Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:44]=[CH:43][C:39]([C:40]([OH:42])=O)=[CH:38][CH:37]=4)[O:33][C:34]=3[CH3:35])=[C:26]([O:47][CH3:48])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.C([N:52]=C=NCCCN(C)C)C.CN(C)C=O>O>[C:40]([C:39]1[CH:38]=[CH:37][C:36]([C:32]2[O:33][C:34]([CH3:35])=[C:30]([CH2:29][O:28][C:27]3[CH:45]=[CH:46][C:24]([CH2:23][O:22][C:12]4[C:11](/[CH:10]=[CH:9]/[P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[CH:15][N:14]([C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:13]=4)=[CH:25][C:26]=3[O:47][CH3:48])[N:31]=2)=[CH:44][CH:43]=1)(=[O:42])[NH2:52]
Reactant: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(OC)c1)OCC
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(N)=O)cc3)oc2C)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.5 %

Procedure:
A mixture of 4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid (0.18 g), 1-hydroxybenzotriazole ammonia complex (0.06 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.08 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give diethyl (E)-2-(3-{[4-({2-[4-(carbamoyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)-3-methoxybenzyl]oxy}-1-phenyl-1H-pyrazol-4-yl)ethenylphosphonate as colorless crystals (0.15 g, yield 83%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-148° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][N:8]2[CH2:12]CC[CH2:9]2)=[CH:4][CH:3]=1.CNC.CO>>[Br:1][C:2]1[S:6][C:5]([CH2:7][N:8]([CH3:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: Brc1ccc(CN2CCCC2)s1
Agent: CNC
Solvent: CO
Product: CN(C)Cc1ccc(Br)s1
Yield: 93 %

Procedure:
The above procedure to make 1-[(5-bromo-2-thienyl)methyl]pyrrolidine was repeated except using 2 M dimethylamine in methanol (0.75 mL, 1.5 mmol) to afford 204 mg (93%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]2)[CH:11]=[CH:10][CH:9]=1.[O:28]1[C:32]2([CH2:37][CH2:36][CH:35]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44]O)=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)[O:31][CH2:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[O:28]1[C:32]2([CH2:33][CH2:34][CH:35]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[C:8]4[N:13]=[C:12]([N:14]5[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]5)[CH:11]=[CH:10][CH:9]=4)=[CH:40][CH:39]=3)[CH2:36][CH2:37]2)[O:31][CH2:30][CH2:29]1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3O)n2)c1C(F)(F)F
Reactant: OCc1ccc(C2CCC3(CC2)OCCO3)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OCc3ccc(C4CCC5(CC4)OCCO5)cc3)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of the title compound from Example 1 Step B (251 mg, 0.67 mmol), the title compound from Example 10 Step C (248 mg, 1.00 mmol), and triphenylphosphine (349 mg, 1.33 mmol) in DCM (3 mL) was added diisopropyl azodicarboxylate (0.259 mL, 1.33 mmol). The resulting mixture was stirred at ambient temperature. After 5 h, the reaction mixture was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 25% EtOAc in hexanes then 25 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 608.06 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.15 (d, J=8.0 Hz, 1H), 8.12 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.85 (t, J=8.0 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.38-7.35 (m, 1H), 7.29 (d, J=7.5 Hz, 2H), 7.23 (d, J=7.5 Hz, 2H), 7.12-7.06 (m, 2H), 5.12 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.98 (s, 4H), 2.60-2.54 (m, 1H), 1.87-1.65 (m, 8H), 1.39 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[N:15][OH:16])=[CH:12][N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(Cl)Cl.[Br:26][CH2:27][C:28](=[CH2:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].Cl[O-].[Na+]>ClCCl.O>[Br:26][CH2:27][C:28]1([C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:16][N:15]=[C:14]([C:13]2[C:8]([NH:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:9]3[CH:19]=[N:18][N:17]([CH2:20][CH3:21])[C:10]3=[N:11][CH:12]=2)[CH2:34]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C=NO)cnc21
Reactant: C=C(CBr)C(=O)OCC
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(CBr)CC(c2cnc3c(cnn3CC)c2NC2CCCCC2)=NO1
Reaction time: 8 h
Yield: 66 %

