Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[O:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C:20]([NH:22][CH2:23][CH2:24][N:25]1[C@H:30]([CH3:31])[CH2:29][NH:28][CH2:27][C@@H:26]1[CH3:32])=[O:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH3:7].[C:1]([N:28]1[CH2:27][C@@H:26]([CH3:32])[N:25]([CH2:24][CH2:23][NH:22][C:20]([C@@H:15]2[CH2:16][CH2:17][CH2:18][CH2:19][N:14]2[C:6]2[O:5][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]=2)=[O:21])[C@@H:30]([CH3:31])[CH2:29]1)(=[O:3])[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1C[C@@H](C)N(CCNC(=O)[C@@H]2CCCCN2c2nc3ccccc3o2)[C@@H](C)C1
Product: N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetyl chloride (0.018 ml) was added to a solution of (2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,6-dimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (0.1 g) [see Example 8] and potassium carbonate (36 mg) in acetonitrile (2 ml). The reaction mixture was stirred at room temperature for 2 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 97:3.5:0.5 changing to 97:3:1, by volume, dichloromethane:methanol: 0.88 aqueous ammonia solution (93:7:1), to afford (2S)-N2-2-[(cis)-4-acetyl-2,6-dimethyl-1-piperazinyl]ethyl-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxamide (91.6 mg) as a white foam.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:28][CH2:29][C:30]1[N:35]=[CH:34][C:33]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OCc1ccc(B(O)O)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccc(CO)nc2)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 89 mg, 0.2 mmol) and (6-(hydroxymethyl)pyridin-3-yl)boronic acid (61.2 mg, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and treated with Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol). The RM was stirred under argon at 95° C. for 2 h in a sealed pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The residue was diluted in MeOH, treated with Si-Thiol (100 mg), the resin was filtered off and the solvent was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (Silica gel column, EtOAc/MeOH, from 0 to 20% MeOH) afforded the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4 min, UPLC-MS (Condition 3) tR=0.87 min, m/z=475.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.76 (m, 1H) 1.77-1.86 (m, 1H) 2.86 (d, J=11.34 Hz, 1H) 3.11-3.26 (m, 2H) 3.33-3.43 (m, 1H) 4.12-4.22 (m, 1H) 4.61 (d, J=5.87 Hz, 2H) 4.84 (d, J=3.13 Hz, 1H) 5.47 (t, J=5.87 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.53 (d, J=8.21 Hz, 1H) 7.74-7.88 (m, 3H) 8.00 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:23].CCN(C(C)C)C(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.Cl.[NH2:46][CH2:47][C:48]([CH3:52])([CH3:51])[C:49]#[N:50]>ClCCl>[CH2:16]([N:13]1[CH2:12][CH2:11][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:37]([NH:50][CH2:49][C:48]([C:47]#[N:46])([CH3:52])[CH3:51])=[O:43])=[C:3]([F:23])[CH:4]=2)=[O:9])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cc1F
Reactant: CC(C)(C#N)CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C#N)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(4-Amino-3-fluorophenyl)(4-benzylpiperazin-1-yl)methanone and Hunig's base (32.5 mmol, 5.38 mL, 4.21 g) were stirred in dichloromethane. Triphosgene (3.54 mmol, 1.051 g) was added and the reaction stirred at ambient temperature for 30 minutes. 3-Amino-2,2-dimethylpropanenitrile hydrochloride (9.57 mmol, 1.289 g) was added and the reaction stirred for a further 30 minutes. The reaction mixture was washed with water and the organic layer concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (eluant dichloromethane/methanol 0% to 5%) to afford the title compound (1.809 g). MS (ESI) m/z 438.1 [M+H]+
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([O:14][C:15](=[O:25])[CH2:16][C:17](=O)[CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:13].[N:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[N+:27]=[N-:28].O>CN(C=O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:26]1[C:17]([CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:25])[N:28]=[N:27]1
Reactant: [N-]=[N+]=Nc1ccccc1F
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1nnn(-c2ccccc2F)c1C1CCOCC1
Reaction time: 0.25 h

