Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:13]([C:12]([F:11])([F:21])[F:20])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:1][N:2]=1
Reactant: ON=C(Cl)c1ccccn1
Reactant: CCOC(=O)C#CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1onc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.7 %

Procedure:
To a yellow, homogeneous mixture of N-hydroxypicolinimidoyl chloride (4.67 g, 29.8 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (4.50 g, 27.1 mmol) in dichloromethane (90 mL) at room temperature was added triethylamine (7.93 mL, 56.9 mmol) slowly over 30 min. During the addition, the reaction mixture slowly became dark in color. The reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was diluted with ether (100 mL) and washed with water (100 mL). The organic layer was collected, and the aqueous layer was extracted with ether (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By HPLC, the product mixture contained a ˜15:85 mixture of the desired isomer and its regioisomer. The mixture was purified by preparative HPLC, and the desired fractions were concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with a saturated aqueous solution of sodium bicarbonate (100 mL), washed with brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (0.518 g, 1.81 mmol, 6.7% yield) as a pale yellow, viscous oil. The compound had an HPLC ret. time=2.18 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=286.9. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (t, J=7.15 Hz, 3H), 4.54 (q, J=7.03 Hz, 2H), 7.46 (ddd, J=7.53, 4.77, 1.25 Hz, 1H), 7.76-7.81 (m, 1H), 7.83-7.89 (m, 1H), and 8.78 (d, J=4.77 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH:11](Br)Br)[CH:3]=1.Cl.C([OH:17])C.O>[N+]([O-])([O-])=O.[Ag+]>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([CH:11]=[O:17])[CH:3]=1
Reactant: COC(=O)c1sc(Br)cc1C(Br)Br
Reactant: CCO
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: COC(=O)c1sc(Br)cc1C=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
Silver nitrate (1.43 g, 8.39 mmol) was added to a mixed solution of methyl 5-bromo-3-(dibromomethyl)thiophene-2-carboxylate obtained in Example (246a) (1.57 g, 4.00 mmol) in ethanol/water (30 mL/10 mL), and the mixture was stirred at 80° C. for three hours. Concentrated hydrochloric acid was added to the reaction solution at 0° C., and then the mixture was filtered. The filtrate was concentrated under reduced pressure. Then, saturated aqueous sodium bicarbonate solution was added to the resulting residue, and the aqueous layer was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate, and then the filtrate was concentrated under reduced pressure to obtain 980 mg of the title compound as a pale yellow solid (98%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[C:5]([NH2:13])[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:56]([O:60][C:61]([NH:63][C:64]1[S:68][C:67]([C:69]2[C:74]([F:75])=[CH:73][CH:72]=[CH:71][C:70]=2[F:76])=[N:66][C:65]=1[C:77](O)=[O:78])=[O:62])([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl>[F:76][C:70]1[CH:71]=[CH:72][CH:73]=[C:74]([F:75])[C:69]=1[C:67]1[S:68][C:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:58])([CH3:57])[CH3:59])=[C:65]([C:77](=[O:78])[NH:13][C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[N:66]=1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Cn1ncc(N)c1C1CCOCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.5 %

Procedure:
A solution of 5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.38 mmol) in MeOH (20 mL) was passed through the H-Cube® (30 bar, 25° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude 1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine as a light yellow oil (64 mg, 0.35 mmol). To a solution of this amine (60 mg, 0.33 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.34 g, 0.66 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (124 mg, 0.35 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (102 mg, 59%). This solid (100 mg, 0.19 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 1.9 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7 N ammonia in MeOH to yield 301 as a peach solid (59 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.69 (s, 1H), 7.34-7.29 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.09 (dd, J=11.6, 4.2 Hz, 2H), 3.88 (s, 3H), 3.50 (t, J=11.6 Hz, 2H), 3.02-2.95 (m, 1H), 2.17-2.08 (m, 2H), 1.78 (d, J=13.4 Hz, 2H). LCMS (ES+) m/z 420 (M+1)
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:17])[CH2:8][C:9](=[O:16])[CH2:10][O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:5].[C:18](Cl)(=[O:20])[CH3:19].[Cl-].[NH4+]>ClCCl.N1C=CC=CC=1>[CH2:4]([O:6][C:7](=[O:17])[CH:8]([C:18](=[O:20])[CH3:19])[C:9](=[O:16])[CH2:10][O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH3:5]
Reactant: CCOC(=O)CC(=O)COC(C)(C)C
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C(C)=O)C(=O)COC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of dry magnesium chloride (0.471 g) in dichloromethane (6 ml) was treated with 4-tert-butoxy-3-oxo-butyric acid ethyl ester [1.00 g, Reference Example 43]. This mixture was cooled to 0° C., then treated with pyridine (0.80 ml), then stirred for 15 minutes at 0° C. and then treated with acetyl chloride (0.352 ml). After stirring for a further 15 minutes at 0° C. and then for 1 hour at ambient temperature the reaction mixture was treated with saturated aqueous ammonium chloride solution and then extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated to yield 2-acetyl-4-tert-butoxy-3-oxo-butyric acid ethyl ester (1.15 g) as a yellow oil which was used without further purification. LC-MS (METHOD B): RT=3.16 minutes; 243 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[C:20](=[O:29])[CH:19]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[C:20](=[O:29])[CH:19]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C1C=C(OCCCCCCO)c2ccccc2C1=O
Reactant: N#Cc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: N#Cc1ccc(OCCCCCCOC2=CC(=O)C(=O)c3ccccc32)cc1
Temperature: 10 °C
Reaction time: 10 h
Yield: 62.4 %