Procedure:
4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (200 mg, 0.0006 mole) (example 8) was taken in dichloromethane: chloroform mixture (10 ml: 5 ml). Ethyl 2-(bromomethyl)acrylate (0.2 ml, 0.00103 mole) was added. Sodium hypochlorite (2.5 ml) was added drop wise. The reaction mixture was stirred overnight. Water was added, the mixture was extracted with chloroform, washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude compound obtained was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:28])([CH3:27])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[C:6]([CH:13]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].Br[C:39]1[C:44]([C:45]#[N:46])=[CH:43][C:42]([C:47]([F:50])([F:49])[F:48])=[N:41][CH:40]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[Cl:1][C:2]1[CH:13]=[C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([S:14]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH3:27])([CH3:28])[CH2:19][CH2:18]2)(=[O:15])=[O:16])=[CH:4][C:3]=1[C:39]1[C:44]([C:45]#[N:46])=[CH:43][C:42]([C:47]([F:49])([F:50])[F:48])=[N:41][CH:40]=1
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc2OCCCCO)c2ccccc21
Reactant: N#Cc1cc(C(F)(F)F)ncc1Br
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: O
Solvent: C1COCCO1
Product: CC1(C)CCN(S(=O)(=O)c2cc(-c3cnc(C(F)(F)F)cc3C#N)c(Cl)cc2OCCCCO)c2ccccc21
Temperature: 100 °C
Yield: 35.5 %

Procedure:
A mixture of 4-[5-Chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-butan-1-ol (270.0 mg, 0.49 mmol), 5-bromo-2-trifluoromethyl-isonicotinonitrile (112 mg, 0.45 mmol), Pd(Ph3P)4 (57 mg, 0.05 mmol) and Na2CO3 (286 mg, 2.7 mmol) in dioxane (4 mL) and water (0.4 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 100° C. for 16 hrs. The mixture was then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (2×10 mL), dried over MgSO4, filtered and concentrated to give a material which was purified by TLC plates eluting with 30% acetone in hexanes to give 5-[2-chloro-5-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-4-(4-hydroxy-butoxy)-phenyl]-2-trifluoromethyl-isonicotinonitrile 11-1 as a white solid (95 mg). MS: 594.2 (M+H)+; tR=2.94 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([C:20]([CH2:24][CH2:25][CH3:26])=[CH:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12>C(O)(=O)C.[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:15][CH2:14][CH2:13][C:12]2=[C:16]([CH:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])[N:17]([CH3:19])[N:18]=[C:11]12
Reactant: CCC=C(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCC(CCC)c1c2c(nn1C)N(c1c(C)cc(C)cc1Cl)CCC2
Reaction time: 12 h
Yield: 24.4 %

Procedure:
7-(2-Chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbut-1-enyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine (41.5 mg) was dissolved in acetic acid (1 mL) and 12 mg of 10% palladium on carbon was added. The mixture was stirred under hydrogen at one atmosphere for 12 h. The mixture was diluted with ethyl acetate and filtered through diatomaceous earth which was then washed with ethyl acetate. The ethyl acetate filtrate was washed with aqueous sodium bicarbonate, dried with magnesium sulfate, and concentrated. The residue was chromatographed on silica gel eluting with an acetone/hexane gradient to provide 10.2 mg of 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-3-(1-propylbutyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridine, as a crystalline film, ms m/z 374 (MH+).
Reaction SMILES: [CH:1](=[C:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H][H]>[Pd].CO>[CH2:1]([CH:8]1[C:20]2[N:19]3[CH:21]=[CH:22][N:23]=[C:18]3[C:17](=[O:24])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ccccc3)c2n2ccnc12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ccccc1)c1ccccc1-2
Yield: 37.3 %

