Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=O)C)[CH:5]=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:22]=[CH:21][C:20]2C(=[CH:16][CH:17]=[CH:18][C:19]=2[N:23]2[CH2:28][CH2:27][N:26]([CH2:29]CC3C=C(C=CC=3)N)[CH2:25][CH2:24]2)N=1.[C:38]([BH3-])#[N:39].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:9])[CH2:29][N:26]2[CH2:27][CH2:28][N:23]([C:19]3[CH:18]=[CH:17][CH:16]=[C:38]4[C:20]=3[CH:21]=[CH:22][C:13]([CH3:12])=[N:39]4)[CH2:24][CH2:25]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)Cc1cccc(Br)c1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc(Br)c4)CC3)cccc2n1
Reaction time: 0.17 h
Yield: 50 %

Procedure:
A solution of zinc(II)chloride (0.5 M, THF, 0.5 eq., 234 uL) was added to a stirred solution of 1-(3-bromophenyl)-2-propanone (50 mg) and 2-methyl-5-(1-piperazinyl)quinoline (D3) (2.0 eq., 107 mg) in methanol (1 ml). The mixture was stirred 10 minutes then a solution of sodium cyanoborohydride (1M, THF, 1.0 eq., 234 uL) was. added. The resulting white mixture was stirred at room temperature until hplc showed the complete disappearance of starting material. The mixture was concentrated under reduced pressure, diluted with aqueous sodium hydroxide solution (1M), and extracted with DCM. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography using a SPE cartridge (SiO2) with DCM-methanol (98:2) as eluent to afford the title compound (50 mg, 50% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:18]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH:6]=[CH:5]2.C(O)C.[Cl-].[NH4+].O>[Fe].ClCCl>[NH2:18][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]([C@@H:13]([CH3:17])[C:14]([NH2:16])=[O:15])[C:8]2=[O:12]
Reactant: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])c(Cl)ccc2c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: C[C@@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-2-(6-chloro-5-nitro-1-oxoisoquinolin-2(1H)-yl)propanamide (201 mg, 0.000679 mol), ethanol (10 mL, 0.2 mol), ammonium chloride (363.03 mg, 0.0067868 mol) and water (10 mL, 0.6 mol) was heated at 85° C. and iron (152 mg, 0.00271 mol) was added in three portions 2 minutes apart. The reaction was stirred at that temperature for 1 hour and poured into dichloromethane (150 mL) and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and the solvent removed under reduced pressure to obtain the pure product as a light yellow solid. MS m/z=232.5 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccccc1O
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccccc1Oc1ccccc1[N+](=O)[O-]
Temperature: 130 °C
Yield: 122.9 %

Procedure:
A mixture of 2-chloronitrobenzene (9.5 g, 60 mmol), 2-t-butyl phenol (9.04 g, 60.2 mmol) and potassium carbonate (10.6 g) in DMF was heated at 130° C. for 6 days. The reaction was cooled to rt and partitioned between diethyl ether (400 mL) and water (500 mL). The organic layer was separated and the aqueous layer was extracted with ether (3×100 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 1-tert-butyl-2-(2-nitrophenoxy)benzene (20 g). (M+H)+=216.23.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[H-].[Na+].[CH2:17](I)[CH:18]([CH3:20])[CH3:19].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1
Reactant: CC(C)CI
Reactant: Oc1ccc(Oc2nccs2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(Oc2nccs2)c(Cl)c1
Reaction time: 0.25 h
Yield: 45.1 %

Procedure:
To a solution of Example 9B (3.4 g, 0.015 mol) in N,N-dimethyl formamide was added sodium hydride (0.7 g, 0.018 mol) in portions at room temperature. After stirring for 15 minutes, isobutyl iodide (4.2 g, 0.023 mol) was added rapidly and the mixture was stirred at room temperature for 24 hours. More sodium hydride and isobutyl iodide were added later to complete the reaction. Water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified on silica gel (5˜35% ethyl acetate in hexane) to give 1.92 g of product as clear oil (45% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.02 (d, J=6.62 Hz, 6H) 1.98-2.18 (m, 1H) 3.71 (d, J=6.62 Hz, 1H) 6.79 (d, J=4.04 Hz, 1H) 6.83 (d, J=2.94 Hz, 1H) 6.86 (d, J=2.94 Hz, 1H) 7.00 (d, J=2.94 Hz, 1H) 7.19 (d, J=4.04 Hz, 1H) 7.24 (s, 1H). MS (ESI) m/z 284.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[C:3]=1[F:11].[C-:12]#[N:13].[Na+]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:12]#[N:13])=[C:4]([F:10])[C:3]=1[F:11]
Reactant: Fc1c(Br)ccc(CBr)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc(Br)c(F)c1F
Temperature: 10 °C
Reaction time: 12 h