Procedure:
A mixture of 4-hydroxybenzonitrile (87 mg, 0.73 mmol), naphthoquinone 504 (200 mg, 0.73 mmol), PPh3 (191 mg, 0.73 mmol) in dioxane (10 mL) was cooled to 10° C. and treated with DEAD (140 mg, 0.80 mmol). The reaction mixture was stirred for 10 h, concentrated in vacuo and purified by chromatography (5% EtOAc in benzene) to afford 511 as a yellow solid (171 mg, 53%), 1H NMR (CDCl3) 8.13 (dd, J=7.3, 1.4 Hz, 1H), 8.86 (dd, J=7.7, 1.1 Hz, 1H), 7.67 (dt, J=7.5, 1.5 Hz 1H), 7.60 (dt, J=7.5, 1.5 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.9 Hz, 2H), 5.96 (s, 1H), 4.17 (t, J=6.4 Hz, 2H), 4.03 (t, J=6.3 Hz, 2H), 1.80-2.05 (m, 4H), 1.58-1.68 (m, 4H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:10]=[C:11](CC(O)=O)[CH:12]=[CH:13][CH:14]=1.CN(C=O)C>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([CH2:1][C:2]([Cl:4])=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(CC(=O)O)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
An excess of oxalyl chloride was added dropwise to a stirred mixture of 3-methoxyphenylacetic acid (33.2 g), DMF (4 ml) and methylene chloride (800 ml) and the mixture was stirred at ambient temperature for 65 hours. The mixture was evaporated to leave 3-methoxyphenylacetyl chloride (39.6 g).
Reaction SMILES: CC(C)([O-])C.[K+].[Br-].[O:8]1[CH2:12][CH2:11][O:10][CH:9]1[CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:35]1[CH2:38][N:37]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:36]1>CCOCC>[O:10]1[CH2:11][CH2:12][O:8][CH:9]1[CH2:13][CH:14]=[C:35]1[CH2:36][N:37]([C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:40])[CH2:38]1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CC(=CCC2OCCO2)C1
Temperature: 35 °C
Reaction time: 6 h
Yield: 15.2 %

Procedure:
Potassium tert-butoxide (1.393 g, 12.4 mmol) and [2-(1,3-dioxolan-2-yl)ethyl]-triphenylphosphonium bromide (5.51 g, 12.4 mmol) were stirred in ether (30 mL) at ambient for 1 h. Phenylmethyl 3-oxoazetidine-1-carboxylate (1.025 g, 5.0 mmol), prepared using procedures similar to those described in Reference 3, was added and the mixture was stirred at 35° C. for 6 h and then at ambient for 4 days. Mixture was filtered through celite and the solid was washed with ether. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ether in hexanes) gave phenylmethyl 3-[2-(1,3-dioxolan-2-yl)ethylidene]azetidine-1-carboxylate (220 mg, 0.761 mmol, 15% yield): 1H NMR (400 MHz, CDCl3): 7.39-7.28 (m, 5H), 5.43-5.35 (m, 1H), 5.11 (s, 2H), 4.89 (t, 1H), 4.56 (br d, 4H), 4.00-3.92 (m, 2H), 3.91-3.83 (m, 2H), 2.27 (br t, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:20])=[C:12](C([O-])=O)[CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:21])[O:4][N:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:20])=[CH:12][CH:13]=[N:14]3)=[CH:9][CH:8]=2)=[C:5]([CH3:21])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(O)c(C(=O)[O-])cnc2c1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1noc(C)c1-c1ccc2c(O)ccnc2c1
Yield: 86 %