Procedure:
A mixture of 0.4 g of 10-benzylidene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 90 ml of dimethylformamide and 10 ml of methanol is hydrogenated at a temperature in the region of 20° C. at a pressure of 1.9 bar of hydrogen for 3 hours in the presence of 10% palladium on charcoal. The catalyst is then filtered off under inert atmosphere and the solvents are evaporated off. The brown solid obtained (0.37 g) is purified by chromatography on a column of silica (35 g) with a mixture of dichloromethane and methanol (90/10 by volume). After trituration with 5 ml of dichloromethane, filtration and drying at 100° C., 0.15 g of 10-benzyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is obtained, in the form of a beige solid melting above 260° C. (Analysis % calculated C: 76.66, H: 4.82, N: 13.41, O: 5.11, % found C: 76.3, H: 4.6, N: 13.4).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C:5]([CH3:13])([CH:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:6].[CH:15](O)=O.C=O>[OH-].[Na+]>[CH3:2][O:3][C:4](=[O:14])[C:5]([CH3:6])([C@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([CH3:15])[CH2:8]1)[CH3:13]
Reactant: COC(=O)C(C)(C)C1CCCNC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Agent: [Na+]
Product: COC(=O)C(C)(C)[C@H]1CCCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
0.992 g of 2-methyl-2-piperidin-3-yl-propionic acid methyl ester hydrochloride are dissolved in 2.2 ml of 2M NaOH. The solution is stirred for 10 minutes at room temperature. 7 ml of formic acid and 0.900 ml of 36% aqueous formaldehyde solution are added and the mixture is warmed to 60° C. for 16 hours. The solution is concentrated under reduced pressure. The residue is taken up water and the pH adjusted to 8-9 with saturated sodium carbonate solution. The mixture is extracted with ethyl acetate (3×) and tetrahydrofuran (2×)—the combined extracts are dried over sodium sulphate and concentrated. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (200:20:1 dichloromethane/methanol/25% conc. ammonia).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13]([O:17][C:18]([NH:20][CH2:21][CH2:22][CH2:23]O)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[F:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH2:23][CH2:22][CH2:21][NH:20][C:18]([O:17][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:19])[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCCO
Reactant: COC(=O)c1ccc(F)cc1O
Product: COC(=O)c1ccc(F)cc1OCCCNC(=O)OC(C)(C)C
Yield: 84 %

Procedure:
Using a procedure analogous to Example 1-C, methyl 2-hydroxy-4-fluorobenzoate and 3-(tert-butoxycarbonylamino)propanol gave the desired product as a white solid (20.6 g, 84%). 1NMR IS-MS, m/e: 328 (m+1).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[C:25](=O)([O:36][CH2:37][CH2:38][N:39]1[CH:43]=[CH:42][CH:41]=[N:40]1)[O:26]C1C=CC([N+]([O-])=O)=CC=1.Cl>N1C=CC=CC=1.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([C:25]([O:36][CH2:37][CH2:38][N:39]5[CH:43]=[CH:42][CH:41]=[N:40]5)=[O:26])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(OCCn1cccn1)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCN(C(=O)OCCn4cccn4)CC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.6 %

Procedure:
A mixture of 3.3 g (0.01 mol) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-quinoline-3-carboxylic acid and 2.8 g (0.01 mol) of 4-nitrophenyl 2-(pyrazol-1-yl)-ethyl carbonate in 40 ml of pyridine is stirred for 1 day at room temperature. Thereafter, it is diluted with 30 ml of water and acidified with 2N hydrochloric acid, and the precipitate is filtered off under suction and recrystallised from glycol monomethyl ether. 2.8 g (60% of theory) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-{-4-[(pyrazol-1-yl)-ethoxycarbonyl]-piperazin-1-yl}-quinoline-3-carboxylic acid of melting point 205°-208° C. are obtained.
Reaction SMILES: [S:1]1[C:13]2[N:5]([C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=3)[CH2:4][CH2:3]C1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[S:1]1[CH:3]=[CH:4][N:5]2[C:6]3[CH:7]=[C:8]([CH:14]=[O:15])[CH:9]=[CH:10][C:11]=3[N:12]=[C:13]12
Reactant: OCc1ccc2nc3n(c2c1)CCCS3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc2nc3sccn3c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottomed flask was loaded 1.16 grams of (3,4-Dihydro-2H-1-thia-4a,9-diaza-fluoren-6-yl)-methanol, 25 grams of manganese dioxide and 250 ml chloroform. The mixture was stirred for one hour at room temperature and then filtered through a pad of celite. This yielded 0.42 grams of product (42%). MS: 203.0 (M+H). H-NMR (CDCl3): δ 10.10 (ss, 1H), 8.24 (ss, 1H), 7.85 (m, 3H), 6.96 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[NH:45]1[CH2:49][CH2:48][CH:47]([OH:50])[CH2:46]1>C(#N)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=3)[C:6](=[O:33])[N:7]2[C:21]([N:45]2[CH2:49][CH2:48][CH:47]([OH:50])[CH2:46]2)=[O:22])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=1)#[N:16]
Reactant: OC1CCNC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCC(O)C2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with pyrrolidin-3-ol (32.6 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (58 mg, 81% of theory).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:54][CH2:53][C@@H:52]([CH2:55][N:56]([CH3:70])[C:57]([O:59][CH2:60][C:61]3[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=3)=[O:58])[CH2:51]2)=[O:49])[CH2:43]1.C(OCC)(=O)C>C(#N)C.C(N(CC)C(C)C)(C)C>[OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])=[C:8]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:54][CH2:53][C@@H:52]([CH2:55][N:56]([CH3:70])[C:57]([O:59][CH2:60][C:61]5[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=5)=[O:58])[CH2:51]4)=[O:49])[CH2:43]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN(C[C@@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)C1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@@H](CN(C)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C)C3)[C@H](C)[C@H]12
Yield: 46.9 %

