
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3c[n+]4c(Cl)n(CC(N)=O)cc4s3)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 98.2 %

Procedure:
2-Iodoacetamide (198.0 mg) and 221.9 mg of aluminum perchlorate are added to a solution of 42.6 mg of allyl (1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-chloroimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 64-a), in 1.0 ml of dry acetonitrile. The mixture is stirred in an argon atmosphere at room temperature for 48 hr. The mixture is then filtered to remove insolubles, and the filtrate is subjected to evaporation. The residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) and then ion-exchanged using Amberlyst A-26 (Cl− form) (water) to give 48.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(6-carbamoylmethyl-5-chloroimidazo[5,1-b]thiazolium-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate chloride as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[NH2:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])[CH2:19][CH2:20]3)[CH:26]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: NCc1ccc(F)c(Br)c1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CN)ccc3F)c2)CC1
Temperature: 15 °C
Yield: 198.2 %

Procedure:
To two vials which each contained a solution of [(3-bromo-4-fluorophenyl)methyl]amine hydrochloric salt (0.601 g, 2.5 mmol) in p-dioxane/H2O (15/5 mL) was each added {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.2 g, 3.75 mmol), Pd(PPh3)4 (145 mg, 0.125 mmol), and K2CO3 (1.38 g, 10 mmol). The resulting mixture was heated in a microwave machine at about 15° C. for about 15 mins. The organic layer of both vials was separated, combined, concentrated and purified by CombiFlash chomatograph to afford 1.98 g (99%) of the title compound. LC-MS m/z 400 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH2:10](OC(OCC)OCC)C.C(OC(=O)C)(=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][NH2:37])=[CH:31][CH:30]=1.C([O-])(=O)C.[Na+]>CCOCC.O>[CH3:9][C:5]1[C:6]2[C:7]([NH:37][CH2:36][CH2:35][C:32]3[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[N:8][CH:10]=[N:1][C:2]=2[O:3][CH:4]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CCOC(OCC)OCC
Reactant: Cc1coc(N)c1C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COc1ccc(CCNc2ncnc3occ(C)c23)cc1
Temperature: 135 °C

Procedure:
A mixture of 4 g of 2-amino-3-cyano-4-methylfuran, 3 mL of triethylorthoformate and 0.5 mL of acetic anhydride was heated at 135° C. for three hours. To the hot solution was added 4.5 g of 2-(4-methoxyphenyl)ethylamine, 5 mL of acetic anhydride, and 3.1 g of sodium acetate. The temperature of the mixture was kept at 135° C. for three additional hours, then the mixture was cooled and combined with a mixture of water and ether. The ether layer was separated, and product was extracted from the remaining aqueous layer with large volumes of ether. The ether extracts were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was recrystallized from acetone/ether. Yield 2.6 g. M.P. 184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C:11](=[O:17])[N:10]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1.B(F)(F)F.[CH3:28]O>>[CH3:28][O:15][C:14]([CH:13]1[CH2:12][C:11](=[O:17])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:16]
Reactant: CO
Reactant: COc1cccc(C2C(C(=O)O)CC(=O)N2c2ccccc2)c1
Agent: FB(F)F
Product: COC(=O)C1CC(=O)N(c2ccccc2)C1c1cccc(OC)c1

Procedure:
A solution of 25.0 gm. of 2-(3-methoxyphenyl)-5-oxo-1-phenylpyrrolidin-3-carboxylic acid in 200 ml 10-15% boron fluoride-methanol was refluxed for 8 hours and upon following the workup for example 1C the product was obtained as an oil.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:32][CH2:31][N:30]([CH:29]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:26]3[CH:25]=[CH:24][C:23]([F:22])=[CH:28][CH:27]=3)[CH2:35][CH2:34]2)=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(C(c4ccc(F)cc4)c4ccc(F)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
141 mg (80%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (86 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:4](=[O:20])[NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)(=[O:34])[CH3:33]>>[C:18]([C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([N:5]2[C:6](=[O:7])[C:2]([CH3:21])([CH3:1])[N:3]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][C:32](=[O:34])[CH3:33])[C:4]2=[O:20])=[CH:9][CH:10]=1)#[N:19]
Reactant: CC(=O)OCCCCBr
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c3ccccc23)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC(=O)OCCCCN1C(=O)N(c2ccc(C#N)c3ccccc23)C(=O)C1(C)C

Procedure:
This compound was prepared from the compound of Example 17 by KHMDS deprotonation and N-alkylation with 4-acetoxybutyl bromide in a manner similar to that previously described in Example 9, to afford the desired hydantoin as a solid. LC/MS (ES) m/z 394 [M+H]+.