Procedure:
7-(3,5-dimethyl-4-isoxazolyl)-4-hydroxy-3-quinolinecarboxylate (for a preparation see Intermediate 9, 10 g, 35.21 mmol) was suspended by small portions to boiling diphenyl ether (200 ml) and allowed to reflux for 2 h. The reaction mixture was poured into hexane (500 ml) at 0° C., the precipitate was filtered and washed several times with hexane to give the title compound as a white solid (6.8 g, 86%). [APCI-MS] m/z: 240 MH+, Rt 1.89 min. 1H NMR (300 MHz, CDCl3, ppm) δ: 12.44 (brs, 1H), 8.67 (d, J=8.5 Hz, 1H), 8.10 (d, J=7.2 Hz, 1H), 7.80 (s, 1H), 7.62-7.55 (m, 1H), 7.25 (d, J=8.5 Hz, 1H), 6.61 (d, J=7.4 Hz, 1H), 2.64 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=[O:10])=[O:6])[CH3:3].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1O.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[O:10][C:9](=[O:11])[CH2:8][NH:7][C:5]([O:4][C:2]([CH3:12])([CH3:1])[CH3:3])=[O:6]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 99.9 %

Procedure:
N-(1,1-Dimethylethoxycarbonyl)glycine (6.12 9, 35 mmol) was stirred with 2,4,5-trichlorophenol (6.91 g, 35 mmol) and dicyclohexylcarbodiimide (7.22 g, 35 mmol) in ethyl acetate (100 mL) at 0° C. for 4 h. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate. The residue was dissolved in ethyl acetate. The suspension was filtered and the solvent was evaporated under reduced pressure from the filtrate to give N-(1,1-dimethylethoxycarbonyl)glycine 2,4,5-trichlorophenyl ester (12.4 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1/[CH:4]=[N:5]/[NH:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[C:4]([Cl:20])=[N:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([I:13])=[CH:11][CH:12]=1
Reactant: Fc1cccc(Cl)c1/C=N/Nc1ccc(I)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Fc1cccc(Cl)c1C(Cl)=NNc1ccc(I)cc1
Yield: 76.4 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-1 using (1E)-1-(2-chloro-6-fluorobenzylidene)-2-(4-iodophenyl)hydrazine (1.2 g, 3.20 mmol), PCl5 (0.990 g, 4.8 mmol) and benzene (20 mL) to afford 1.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.00 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.48-7.60 (m, 4H), 10.22 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([O:45]C(C)(C)C)=[O:44])([CH3:42])[CH3:41])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[I-].[Na+].C(OC([NH:59][CH2:60][C:61]1[CH:62]=[N:63][N:64]([CH2:86][CH2:87][O:88]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:65]=1[NH:66]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)(C)(C)C.O>CN(C)C=O>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:38]/[O:39][C:40]([C:43]([OH:45])=[O:44])([CH3:41])[CH3:42])/[C:8]([NH:10][C@@H:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][N+:63]4[N:64]([CH2:86][CH2:87][OH:88])[C:65]([NH2:66])=[C:61]([CH2:60][NH2:59])[CH:62]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1cnn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1nsc(N)n1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(CN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
To a solution of benzhydryl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-chloromethyl-3-cephem-4-carboxylate (5.82 g) in N,N-dimethylformamide (12 ml) was added sodium iodide (1.44 g). After stirring at room temperature for 1 hour, 4-(tert-butoxycarbonylaminomethyl)-5-(tritylamino)-1-[2-(trityloxy)ethyl]-1H-pyrazole (14.8 g) was added to the mixture. The stirring was continued at 35° C. for 24 hours. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and added to diisopropyl ether (500 ml) dropwise. The resulting precipitate was collected by filtration. The filter cake was washed with diisopropyl ether and dried over phosphorous pentoxide in vacuo. The solid (15.6 g) was dissolved in dichloromethane (47 ml), and to the solution were added anisole (16 ml) and trifluoroacetic acid (32 ml) successively. After stirring at room temperature for 3 hours, the reaction mixture was poured into diisopropyl ether (500 ml). The precipitate was collected by filtration, washed with diisopropyl ether and dried over phosphorous pentoxide in vacuo. The crude product was dissolved in a phosphate buffer (pH 7.0) and purified by preparative HPLC (eluent: pH 7.0 phosphate buffer and acetonitrile). The eluate was subjected to column chromatography on Diaion® HP-20 (Mitsubishi Chemical Corporation) and freeze-dried to give 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-[3-amino-4-aminomethyl-2-(2-hydroxyethyl)-1-pyrazolio]methyl-3-cephem-4-carboxylate (940 mg).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([CH:12]=[CH:11][C:9]([OH:10])=[CH:8][CH:7]=1)[OH:6]>>[C:1]([O:6][C:5]1[CH:12]=[CH:11][C:9]([OH:10])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: Oc1ccc(O)cc1
Reactant: CC(=O)Cl
Product: CC(=O)Oc1ccc(O)cc1