Procedure:
To a solution of 1-bromo-4-(bromomethyl)-2,3-difluorobenzene (330 mg, 1.154 mmol) in EtOH (10 mL) stirred under N2 at 0° C. was added NaCN (73.5 mg, 1.500 mmol) in one charge. The reaction mixture was stirred at 10° C. for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2,3-difluorophenyl)acetonitrile was used in the next step without further purification. TLC (PE/EA=5:1, Rf 0.6): 1H NMR (400 MHz, CDCl3) δ 7.39 (ddd, J=1.8, 6.1, 8.2 Hz, 1H), 7.15 (t, J=6.8 Hz, 1H), 3.78 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([F:9])=[CH:4][N:3]=1.[H-].[Na+].[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:14]=1[C:15](Cl)=[O:16].O>CN(C)C=O>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:14]=1[C:15]([NH:8][C:6]1[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)=[O:16]
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1cc(Cl)ncc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Cl)ncc1F)c1c(Cl)cc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 54 %

Procedure:
To a solution of 2-chloro-5-fluoropyridin-4-amine (200 mg, 1.36 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium hydride (65.5 mg, 2.73 mmol) in one portion at room temperature under N2. The reaction mixture was then stirred for 15 min and then a solution of 2,4,6-trichlorobenzoyl chloride (320 uL, 2.0 mmol) in N,N-dimethylforamide (400 uL) was added dropwise. The mixture was stirred at room temperature for 10 mins, and then poured into water (30 mL). The mixture was extracted with ethyl acetate (2×50 mL), and combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-5% methanol/dichloromethane) to give 2,4,6-trichloro-N-(2-chloro-5-fluoropyridin-4-yl)benzamide (260 mg, yield: 54%). 1H NMR (DMSO-d6, 400 MHz): δ 11.52 (s, 1H), 8.49 (s, 1H), 8.33 (d, J=5.5 Hz, 1H), 7.84 (s, 2H). LCMS (ESI) m/z: 354.9 [M+H+].
Reaction SMILES: [C:1]([CH:3]([CH2:9][C:10]([C:12]1[C:17](F)=[CH:16][CH:15]=[CH:14][C:13]=1F)=O)[C:4]([O:6][CH2:7]C)=[O:5])#[N:2].C(OCC)(=O)C.[ClH:26]>C(OCC)(=O)C>[Cl:26][C:1]1[NH:2][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: Cl
Reactant: CCOC(=O)C(C#N)CC(=O)c1c(F)cccc1F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2ccccc2)[nH]c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
To a suspension of methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate (4.66 g) synthesized from methyl cyanoacetate and phenacyl bromide in the same manner as in Reference Example 95 and Reference Example 97 in acetonitrile (200 mL) was added 2,6-dichloro-N-fluoropyridinium triflate (6.26 g) over 10 min under ice-cooling. The reaction mixture was stirred at the same temperature for 2 hr and at room temperature for 2 hr, and concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→7:3) to give the title compound as a pale-yellow solid (yield 815 mg, 16%). More specifically, to a solution of methyl cyanoacetate (41 g) and diisopropylethylamine (117 g) in tetrahydrofuran (2600 mL) was added dropwise a solution of phenacyl bromide (75 g) in tetrahydrofuran (370 mL). The mixture was stirred at room temperature for 12 hr. The reaction mixture was filtered, and the obtained filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 1 mol/L hydrochloric acid, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diethyl ether to give methyl 2-cyano-4-phenyl-4-oxobutanoate as a brown oil (yield 77.4 g, 95%). To a solution (125 mL) of ethyl 2-cyano-4-(2,6-difluorophenyl)-4-oxobutanoate (25 g) in ethyl acetate was added dropwise 4 mol/L hydrogen chloride-ethyl acetate solution (25 mL). The mixture was stirred at room temperature for 18 hr, and concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate as colorless crystals (yield 10.0 g, 37%). The title compound was synthesized from the thus-obtained methyl 2-chloro-5-phenyl-1H-pyrrole-3-carboxylate.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[F:22])=O>O1CCCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:22][C:15]1[CH:16]=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[C:12]([CH3:1])=[CH2:11]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1ccc(OC)cc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of sodium bis(trimethylsilyl)-amide, 1.0M in tetrahydrofuran (714 ml, 0.714 m) was added to a suspension of methyltriphenylphosphonium bromide (255 g, 0.714 m) in THF (2.50 L) cooled with an ice bath. The resultant yellow colored suspension was stirred for 30 minutes at ice bath temperature and then cooled to −78° C. A total of 2-fluoro-4-methoxyacetophenone (100 g, 0.595 m) in THF (200 ml) was added dropwise and stirred at −78° C. for 1.5 hours. Reaction mixture was allowed to warm to room temperature for one hour, quenched with acetic acid (˜80 ml) where color change was observed from yellow to off white and stirred for 30 minutes (pH˜7)(slight exotherm noted). The mixture was concentrated to a slush, diluted with 7:2 hexane:ethyl acetate, and was allowed to sit overnight. Solids were removed by filtration and the filtrate was concentrated to yellow oil. The title compound was obtained after flash column using 9:1 hexane:ethyl as the eluant.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:7]=1)[CH3:2].[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][N:25]([C:32]([CH:29]2[CH2:31][CH2:30]2)=[O:33])[CH2:26][CH3:27])[CH:7]=1)[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc([N+](=O)[O-])ccc1Oc1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CN(CC)C(=O)C2CC2)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 3, using the following starting materials: [3-(2-ethylaminomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH:9]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=O)=O.[NH:26]1[CH:30]=[N:29][CH:28]=[N:27]1>CN(C)C=O>[ClH:18].[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][N:26]2[CH:30]=[N:29][CH:28]=[N:27]2)=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)OCC(CCc1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cl
Product: Clc1ccc(CCC(Cn2cncn2)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
To a stirred mixture of 3.8 parts of a sodium hydride dispersion 78% and 90 parts of N,N-dimethylformamide is added dropwise a solution of 21 parts of 2,4-bis(4-chlorophenyl)butyl methanesulfonate in 45 parts of N,N-dimethylformamide. After stirring for 15 minutes at room temperature, there is added a solution of 7.6 parts of 1H-1,2,4-triazole in 45 parts of N,N-dimethylformamide. The whole is heated slowly to 100° C. and stirring is continued for 2 hours at 100° C. The reaction mixture is poured onto water and the product is extracted with 1,1'-oxybisethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (97.5:2.5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is converted into the hydrochoride salt in 2,2'-oxybispropane. The salt is filtered off and crystallized from a mixture of methanol and 2,2'-oxybispropane, yielding 7 parts (32.5%) of 1-[2,4-bis(4-chlorophenyl)butyl]-1H-1,2,4-triazole hydrochloride; mp. 173.4° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].O(C1C=CC(C2CCNCC2)=CC=1)C1C=CC=CC=1.ClCC(Cl)=O.[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][C@H:58]2[CH2:63][CH2:62][C@H:61]([OH:64])[CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:65]([F:68])([F:67])[F:66])([O-:50])=[O:49]>>[N+:48]([C:51]1[CH:56]=[CH:55][C:54]([NH:57][C@H:58]2[CH2:63][CH2:62][C@H:61]([O:64][CH2:2][C:3]([N:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:13][CH:12]=4)[CH2:7][CH2:6]3)=[O:4])[CH2:60][CH2:59]2)=[CH:53][C:52]=1[C:65]([F:66])([F:67])[F:68])([O-:50])=[O:49]
Reactant: O=C(CCl)N1CCC(c2ccc(Oc3ccccc3)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(N[C@H]2CC[C@H](O)CC2)cc1C(F)(F)F
Agent: O=C(Cl)CCl
Agent: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCC(c2ccc(Oc3ccccc3)cc2)CC1