Procedure:
DBU (1.32 ml; 8.82 mmol; 1.10 eq.) was dissolved in DMF (16.5 ml) and put under nitrogen atmosphere. 3-Oxo-3-(tetrahydro-pyran-4-yl)-propionic acid ethyl ester (Pharmacore, 1.767 g; 8.82 mmol; 1.10 eq.) was added to the mixture and it was stirred for 15 min. Then a solution of 1-azido-2-fluorobenzene, prepared according to Platz, M. S. et al. J. Org. Chem. 1989, 54, 5938-5945, (1.1 g; 8.02 mmol; 1 eq.) in DMF (15 mL) was added dropwise to the solution at room temperature. The reaction mixture was stirred at 70° C. for 2 hours. Water (40 mL) was added to the reaction mixture. The aqueous layer was extracted with EtOAc (3×40 mL). Combined organic layers were washed with HCl 0.1N, brine, dried over MgSO4 and concentrated under vacuum giving the title compound as a yellow oil. It was used in the next step without further purification. LC/MS (Method B): 320.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.[CH2:44]([O:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58]Br)[CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH2:44]([O:51][C:52]1[CH:53]=[C:54]([CH:55]=[CH:56][CH:57]=1)[CH2:58][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: BrCc1cccc(OCc2ccccc2)c1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2cccc(OCc3ccccc3)c2)c2ccccc2C12COc1cc3c(cc12)CCO3

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 1-(benzyloxy)-3-(bromomethyl)benzene to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[3-(benzyloxy)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: mp 66-68° C.; 1H NMR (300 MHz, CDCl3) δ7.43-7.14 (m, 8H), 7.06-6.99 (m, 1H), 6.97-6.87 (m, 3H), 6.81-6.75 (m, 1H), 6.48 (s, 1H), 6.43 (s, 1H), 5.10-5.00 (m, 3H), 4.85-4.75 (m, 1H), 4.84 (ABq, 2H), 4.56-4.47 (m, 2H), 2.98-2.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.9, 161.8, 161.3, 159.2, 142.1, 137.4, 136.6, 132.7, 129.9, 128.7, 128.6, 128.0, 127.5, 123.8, 123.4, 120.2, 119.9 (2C), 118.8, 114.0, 113.9, 109.3, 93.2, 80.5, 72.3, 70.0, 57.7, 44.0, 29.0; MS (ES+) m/z 476.1 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].ClCCl>[Pd].C(OCC)(=O)C.C(O)(=O)C>[CH3:1][S:2]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CCN(c2cc(-c3ccccc3)cc([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)(=O)N1CCN(c2cc(N)cc(-c3ccccc3)c2)CC1
Reaction time: 1.5 h

Procedure:
Palladium on carbon (10 wt %, 13 mg, 0.012 mmol) was added to a solution of 1-(methylsulfonyl)-4-(5-nitrobiphenyl-3-yl)piperazine (44.1 mg, 0.122 mmol) in ethyl acetate (1 mL) and acetic acid (0.1 mL) and the reaction mixture was stirred under an atmosphere of H2 (balloon) for 90 minutes. Dichloromethane was added to the reaction mixture, and the mixture was filtered through CELITE, rinsed with ethyl acetate and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes) to provide 5-[4-(methylsulfonyl)piperazin-1-yl]biphenyl-3-amine as a white foam. 1H NMR (400 MHz, Acetone) δ 9.18 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 7.77-7.63 (m, 3H), 7.47 (dd, J=10.4, 4.7 Hz, 2H), 7.37 (t, J=7.4 Hz, 1H), 7.23 (d, J=4.9 Hz, 1H), 7.02 (d, J=1.5 Hz, 1H), 3.43 (dd, J=12.4, 5.3 Hz, 8H), 2.91 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]3[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=[CH:21][C:7]=3[N:6]2[CH:25]=1.C(=O)([O-])[OH:27].[Na+]>O1CCOCC1.O>[N+:22]([C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[CH:25]=[C:3]([CH2:2][OH:27])[N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:8]=2[CH:18]=1)([O-:24])=[O:23]
Reactant: O=C([O-])O
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nc(CCl)cn1-2
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nc(CO)cn1-2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 50.7 %

