Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH2:21])=[O:20].[C:25](=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19]([NH:21][CH2:25][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[O:20]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1cccc(Cl)c1
Agent: C=O
Agent: [K+]
Solvent: CCO
Product: O=C(NCN1CCN(c2ccccn2)CC1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (16 mg, 0.1 mmol, Aldrich), paraformaldehyde (30 mg, 1 mmol), 3-chlorobenzamide (78 mg, 0.5 mmol, Maybridge), and 42 mg of potassium carbonate (0.3 mmol) in 2 mL absolute ethyl alcohol was heated to reflux under nitrogen overnight. The mixture was cooled to room temperature, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% methanol:ethyl acetate) to give 26 mg (52%) pure compound; 1H NMR (500 MHz, DMSO-d6) δ 2.58 (t, J=4 Hz, 4H), 3.50 (t, J=4 Hz, 4H), 4.19 (d, J=5 Hz, 1H), 6.62 (t, J=5 Hz, 1H), 6.81 (d, J=6 Hz, 1H), 7.51 (m, 2H), 7.61 (m, 1H), 7.82 (d, J=6 Hz, 1H), 7.92 (s, 1H), 8.12 (d, J=5 Hz, 1H), 8.93 (t, J=5 Hz, 1H); MS (ESI/APCI−) m/e 329 (M−H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([F:23])[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([CH3:22])=[N:20][N:19]=[N:18]2)=[C:13]([F:23])[CH:12]=1)[CH2:5][CH:6]1[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCC1)c1ccc(-n2nnnc2C)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
A solution of nickel (II) chloride hexahydrate (115 mg, 0.24 mmol) and (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (400 mg, 1.21 mmol) in methanol (10 mL) was cooled to 0° C. and then treated with sodium borohydride (275 mg, 3.63 mmol) in two portions. After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with a 3N aqueous hydrochloric acid solution (30 mL) and ethyl acetate (50 mL). The two layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid methyl ester (400 mg, 99%) as a viscous oil: EI-HRMS m/e calcd for C17H21FN4O2 (M+) 332.1648, found 332.1645.
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1C=CC(S(OCC)(=O)=O)=CC=1.[CH3:21][N:22]([CH:24]=[N:25][S:26]([C:29]1[C:30]([C:35]2[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=2)=[CH:31][CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27])[CH3:23].C([BH3-])#N.[Na+]>ClCCl>[C:6]([CH:2]([NH:1][CH2:41][C:38]1[CH:39]=[CH:40][C:35]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[S:26]([N:25]=[CH:24][N:22]([CH3:23])[CH3:21])(=[O:28])=[O:27])=[CH:36][CH:37]=1)[C:3]([O:5][CH2:8][CH3:9])=[O:4])#[N:7]
Reactant: N#CC(N)C(=O)O
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(C=O)cc1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(C#N)NCc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.9 %

Procedure:
2 g of ethyl mono (4-methylbenzenesulfonate) aminocyano acetate of Stage B of Example 1 and 1.9 g of N-[(dimethylamino) methylene]-4'-formyl-(1,1'-biphenyl)-2-sulfonamide of Stage A of Example 1 were stirred in dichloromethane at 35° for 3 hours and then 0.396 g of sodium cyano borohydride were added. The solution was stirred at ambient temperature for 18 hours and the reaction mixture was filtered, washed with water and evaporated. After chromatography on silica (dichloromethane-ethyl acetate 85-15), 770 mg of the expected product were obtained, identical to that of Stage C of Example 1.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38]O)[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:59]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH2:37][CH2:38][Br:59])[CH:30]=2)=[CH:24][CH:23]=1)[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCO)c2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCBr)c2)cc1
Yield: 63 %

