Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:11]([Cl:24])=[C:12]([CH:21]=[CH:22][CH:23]=1)[C:13]([NH:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1)=[O:14])=O)(C)(C)C.[ClH:25]>CCOC(C)=O>[ClH:24].[ClH:25].[NH2:8][CH2:9][C:10]1[CH:23]=[CH:22][C:21]([Cl:25])=[C:12]([CH:11]=1)[C:13]([NH:15][C:16]1[NH:17][CH:18]=[CH:19][N:20]=1)=[O:14]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)Nc2ncc[nH]2)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1ccc(Cl)c(C(=O)Nc2ncc[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
Dissolve 5-[(tert-butoxycarbonylaminomethyl)-2-chloro-N-(1H-imidazol-2-yl)benzamide (640 mg, 1.82 mmol, 1.0 equiv) in hydrochloric acid (4 M in dioxane, 4.56 mL, 18.24 mmol, 10.0 equiv) and stir at room temperature for 1 h. Pour the reaction mixture into vigorously swirling EtOAc (50 mL), isolate the resulting white precipitate by filtration, wash with EtOAc (25 mL), and dry in a 40° C. vacuum oven overnight to provide the title compound as a white solid (590 mg, 100%). 1H NMR (D2O, 400 MHz) δ 7.53 (d, 1H, J=2.0 Hz), 7.48 (d, 1H, J=8.3 Hz), 7.46 (dd, 1H, J=8.3, 2.0 Hz), 7.04 (s, 2H), 4.05 (s, 2H).
Reaction SMILES: [Ca].N.C([N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][S:20]([N:23](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:24])(=[O:22])=[O:21])=[CH:16][CH:17]=2)[C:12]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[CH3:44])=[CH:11]1)C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.O>[CH3:24][NH:23][S:20]([CH2:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[NH:10][CH:11]=[C:12]2[CH2:38][C@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1[CH3:44])(=[O:21])=[O:22]
Reactant: CN1CCC[C@@H]1Cc1cn(Cc2ccccc2)c2ccc(CS(=O)(=O)N(C)C(c3ccccc3)c3ccccc3)cc12
Agent: N
Agent: [Ca]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CNS(=O)(=O)Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.1 %

Procedure:
Into a stirred slurry of calcium tunings (1.11 g, 27.7 mmol) in tetrahydrofuran (1.2 ml) at −40° C. was added condensed liquid ammonia (16 ml). The blue bronze was stirred at −50 to −40° C. for a further 15 min, before a solution of (R)-1-[1-benzyl-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indol-5-yl]-N-diphenylmethyl-N-methylmethanesulfonamide (from step (e), 4.0 g, 6.93 mmol) in tetrahydrofuran (10 ml) was added dropwise, maintaining the temperature below −40° C. The dark blue solution was stirred at −40° C. for a further 30 min, before saturated ammonium chloride solution (10 ml) was added dropwise and the grey solution warmed to ambient temperature. Water (10 ml) was then added and the white slurry stirred for 15 min, before being filtered in vacuo. The solid was then dissolved in 5N HCl (12 ml) and the resulting orange solution extracted with ethyl acetate (10 ml). The pH of the aqueous phase was then adjusted (pH=10) with 10N NaOH which resulted in precipitation. The solid was filtered and dried in vacuo at 50° C. overnight to yield the title compound (1.54 g, 73%) as a white solid. m.p. 209-212° C.
Reaction SMILES: B.[CH3:2][O:3][C:4]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Br:13])=[O:7].Cl>O1CCCC1>[Br:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:6]([C:5]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:4]=1[O:3][CH3:2])[OH:7]
Reactant: COc1cc(Cl)ccc1C(=O)CCCCCBr
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1C(O)CCCCCBr
Reaction time: 0.75 h