Procedure:
A solution of 5.1 g of 2-chloromethyl-8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine in 70 ml of dioxan was treated with a solution of 1.54 g of sodium hydrogen carbonate in 30 ml of water and the mixture was stirred at 80° C. for 2.5 h. The mixture was filtered and the filtrate was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloric acid. The filtrate was evaporated in a vacuum and the residue was taken up in chloroform and water. The chloroform phase was washed with water, dried over sodium sulphate and evaporated in a vacuum. The crystalline residue (3.2 g) was dissolved in chloroform and chromatographed over 130 g of silica gel. With chloroform and with chloroform/ethanol 98:2 there were eluted small amounts of various impurities, with chloroform/ethanol 97:3 and 96:4 there was eluted 8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. After recrystallization from ethanol there were obtained 2.45 g of pure 8-nitro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 250-251° C. which was converted into the hydrochloride (m.p. 295-297° C.).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:29]([CH:33]1[CH2:35][O:34]1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:35][CH:33]([OH:34])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC(C)(C)C1CO1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(O)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 80 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2-tert-butyloxirane (0.78 g), potassium carbonate (1.1 g) and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.63 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].OC1C=CC(C=O)=C(OC)C=1.CC1OC(C2C=CC=CC=2)=NC=1CCOS(C)(=O)=O.[CH2:56]([C@H:63]1[CH2:67][O:66][C:65](=[O:68])[N:64]1[C:69](=[O:74])[CH2:70][O:71][CH2:72][CH3:73])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC>>[CH2:56]([C@H:63]1[CH2:67][O:66][C:65](=[O:68])[N:64]1[C:69](=[O:74])[C@@H:70]([O:71][CH2:72][CH3:73])[C@H:5]([OH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:10][C:3]=1[O:2][CH3:1])[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1C=O
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Agent: COc1cc(O)ccc1C=O
Agent: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1OC

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (prepared from 4-hydroxy-2-methoxy-benzaldehyde and methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in analogy to the procedure described in example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (2S)-2-ethoxy-3-{2-methoxy-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: C([Cl:4])(=O)C.[OH:5][C@H:6]1[C@H:11]([CH3:12])[CH2:10][CH2:9][C@@H:8]([NH:13]C(=O)OC(C)(C)C)[CH2:7]1>CO>[ClH:4].[NH2:13][C@H:8]1[CH2:7][C@@H:6]([OH:5])[C@H:11]([CH3:12])[CH2:10][CH2:9]1
Reactant: CC(=O)Cl
Reactant: C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)C[C@H]1O
Solvent: CO
Product: C[C@@H]1CC[C@@H](N)C[C@H]1O
Product: Cl
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
To vigorously stirring methanol (149 mL) at 0° C. was added acetyl chloride (15.87 mL, 223 mmol) and the resulting mixture stirred for 10 min. To this solution was added tert-butyl (1R,3R,4R)-3-hydroxy-4-methylcyclohexylcarbamate (17.08 g, 74.5 mmol) and the mixture was stirred for 22 h at room temperature. The crude reaction was concentrated and then triturated with ethyl ether (2×300 mL) to afford (1R,2R,5R)-5-amino-2-methylcyclohexanol hydrochloride (12.2 g, 73.6 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (br. s., 3H), 4.77 (d, J=5.86 Hz, 1H), 2.85-3.10 (m, 2H), 2.03-2.21 (m, 1H), 1.83 (d, J=11.71 Hz, 1H), 1.65 (dd, J=13.47, 3.32 Hz, 1H), 1.24 (q, J=11.58 Hz, 2H), 1.12 (dd, J=6.05, 3.32 Hz, 1H), 0.82-1.03 (m, 4H).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1.C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+]>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.O.C(O)C>[C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:3][CH:2]=1
Reactant: Brc1ccco1
Reactant: Cc1ccc(B(O)O)cc1
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: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(-c2ccco2)cc1

Procedure:
4-tolylboronic acid (500 mg), 2-bromofuran, and tetrakis(triphenylphosphine)palladium (177 mg) were added to the mixture of 24 ml of dimethoxyethane and 15 ml of ethanol under nitrogen atmosphere. Additionally 1N sodium carbonate (12 ml) was added to the mixture and the resulting mixture was heated at reflux for 2 h. Water was added to the mixture and the mitture was extracted with diethyl ether. The organic layer was dried and the solvent was removed under reduced pressure. The residue was purified by the use of silica gel column chromatography to give 438 mg of 2-(4-tolyl)furan.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:5]([CH3:18])=[C:4]([CH3:19])[N:3]=1.O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].[N-:31]=[N+:32]=[N-:33].[Na+].C(#N)C>O>[CH3:19][C:4]1[N:3]2[N:31]=[N:32][N:33]=[C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[C:5]=1[CH3:18]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCO)c1C
Reactant: [N-]=[N+]=[N-]
Agent: [Ce+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1c(NCCCCCO)c([N+](=O)[O-])c2nnnn2c1C
Temperature: 25 °C