Procedure:
The crude product from Example 72C and triphenylphosphine (0.730 g, 2.78 mmoles) in anhydrous DMF (5 mL) at 0° C. were treated with N-bromosuccinimide (0.396 g, 2.24 mmoles). Reaction mixed at 0° C. for 30 minutes. Reaction diluted with ethyl acetate, washed with H2O (2×), brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 30% ethyl acetate:hexanes) to provide the title compound (0.214 g, 63%). MS (ESI+) m/z 609 (M+H)+.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[N:34]1[CH:39]=[CH:38][N:37]=[C:36]2[NH:40][CH:41]=[CH:42][C:35]=12.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[N:34]1[CH:39]=[CH:38][N:37]=[C:36]2[N:40]([CH2:6][C@H:7]3[CH2:12][N:11]([S:13]([C:16]4[S:17][CH:18]=[CH:19][CH:20]=4)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]3[C:21]3[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=3)[CH:41]=[CH:42][C:35]=12
Reactant: c1cnc2[nH]ccc2n1
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2Cn2ccc3nccnc32)cc1)C(F)(F)F
Temperature: 80 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a 50-mL round-bottomed flask was added ((2R)-4-(thiophen-2-ylsulfonyl)-1-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)piperazin-2-yl)methyl methanesulfonate (50 mg, 0.095 mmol, Intermediate B), 5H-pyrrolo[2,3-b]pyrazine (17 mg, 0.142 mmol, ARK Pharm., Libertyville, Ill.) and cesium carbonate (62 mg, 0.19 mmol) in acetonitrile (2 mL). The reaction mixture was stirred at 80° C. for 18 h. The mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an off-white glass. The crude product was purified by silica gel chromatography, eluting with 100% EtOAc to give 2-(4-((S)-2-((5H-pyrrolo[2,3-b]pyrazin-5-yl)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)-1,1,1-trifluoro-2-propanol (38 mg) as a white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH2:24][OH:25])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH2:29][CH2:28]1.[C:42](=[O:45])([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[C:4]([O:45][C:42]1[CH:17]=[CH:18][C:9]([C@H:24]([C:12]2[C:13]([CH:21]([CH3:23])[CH3:22])=[N:14][C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[CH2:18][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C:10]=3[C:11]=2[C:30]2[CH2:29][CH2:28][O:27][CH2:32][CH:31]=2)[OH:25])=[CH:10][CH:15]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1nc2c(c(I)c1CO)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@H](O)c1ccc(OC(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (R)-(4-tert-butoxyphenyl)((S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-ylmethanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 5:1.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]\[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH3:22]
Reactant: C/C(=C\C(C)c1ccccc1C)CO
Reactant: CC[Zn]CC
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1ccccc1[C@H](C)[C@@H]1C[C@@]1(C)CO
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 6.92 g, 8.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −20° C. Chloroiodomethane (2.96 g, 16.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −5 to −15° C. for 10 minutes, and then cooled to −25° C. (E)-2-Methyl-4-(2-methylphenyl)pent-2-en-1-ol (0.80 g, 4.2 mmol) was added dropwise at −20 to −25° C. over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (3.1 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(2-methylphenyl)ethyl)cyclopropyl]methanol (0.32 g, 1.6 mmol, 37% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(2-methylphenyl)ethyl)cyclopropyl]methanol (0.025 g, 0.12 mmol, 3% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [C:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)(=[O:3])[NH2:2].[Si:9](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CN=C1.C(O)C>CN(C)C=O>[Si:9]([O:8][CH:6]1[CH2:7][N:4]([C:1](=[O:3])[NH2:2])[CH2:5]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: NC(=O)N1CC(O)C1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)[Si](OC1CN(C(N)=O)C1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 18 %