Procedure:
Borane in tetrahydrofuran (240 ml. of 1M) was added over a period of 15 minutes to a solution of 72 g. of 5-(2-methoxy-4-chlorobenzoyl)pentyl bromide in 240 ml. of tetrahydrofuran. The mixture was stirred 45 minutes in an ice bath, and then 300 ml. of 2N hydrochloric acid was cautiously added. The mixture was concentrated to a volume of 500 ml., extracted with ether, the ether extracts washed with sodium bicarbonate and dried over anhydrous magnesium sulfate. Evaporation of the solvent afforded 74 g. of oil used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([CH2:27][O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=O)[CH2:26][CH2:25][CH2:24]1.[O-]CC.[Na+]>C(O)C>[CH:23]1([CH2:27][O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2/[CH:31]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH2:24][CH2:25][CH2:26]1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC1CCC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CCC1
Yield: 54.6 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (350 mg, 1.012 mmol) with 2-cyclobutylmethoxy-3-methoxybenzaldehyde (330 mg, 1.501 mmol) in the presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to give 292 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.80-1.90 (m, 5H), 2.00-2.08 (m, 2H), 3.77 (s, 3H), 3.83 (d, J=6.9 Hz, 2H), 6.80-6.87 (m, 2H), 6.91-6.99 (m, 2H), 7.40-7.46 (m, 4H), 7.51 (d, J=4.8 Hz, 1H), 7.99 (d, J=3.6 Hz, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.13 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH2:21]C1C=C(B(O)O)C=CC=1>>[NH2:21][C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:10][CH:9]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: COC(=O)CCCc1ccc(-c2ccc(N)cc2)cc1
Reactant: Nc1cccc(B(O)O)c1
Product: COC(=O)CCCc1ccc(-c2cccc(N)c2)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 29, using (3-aminophenyl)boronic acid as in place of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline ES/MS calcd. for C17H20NO2+ 270.2. Found m/z=270.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][CH:31]=[C:32]([C:34]#[N:35])[N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(CC)CC.C[Si]([N:47]=[C:48]=[O:49])(C)C>C(Cl)Cl>[C:34]([C:32]1[N:33]=[C:29]([C:27]([NH:26][C:15]2[CH:16]=[CH:17][C:18]([CH:20]3[CH2:21][CH2:22][N:23]([C:48]([NH2:47])=[O:49])[CH2:24][CH2:25]3)=[CH:19][C:14]=2[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=2)=[O:28])[NH:30][CH:31]=1)#[N:35]
Reactant: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCNCC3)cc2C2=CCCCC2)n1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CCN(C(N)=O)CC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 71.7 %

Procedure:
A flask was charged with 4-cyano-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-4-piperidin-4-yl-phenyl)-amide TFA salt (51 mg, 0.10 mmol) (as prepared in Example 14, step (b)), NEt3 (22 μL, 0.15 mmol), trimethylsilyl isocyanate (16 μL, 0.11 mmol) and 1.0 mL of DCM and stirred for 10 h at 25° C. The solvent was evaporated and the title compound was purified by RP-HPLC (C18), eluting with 35-60% CH3CN in 0.1% TFA/H2O over 11 min to give 30 mg (70%) of a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 14.28 (br s, 1H), 9.76 (s, 1H), 8.34 (s, 1H), 7.84 (d, 1H), 7.18 (dd, 1H), 7.08 (d, 1H), 6.00 (br s, 2H), 5.72 (m, 1H), 4.18 (m, 2H), 2.80-2.60 (m, 3H), 2.24-2.10 (m, 4H), 1.80-1.60 (m, 6H), 1.50 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C23H26N6O, 419.2 (M+H). found 419.0.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[C:20]([N:23]3[CH2:26][CH:25]([S:27][C:28]4[C@H:29]([CH3:52])[C@@H:30]5[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]5[C:32]=4[C:33]([O:35]CC4C=CC([N+]([O-])=O)=CC=4)=[O:34])[CH2:24]3)[S:21][CH:22]=2)=[O:17])=O)=CC=1)([O-])=O>O1CCCC1>[NH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:24][CH:25]([S:27][C:28]3[C@H:29]([CH3:52])[C@@H:30]4[C@@H:47]([C@H:48]([OH:50])[CH3:49])[C:46](=[O:51])[N:31]4[C:32]=3[C:33]([OH:35])=[O:34])[CH2:26]2)[S:21][CH:22]=1)=[O:17]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)NCCNC(=O)OCc5ccc([N+](=O)[O-])cc5)cs4)C3)[C@H](C)[C@H]12
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(SC3CN(c4nc(C(=O)NCCN)cs4)C3)[C@H](C)[C@H]12
Reaction time: 2 h
Yield: 49.1 %