Procedure:
The preparation of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol was described in Part A of Example 85. Under a nitrogen atmosphere, cerium (III) chloride heptahydrate (8.08 g, 21.7 mmol) and sodium azide (5.64 g, 86.8 mmol) were added to a solution of 5-(2-chloro-5,6-dimethyl-3-nitropyridin-4-ylamino)pentan-1-ol (12.48 g, 43.38 mmol) in a 9:1 mixture of acetonitrile and water (145 mL). The reaction was stirred and heated at reflux for two days then allowed to cool to room temperature. A precipitate was removed by filtration and washed with acetonitrile. The filtrate was concentrated under reduced pressure to provide 12.13 g of 5-[(5,6-dimethyl-8-nitrotetrazolo[1,5-a]pyridin-7-yl)amino]pentan-1-ol as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Br:13]Br.C([O-])(O)=O.[Na+]>C(OCC)C.O>[Br:13][CH:3]1[C:2](=[O:1])[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1
Reactant: BrBr
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a 0° C. solution of ethyl 4-oxocyclohexanecarboxylate (6.0 g, 35.3 mmol) in diethyl ether (200 mL) was added dropwise a solution of bromine (5.3 g, 33.3 mmol) in diethyl ether (20 mL). The resulting mixture was stirred at room temperature for 40 min, then was cooled in an ice/water bath, diluted with water, and neutralized with aqueous NaHCO3 solution. The organic layer was separated and washed with water then brine, then was dried over MgSO4 and concentrated to an oil, which was used in next reaction without purification.
Reaction SMILES: N[C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12.N([O-])=O.[Na+].[Cl-:27].[Na+]>C(O)C.O.Cl>[Cl:27][C@H:2]1[C:21](=[O:22])[N:4]2[C:5]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:6]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH2:7][S:8][C@H:3]12
Reactant: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](N)[C@H]2SC1
Reactant: [Cl-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)OCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@H](Cl)[C@H]2SC1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an ice-cooled solution of t-butyl 7α-amino-3-acetoxymethyl-3-cephem-4-carboxylate (4.0 g, 0.0122 mol) in 75 ml of ethanol, 16.7 ml of water and 16.7 ml of concentrated hydrochloric acid was added portionwise over 15-20 minutes sodium nitrite (1.18 g, 0.017 mol). The reaction mixture was stirred at 0°-5° C. for 2.5 hours, saturated with sodium chloride, extracted with methylene chloride, washed with water, brine, dried Na2SO4 and concentrated to give 3.1 g (73%) of t-butyl 7α-chloro-3-acetoxymethyl-3-cephem-4carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:3]=1[O:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:18][CH:17]2[O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][C:40](=O)[N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=3[CH:49]=2)=[CH:12][CH:11]=1)=O.B1C2CCCC1CCC2.C(CN)O>O1CCCC1>[F:1][C:2]1[CH:53]=[CH:52][C:51]([F:54])=[CH:50][C:3]=1[O:4][CH2:5][CH2:6][NH:7][CH2:8][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:18][CH:17]2[O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]3[O:42][CH2:41][CH2:40][N:39]([CH2:44][CH2:45][CH2:46][O:47][CH3:48])[C:38]=3[CH:49]=2)=[CH:12][CH:11]=1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(C(=O)NCCOc4cc(F)ccc4F)cc3)cc21
Agent: B1C2CCCC1CCC2
Solvent: NCCO
Solvent: C1CCOC1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CNCCOc4cc(F)ccc4F)cc3)cc21

Procedure:
The solution of 0.440 g of benzyl 4-{4-[2-(2,5-difluorophenoxy)ethylcarbamoyl]phenyl}-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 2.0 ml of tetrahydrofuran is admixed with 13.6 ml of 9-BBN (0.5M in tetrahydrofuran) and stirred at reflux over 18 hours. The reaction mixture is cooled, admixed with 0.412 ml of ethanolamine and concentrated by evaporation. The residue is stirred at 0° C. in 40 ml of EtOAc-heptane (1:1) overnight and clarified by filtration, and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.11 (1:3 EtOAc-heptane); Rt=4.76.