Procedure:
To a solution of 1-carbamoyl-3-hydroxyazetidine (obtained as described in Reference Example 21(1)) in dimethylformamide (100 ml) were added t-butyldiphenylsilyl chloride (18.0 ml, 66.9 mmol) and imidazole (4.55 g, 66.9 mmol) in an ice bath. After stirring the mixture in an ice bath for 10 minutes, the resulting mixture was stirred at room temperature overnight. After checking the completion of the reaction, ethanol (1 ml) was added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (10:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-carbamoylazetidine (1.45 g, total yield 18%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]([CH3:12])([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][Br:10])[CH3:2].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Br-:10].[CH2:1]([O:3][C:4]([C:5]([CH3:12])([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:13])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
6-Bromo-2,2-dimethylhexanoic acid ethyl ester (38.0 g, 0.15 mol) and triphenylphosphine (40.0 g, 0.15 mol) were dissolved in toluene (100 mL) and heated to reflux for 24 hours under an argon atmosphere. After 24 hours of heating, the flask was allowed to cool to room temperature and stirred for an additional 24 hours at room temperature. After 48 hours, the toluene was removed under reduced pressure. The remaining material was dissolved in dichloromethane (100 mL) and added drop-wise to t-butyl methyl ether (600 mL). The ether was decanted away from the precipitate, which was dried to a constant weight under high vacuum to provide (5-ethoxycarbonyl-5-methylhexyl)-triphenylphosphonium bromide (71.5 g, 93.1% yield) as a light yellow foam. 1H NMR (300 MHz, CDCl3/TMS): S=7.87-7.57 (m, 15H), 4.05 (l, 2H, J=7.2 Hz), 3.67 (m, 2H), 1.78-1.45 (m, 6H), 1.20 (t, 3H, J=7.2 Hz), 1.12 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ=177.02, 134.56 (d, 3C, J=2.4 Hz), 132.94 (d, 6C, J=10.1 Hz), 129.99 (d, 6C, J=12.6 Hz), 117.44 (d, 3C, J=85.4 Hz), 59.78, 41.47, 39.12, 25.44 (d, 1H, J=15.5 Hz), 24.62, 22.59 (d, 1H, J=4.1 Hz), 21.96, 13.83. HRMS (ESI-TOF): Calculated for (M+): 433.2291. Found: 433.2330.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=1[F:23])[C:10]([CH3:25])([CH3:24])[CH:9]2O)=[O:5])[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([Br:22])[CH:19]=[CH:18][C:17]=1[F:23])[C:10]([CH3:24])([CH3:25])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cc(Br)ccc1F)N2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(Br)ccc1F)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.7 %

Procedure:
To a mixture of 2-(5-bromo-2-fluoro-phenyl)-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (3.33 g, 7.9 mmol) and triethylsilane (5 mL) at 25° C. was added trifluoroacetic acid (1 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×20 mL), washed with saturated aqueous sodium bicarbonate solution (2×10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 2-(5-bromo-2-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.76 g, 24%) as a white solid: LC/MS m/e calcd for C20H21BrFNO2 M+: 406.3, observed: 406.3, 408.2.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:20]([O:22][C:23]([C@:25]1([NH2:37])[CH2:30][C@H:29]([OH:31])[C@@H:28]2[C@H:26]1[C@H:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:24])[CH3:21]>ClCCl>[CH2:20]([O:22][C:23]([C@:25]1([NH:37][C:17](=[O:19])[CH:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:30][C@H:29]([OH:31])[C@@H:28]2[C@H:26]1[C@H:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:24])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](N)(C(=O)OCC)C[C@@H]2O
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2O
Yield: 87 %

Procedure:
Prepare according to the General Procedure A using Boc-L-phenylalanine (772 mg, 2.91 mmoles) and (1S,2S,4S,5R,6R)-2-amino-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (480 mg, 1.94 mmoles, Preparation 22). Concentrate the crude reaction mixture, dissolve in dichloromethane, flash through a short silica gel plug with ethyl acetate/DCM (1:1), and concentrate in-vacuo to give a yellow oil. Further purify the material by silica gel chromatography eluting with 30% ethyl acetate/hexanes to 80% ethyl acetate/hexanes to afford 852 mg (87%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:28][CH:29]([F:31])[F:30])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.O.[OH-].[Na+].C(O)(=O)C>CO>[F:31][CH:29]([F:30])[O:28][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:32])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
A solution of [4-difluoromethoxy-2-ethyl-8-fluoro-3-(4-methoxybenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.30 g) in methanol (10 mL), and water (1.0 mL) was treated with 5.0 M aqueous sodium hydroxide solution (0.67 mL) and the resulting mixture was stirred at room temperature for 1 hour. The mixture was acidified by the addition of glacial acetic acid, concentrated under reduced pressure, and the residue purified by preparative reverse-phase HPLC to afford title compound as a pale yellow solid (0.086 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:45])[CH2:10][C:11]1[CH:44]=[CH:43][CH:42]=[CH:41][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:40]=[CH:39][C:29]([CH2:30][NH:31]C(=O)OC(C)(C)C)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl>[NH2:31][CH2:30][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=3[CH2:10][C:9]([NH2:8])=[O:45])[C:20]([C:21]([F:23])([F:24])[F:22])=[CH:19][N:18]=2)=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(Nc2ncc(C(F)(F)F)c(CCc3ccccc3CC(N)=O)n2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.8 %