Procedure:
p-Nitrobenzyl (1R,5S,6S)-2-(1-{4-[(2-(p-nitrobenzyloxycarbonylamino)ethyl)carbamoyl]-1,3-thiazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (328.4 mg, 0.42 mmol) (obtained as described in Example 61(1)) in a mixture of tetrahydrofuran (16.4 ml) and distilled water (8.2 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (328.4 mg) in a water bath (30° C.) for 2 hours. After checking the completion of the reaction, the reaction mixture was filtered and to the filtrate were added ethyl acetate-tetrahydrofuran (1:1) and distilled water. The mixture was shaken in a separatory funnel. The aqueous layer was separated, washed with the above-mentioned mixed solvent, and concentrated under reduced pressure. The residue was purified by chromatography on a Cosmosil column (eluant: distilled water→5% acetonitrile in distilled water→10% acetonitrile in distilled water→15% acetonitrile in distilled water) and the eluate was lyophilized to afford the desired compound (1R,5S,6S)-2-{1-[4-((2-aminoethyl)carbamoyl)-1,3-thiazol-2-yl]azetidin-3-yl}thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (96.4 mg, yield 49%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)CNS(=O)(=O)c1cccc(N)c1
Product: CC(C)(C)CNS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-(2,2-dimethyl-propyl)-benzenesulfonamide (example B.4) according to general procedure II. Light yellow solid. MS (ISP) 598.1 [(M−H−]; mp 231° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8](Cl)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:8]([CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([O:24][CH2:25][CH3:26])=[O:23])[CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(N)c1C(=O)OC
Temperature: 60 °C
Yield: 76.1 %

Procedure:
A mixture of methyl 2-amino-6-chloro-3-nitrobenzoate (4.11 g, 17.8 mmol), diethyl malonate (4.85 g, 30.3 mmol) and solid K2CO3 (powder, 9.11 g, 65.9 mmol) in DMF (71 mL) was heated at 60° C. for 10 h. The reaction mixture was poured into aqueous 1N HCl solution (400 mL) and the resulting solution was extracted with EtOAc (2×250 mL). The combined organic layers were washed with water (3×150 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (10-40μ silica gel; hexane:EtOAc 3:1) provided the title compound (4.80 g, 76% yield) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].[H-].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:12]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Yield: 13.3 %

Procedure:
In THF (400 ml) were dissolved 2,4-difluoronitrobenzene (17.4 g, 109 mmol) and di-tert-butyl malonate (27.0 ml, 120 mmol). Under stirring at 0° C., sodium hydride (60% in oil, 4.82 g, 120 mmol) was added in portions. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was poured in 1.0N-HCl (300 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (20:1 to 10:1) eluate fractions, di-tert-butyl (3-fluoro-4-nitrophenyl)malonate (5.17 g, 13%) was obtained as a pale yellow oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16](/[CH:19]=[N:20]/[NH:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][N:23]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]3=[N:21][N:20]=1)[CH:15]=[CH:14]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1ccnc(N/N=C/c2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: ClCCl
Product: Cc1ccn2c(-c3ccc4cccc(O[Si](C)(C)C(C)(C)C)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
(E)-8-(tert-Butyldimethylsilyloxy)-2-((2-(4-methylpyridin-2-yl)hydrazono)methyl)quinoline (0.720 g, 1.83 mmol) was suspended in DCM (6 mL) at ambient temperature. Iodobenzene diacetate (0.650 g, 2.02 mmol) was added and the solution was allowed to stir at ambient temperature overnight. The mixture was concentrated to an orange oil and purified directly by column chromatography (20% EtOAc/DCM to 50% EtOAc/DCM) to provide the desired product (0.590 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[H-].[Na+].[CH3:16]I>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1.[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[N:12]([CH3:16])[C:11](=[O:13])[CH2:10][CH2:9]2)[CH:5]=[N:6][CH:7]=1
Reactant: CI
Agent: O=C1CCC(c2cncc(Br)c2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CCC1c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 146.5 %