Procedure:
2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-ethanone was prepared using a two-step synthesis. In the first step, 1-chloracetyl-4-(4-phenoxy-phenyl)-piperidine (also known as 2-chloro-1-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-ethanone) was prepared with a 74% yield from 4-(4-phenoxy-phenyl)-piperidine (prepared in accordance with Example 8) and chloroacetyl chloride using the procedure illustrated in Example 4. In the second step, the 2-[trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-phenoxy-phenyl)-piperidin-1-yl]-ethanone was prepared from the 1-chloracetyl-4-(4-phenoxy-phenyl)-piperidine and trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (prepared in accordance with Example 5) using the procedure illustrated in Example 11. This afforded the product as a yellow solid (14% yield). The structure was confirmed using Protocol I-A. Calculated mass=598; observed mass=598; HPLC retention time=4.81 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][NH2:13]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:13][CH3:12]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CN
Solvent: CCO
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25 g) in ethanol (100 mL) was added methylamine (40% in methanol, 34.8 mL) at room temperature, and the mixture was stirred for 1 hr. The obtained mixture was cooled to 0° C., and the resulting precipitate was collected by filtration and washed with ice-cooled ethanol and diisopropyl ether. The obtained solid was dried to give the title compound (24.8 g) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:29]([CH:32]=[CH2:33])[CH2:30][S:31][C@H:26]12)[C:9](=[O:24])[CH:10]([C:12]1[N:13]=[C:14]([NH:17]C(=O)C(F)(F)F)[S:15][CH:16]=1)[NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+]>O1CCCC1.CC(C)=O.O>[C:1]([O:5][C:6]([N:8]([CH:25]1[C:50](=[O:51])[N:27]2[C:28]([C:34]([O:36][CH:37]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:35])=[C:29]([CH:32]=[CH2:33])[CH2:30][S:31][C@H:26]12)[C:9](=[O:24])[CH:10]([C:12]1[N:13]=[C:14]([NH2:17])[S:15][CH:16]=1)[NH2:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N(C(=O)OC(C)(C)C)C(=O)C(N)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of benzhydryl 7-[N-tert-butoxycarbonyl-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}glycinamido]-3-vinyl-3-cephem-4-carboxylate (2.5 g) and sodium acetate (2.8 g) in tetrahydrofuran (20 ml), acetone (20 ml) and water (40 ml) was stirred at ambient temperature for 2 hours. After the reaction mixture was evaporated, the residue was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then evaporated to give a residue, which was subjected to column chromatography on silica gel (50 g). Elution was carried out with methylene chloride and then a mixture of methylene chloride and diethyl ether (9:1 by volume), and the fractions containing the desired compound were collected and evaporated to give benzhydryl 7-[N-tert-butoxycarbonyl-2-(2-aminothiazol-4-yl)glycinamido]-3-vinyl-3-cephem-4-carboxylate (1.0 g).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([CH2:25][CH2:26][N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:30]([O:34][C:35]([N:37]1[CH2:41][C@@H:40]([F:42])[CH2:39][C@@H:38]1[CH:43]=[O:44])=[O:36])([CH3:33])([CH3:32])[CH3:31]>C1COCC1.C(OCC)(=O)C>[C:30]([O:34][C:35]([N:37]1[CH2:41][C@@H:40]([F:42])[CH2:39][C@@H:38]1[C@H:43]([OH:44])[C@@H:26]([N+:27]([O-:29])=[O:28])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31].[C:30]([O:34][C:35]([N:37]1[CH2:41][C@@H:40]([F:42])[CH2:39][C@@H:38]1[C@@H:43]([OH:44])[C@@H:26]([N+:27]([O-:29])=[O:28])[CH2:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: O=[N+]([O-])CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1[C@H](O)[C@H](Cc1ccccc1)[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46 %
Yield: 29 %