Procedure:
TFA (954 μL, 12.5 mmol) was added to a solution of tert-butyl 4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate (A16) (220 mg, 0.415 mmol) in DCM (10 mL) and the resulting mixture stirred for 20 hours at room temperature. The volatiles were removed in vacuo and the resulting residue partitioned between EtOAc (100 mL) and 2 M aqueous NaOH (100 mL). The layers were separated and the organic layer washed with water (100 mL), brine (50 mL), dried (MgSO4) then evaporated in vacuo to yield a white solid. The solid was taken up in DCM (10 mL) and sonicated for 2 minutes then petroleum benzine 40-60° C. (100 mL) was added and sonication continued for a further 10 minutes. The resulting suspension was filtered and the filter cake dried to give the title compound 3 as a white solid (135 mg, 76%); 1H NMR (400 MHz, d4-MeOH) δ 8.57 (s, 1H), 7.68 (d, J=8.6 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.31-7.17 (m, 4H), 3.81 (s, 2H), 3.69 (s, 2H), 3.22-3.06 (m, 4H). LCMS-A: rt 4.722 min; m/z 428 [M−1]−.
Reaction SMILES: [BH4-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]([NH:11][CH:12]1[C:41](=[O:42])[N:14]2[C:15]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:16]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[C:17](=[CH2:19])[S:18][C@H:13]12)=[O:10].CC(O)=O>CCO.O1CCCC1>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]([NH:11][CH:12]1[C:41](=[O:42])[N:14]2[CH:15]([C:25]([O:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:26])[C:16]([CH2:20][O:21][C:22](=[O:24])[CH3:23])=[C:17]([CH3:19])[S:18][C@H:13]12)=[O:10]
Reactant: C=C1S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1COC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)OCC1=C(C)S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.12 h
Yield: 41.4 %

Procedure:
A solution of 4.4 g of NaBH4 in 250 ml of EtOH was added to a solution of 45 g of diphenylmethyl 7-(2-thienylacetamido)-2-methylene-3-acetoxymethylceph-3-em-4-carboxylate in 150 ml of tetrahydrofuran at 0° C., and the mixture was stirred for 7 minutes, followed by adding 15 ml of AcOH. After distilling off the solvent under reduced pressure, AcOEt and H2O were added to the residue to separate out the AcOEt layer. The AcOEt layer was washed with 5% aqueous NaHCO3 and saturated aqueous sodium chloride solution, and dried over Na2SO4 to distill off the AcOEt under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (10:1) were collected, followed by distilling off the solvent under reduced pressure, yielding 18.7 g (41%) of diphenylmethyl 7-(2-thienylacetamido)-2-methyl-3-acetoxymethylceph-2-em-4-carboxylate.
Reaction SMILES: CS(O[C:6]#[C:7][CH3:8])(=O)=O.[Br:9][C:10]1[C:11]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]([Cl:28])=[CH:23][C:22]=2[F:29])=[C:12]([Cl:20])[N:13]([CH3:19])[C:14]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].O>CC(CC(C)C)=O>[Br:9][C:10]1[C:11]([C:21]2[CH:26]=[C:25]([O:27][CH2:8][C:7]#[CH:6])[C:24]([Cl:28])=[CH:23][C:22]=2[F:29])=[C:12]([Cl:20])[N:13]([CH3:19])[C:14]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CC#COS(C)(=O)=O
Reactant: Cn1c(Cl)c(-c2cc(O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: C#CCOc1cc(-c2c(Br)c(C(F)(F)F)n(C)c2Cl)c(F)cc1Cl
Temperature: 80 °C
Yield: 42.8 %

Procedure:
2 propinyl methanesulfonate (0.22 g; 1.61 mmoles) is added to a mixture of 4-bromo-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-chloro-1-methyl-5-trifluoromethyl pyrrole (0.6 g; 1.47 mmoles) and potassium carbonate (0.21 g; 1.54 mmoles) in methylisobutylketone (6 ml). The mixture is heated to 80° C. for 3 hours. The reaction mixture is poured into water (10 ml), extracted with ethyl ether (3×20 ml), the ether phase is washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated in a rotavapor. The raw product obtained (0.65 g) is chromatographed on silica gel, eluating with n-hexane/ethyl acetate 85:15. 0.28 g of solid white product with a melting point of 87° C., are obtained.