Procedure:
To a solution of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (0.66 g) in anhydrous acetonitrile (5 ml), N,N-diisopropylethylamine (0.19 ml) and a solution of (2S,4S)-4-mercapto-1-methyl-2-[(3R)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidine (0.53 g) in anhydrous acetonitrile (5 ml) were added while stirring in an ice bath. The resulting mixture was allowed to react overnight at 0° C. To the reaction mixture, ethyl acetate was added. The resulting mixture was washed with water and saturated saline solution, dried over anhydrous sodium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate/methanol=6/4), whereby 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-1-methyl-2-[(3R)-3-(N-methyl-N-4-nitrobenzyloxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (0.43 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][C@H:17]1[O:22][C@@H:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[CH3:23][C@H:21]1[O:22][C@@H:17]([CH3:16])[CH2:18][N:19]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:20]1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: C[C@@H]1CNC[C@H](C)O1
Product: Cc1ccc(-c2oncc2C(=O)N2C[C@@H](C)O[C@@H](C)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and cis-2,6-dimethylmorpholine (6.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (9.9 mg). Calcd for C17H20N2O3: 300.1474, found 300.1472.
Reaction SMILES: [Cl:1][C:2]1[C@:3]2([CH2:13][O:14][CH2:15][CH3:16])[O:12][C@H:6]([C:7](Cl)(Cl)[C:8]=1[Cl:9])[CH:5]=[CH:4]2.CC(C)=[O:19].C(=O)(O)[O-].[Na+]>[N+]([O-])([O-])=O.[Ag+].O>[Cl:9][C:8]1[C:7](=[O:19])[C@H:6]2[O:12][C@@:3]([CH2:13][O:14][CH2:15][CH3:16])([C:2]=1[Cl:1])[CH:4]=[CH:5]2
Reactant: CCOC[C@]12C=C[C@H](O1)C(Cl)(Cl)C(Cl)=C2Cl
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC[C@]12C=C[C@H](O1)C(=O)C(Cl)=C2Cl
Temperature: 65 °C

Procedure:
Silver nitrate (26 g, 0.154 mol) is added to a stirred mixture of (1S*,5S*)-2,3,4,4-tetrachloro-1-ethoxymethyl-8-oxabicyclo[3.2.1]octa-2,6-diene (23.5 g, 0.077 mol), acetone (450 ml) and water (450 ml) and the mixture is heated at 65° C. for 16 hours. The reaction mixture is cooled to room temperature, and a saturated solution of aqueous sodium bicarbonate is added to adjust the pH to 7-8. The mixture is filtered through a plug of diatomaceous earth, and the filtrate is concentrated under reduced pressure to remove most of the acetone. The aqueous mixture is extracted with ethyl acetate (3×250 ml) and the organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated. The residue is purified by column chromatography on silica gel to give (1S*,5S*)-3,4-dichloro-5-ethoxymethyl-8-oxabicyclo[3.2.1]octa-3,6-dien-2-one (6 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:43][N:44]([CH3:48])[CH2:45][CH2:46]O.[H-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([O:37][CH2:46][CH2:45][N:44]([CH3:48])[CH3:43])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCO
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)OCCN(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (100.2 mg, 0.164 mmol) and N,N′-carbonyldiimidazole (68.8 mg, 0.424 mmol, Aldrich) in tetrahydrofuran (5 mL) was stirred at room temperature overnight. N,N-dimethylethanolamine (44.3 mg, 0.495 mmol, Aldrich) was added to a suspension of sodium hydride (12 mg, 0.475 mmol) in tetrahydrofuran (4 mL) and stirred at room temperature for 1 h. It was then added to the above mixture and stirred at room temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous sodium sulfate and concentrated. the crude product was purified by flash chromatography to give chiral 2-(dimethylamino)ethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid (97.2 mg, 86% yield). MS (ES+) m/z calcd. for C35H39Cl2F2N4O4 [(M+H)+]: 687. found: 687.