Procedure:
Add tetrabutylammonium fluoride (2.0 mL of 1.0 M solution in THF) to an ice-cold solution of 1-phenyl-2-nitroethane (0.51 mL, 3.79 mmol) in THF (2 mL). Stir 5 min and add 4-(S)-fluoro-2-(R)-formylpyrrolidine-1-carboxylic acid tert-butyl ester (0.58 g, 1.95 mmol) in THF (6 mL). Stir 90 min, dilute with ethyl acetate, wash with water (3×50 mL), saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with hexanes and ethyl acetate) to give the title compounds as foams, 4-(S)-fluoro-2-(R)-(1-(S)-hydroxy-2-(S)-nitro-3-phenylpropyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.21 g, 29%) and 4-(S)-fluoro-2-(R)-(1-(R)-hydroxy-2-(S)-nitro-3-phenylpropyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.33 g, 46%).
Reaction SMILES: [N:1]#[C:2]Br.[C:4]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:14]([NH:18][CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[C:13]2[CH:34]=[C:35]([CH2:42][CH3:43])[C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:12]1=2)=[O:10])([CH3:7])([CH3:6])[CH3:5].C(N(C(C)C)CC)(C)C>O1CCCC1>[C:4]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:33])[F:32])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=2)[C:2]#[N:1])[C:13]2[CH:34]=[C:35]([CH2:42][CH3:43])[C:36]([C:38]([F:41])([F:39])[F:40])=[CH:37][C:12]1=2)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 67.5 °C
Yield: 76.4 %

Procedure:
Add cyanogen bromide (0.352 g, 3.33 mmol) to a solution of (S)-5-(3,5-Bis-trifluoromethyl-benzylamino)-7-ethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid tert-butyl ester (0.647 g, 1.11 mmol) and diisopropylethylamine (0.679 mL, 3.89 mmol) in tetrahydrofuran (3 mL) at room temperature under nitrogen and heat the mixture at 65-70° C. for 16 hours and then for another 90° C. 16 h. Partition the cooled mixture between dichloromethane (40 mL) and brine (40 mL), separated layers. Extract aqueous with more dichloromethane (40 mL). Combine organic layers, dry over anhydrous sodium sulfate, filter and concentrated under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (0-20%), to provide the title compound (0.517 g, 76%), MS (ES+): 627 (M+NH4), 632 (M+Na).