Procedure:
5-(5-Bromo-pyridin-3-yl)-pyrrolidin-2-one is prepared as described in Example 76. To a solution of 5-(5-bromo-pyridin-3-yl)-pyrrolidin-2-one (202 mg, 0.84 mmol) in THF (5.0 mL) is added 60% NaH (50 mg, 1.3 mmol). The mixture is stirred at room temperature for 5 min and methyl iodide (0.078 mL, 1.3 mmol) is then added dropwise. The mixture is stirred at room temperature for 16 h. The mixture is then concentrated and purified by normal phase chromatography to give 157 mg of 5-(5-bromo-pyridin-3-yl)-1-methyl-pyrrolidin-2-one.
Reaction SMILES: [C:1]12(COC3C(Cl)=CC(C(OC(C)(C)C)=O)=C(F)C=3)[CH2:7][CH:6]1CCCC2.Cl[C:26]1[C:27]([O:40][CH2:41][C:42]2([F:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=1)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>>[CH:1]1([C:26]2[C:27]([O:40][CH2:41][C:42]3([F:48])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:28][C:29]([F:39])=[C:30]([CH:38]=2)[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CCCCC2C3)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(F)CCCCC2)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 342 Step 4 and making variations as required to replace tert-butyl 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 5-chloro-2-fluoro-4-((1-fluorocyclohexyl)methoxy)benzoate, the title compound was obtained as a colorless gum (1.60 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.38 (d, J=8.4 Hz, 1H), 6.49 (d, J=12.5 Hz, 1H), 3.93 (d, J=17.8 Hz, 2H), 2.04-1.87 (m, 4H), 1.73-1.55 (m, 6H), 1.54 (s, 9H), 1.36-1.20 (m, 3H), 0.91-0.80 (m, 2H), 0.65-0.57 (m, 2H).
Reaction SMILES: Cl.CNC.CC(=O)CC.[C-]#N.[K+].[CH3:13][N:14]([CH3:22])[C:15]1([C:20]#[N:21])[CH2:19]C[CH2:17][CH2:16]1>O>[CH3:13][N:14]([CH3:22])[C:15]([CH3:19])([CH2:16][CH3:17])[C:20]#[N:21]
Reactant: CN(C)C1(C#N)CCCC1
Agent: CNC
Agent: Cl
Agent: [C-]#N
Solvent: CCC(C)=O
Solvent: O
Product: CCC(C)(C#N)N(C)C
Yield: 78 %

Procedure:
The title compound (9.95 g, 78%) was prepared from dimethylamine hydrochloride (8.15 g, 0.1 mol), 2-butanone (8.96 ml, 0.1 mol) and potassium cyanide (6.51 g, 0.1 mol) in water (50 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.00 (3H, t, J=7.2 Hz), 1.43 (3H, s), 1.75-1.87 (2H, m), 2.33 (6H, s).
Reaction SMILES: C(C(CC)(OC1C=CC(CCN[C:17]([C:19]2[S:27][C:26]3[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22][C:21]=3[CH:20]=2)=[O:18])=CC=1OCC([O-])=O)C([O-])=O)C.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:31]([O:30][C:28]([N:23]1[CH2:24][CH2:25][C:26]2[S:27][C:19]([CH:17]=[O:18])=[CH:20][C:21]=2[CH2:22]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: CCC(CC)(Oc1ccc(CCNC(=O)c2cc3c(s2)CCN(C(=O)OC(C)(C)C)C3)cc1OCC(=O)[O-])C(=O)[O-]
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2sc(C=O)cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 196.3 %

Procedure:
The solution of the compound prepared in (a) (1.2 g) in dichloromethane (20 ml) was added pyridinium chlorochromate (1.1 g), and the mixture was stirred at room temperature for 4 hours. After the reaction mixture was filtered through FLORISIL, the filtrate was concentrated and purified by column chromatography on silica gel to give 1.07 g of the title compound from the fraction eluted with ethyl acetate:n-hexane=1:3 (yield, 89.8%).
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1(O)C2C=CC=CC=2N=N1.[C:41]([CH2:43][C:44](O)=[O:45])#[N:42].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([C:44](=[O:45])[CH2:43][C:41]#[N:42])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: N#CCC(=O)O
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCN(C(=O)CC#N)CC5)c4)nc23)CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
A solution of (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (130 mg, 0.32 mmol), benzotriazol-1-ol (52 mg, 0.38 mmol), cyano-acetic acid (74 mg, 0.39 mmol), and 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide hydrochloride (74 mg, 0.39 mmol), in DCM (35 ml), was treated with TEA (0.13 ml, 0.97 mmol). After stirring at room temperature for 16 hours, the reaction mixture was partitioned between DCM and water. The organic layers were collected, dried over MgSO4, filtered, and concentrated. Trituration of the resulting solid with 1:1 Et2O/Hex provided 85 mg (56%) of 3-(4-{3-[7-(1-methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazin-1-yl)-3-oxo-propionitrile as an off white solid. MP 214-216° C., M+H=471.
Reaction SMILES: [CH2:1]([O:4][C@H:5]([CH3:10])[C:6]([O:8]C)=[O:7])[CH2:2][CH3:3].[OH-].[Na+].Cl>O>[CH2:1]([O:4][CH:5]([CH3:10])[C:6]([OH:8])=[O:7])[CH2:2][CH3:3]
Reactant: CCCO[C@H](C)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCOC(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
Silver oxide (87.5 g, 0.38 mol) was added to a mixture of (R)-methyl lactate (52.1 g, 0.5 mol) with 1-iodopropane (100 g, 0.59 mol) over 3 hours, followed by allowing the mixture to stand at room temperature for 4 days, adding ether (200 ml) for dilution, filtering the mixture, distilling off ether, washing the residue with 2N-NaOH aqueous solution, drying over anhydrous sodium sulfate, distilling it under reduced pressure to obtain (R)-methyl 2-propoxypropionate (46.1 g, b.p. 33°-34° C./5 mmHg). To this (R)-methyl 2-propoxypropionate (28.2 g) were added water (60 ml) and NaOH (10 g), followed by agitating the mixture at room temperature for 3 hours, pouring the mixture in 6N-hydrochloric acid (80 ml), extracting the resulting organic layer with ether, washing the resulting organic layer with water and distilling off ether to obtain 2-propoxypropionic acid (18.0 g).
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18](O)=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:29])=O>CN(C)C=O.ClCCl>[F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18]([Cl:29])=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1
Reactant: C[C@H](C(=O)O)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C(=O)Cl)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R)-2-[4-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoic acid (1.0 g) and 2.5 ml of oxalyl chloride were added to 20 ml of dichloromethane, to which dimethylformamide (5 drops) was added dropwise at room temperature. After the reaction solution was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure to give 1 g of (2R)-2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoyl chloride as a pale yellow oil. This product was used for the next step without purification.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18]OC(=O)CC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:31][C:32]1[N:36]([CH3:37])[N:35]=[N:34][N:33]=1.C(=O)(O)[O-].[Na+]>O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][S:31][C:32]4[N:36]([CH3:37])[N:35]=[N:34][N:33]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1nnnc1S
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 96.2 %

Procedure:
In 50 ml of water was dissolved 4.32 g of 7-phenylacetamido-3-(3-oxobutyryloxy)methyl-3-cephem-4-carboxylic acid, together with 1.50 g of 5-mercapto-1-methyl-1H-tetrazole and 1.68 g of sodium bicarbonate and the reaction was conducted at 60° C. for 50 minutes. After cooling, the reaction mixture was adjusted to pH 5.0 and washed with ethyl acetate. It was then brought down to pH 2.0 and extracted three times with ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous solution of sodium chloride, treated with magnesium sulfate, filtered and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethyl acetate-ether. The procedure provided 4.29 g (yield 96.2%) of 7-phenylacetamido-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.