Procedure:
Acetyl chloride is reacted with hydroquinone to give 4-acetoxy phenol expressed by the formula (16) shown below.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:45])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([CH2:18][S:19][C:20]2[N:21]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[C:22]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[CH:29]=3)([CH3:27])[CH3:26])=[CH:23][N:24]=2)=[C:13]([Cl:44])[CH:12]=1)[C:3]([OH:5])=[O:4].C([NH:53][C:54](N1C=CC=N1)=[N:55]C(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>CO>[Cl:44][C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([F:17])[C:14]=1[CH2:18][S:19][C:20]1[N:21]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[C:22]([C:25]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([O:35][CH3:36])[CH:29]=2)([CH3:27])[CH3:26])=[CH:23][N:24]=1)[C:10]([NH:9][CH2:8][CH2:7][CH2:6][C@H:2]([NH:1][C:54]([NH2:55])=[NH:53])[C:3]([OH:5])=[O:4])=[O:45]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)NCCC[C@H](N)C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(C(=O)NCCC[C@H](NC(=N)N)C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A solution of (S)-2-amino-5-(3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorobenzamido)pentanoic acid (268 mg, 0.40 mmol), N,N′-di-Boc-1H-pyrazole-1-carboxamidine (135 mg, 0.44 mmol) and triethylamine (175 μL, 1.19 mmol) in MeOH (10 mL) was stirred at 25° C. for 18 h. The reaction mixture was concentrated and reconstituted in EtOAc. The organic layer was washed with 1N HCl (3×5 mL), sat. aq. NaHCO3 (5 mL), dried over Na2SO4 and concentrated to a colorless oil. To the oil was added 4N HCl in Dioxane (10 mL) at 25° C. and stirred for 18 h. Upon completion, the reaction mixture was concentrated and purified by flash chromatography (MeOH/DCM, 0-20%) to give the title product (64 mg, 28% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.91 (t, J=5.2 Hz, 1H), 7.76 (s, 1H), 7.61 (dd, J=10.1, 1.0 Hz, 1H), 7.50-7.10 (br s, 4H), 7.45 (d, J=6.6 Hz, 2H), 7.21 (d, J=8.3 Hz, 1H), 7.17 (s, 1H), 6.95 (t, J=8.4 Hz, 2H), 6.58-6.43 (m, 4H), 4.06 (s, 2H), 3.77 (d, J=4.6 Hz, 1H), 3.67 (s, 3H), 3.23 (s, 2H), 1.71-1.59 (m, 2H), 1.58-1.46 (m, 2H), 1.46 (s, 6H). MS (EI) m/z 719 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3](S(O)(=O)=O)=[CH:4][CH:5]=[C:6](S(O)(=O)=O)[CH:7]=1.[C:16](#[N:18])[CH3:17]>O>[C:2](#[N:1])[C:7]1[C:17](=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]#[N:18]
Reactant: Nc1cc(S(=O)(=O)O)ccc1S(=O)(=O)O
Reactant: CC#N
Solvent: O
Product: N#Cc1ccccc1C#N
Temperature: 40 °C

Procedure:
A solution of aniline 2,5 disulphonic acid (27.5 g) in water (250 ml) was added to intermediate E (63.2 g) in acetonitrile (800 ml) and heated at 40° C. and at pH 5 to 7 overnight. The reaction solvent was removed under reduced pressure, water (50 ml) was added and then brine (60 ml) the solid which precipitated of filtered off, washed with 10% brine and dried to give product (91.1% strength, 22 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([C@@H:17]2[CH2:19][C@H:18]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH3:16])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([C@@H:17]4[CH2:19][C@H:18]4[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH3:16])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)[C@@H]1C[C@H]1c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)[C@@H]4C[C@H]4c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[trans-1-(2-phenyl-cyclopropyl)-ethyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]1([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=[O:15].[Na+]>Cl.O>[N:14]([C:4]1[CH:5]=[CH:6][C:1]([N:7]([CH2:11][CH2:12][OH:13])[CH2:8][CH2:9][OH:10])=[CH:2][CH:3]=1)=[O:15]
Reactant: OCCN(CCO)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=Nc1ccc(N(CCO)CCO)cc1
Temperature: 0 °C

Procedure:
23.9 g of N-phenyldiethanol amine were ground in a mortar and dissolved in 50 ml conc. HCl. The solution was then cooled to 0°C and 10 g NaNO2 in 25 ml of water were added over a period of one hour with stirring. The temperature was maintained between 0°-5°C. After the addition was complete, the mixture was stirred one hour more and then filtered. The orange precipitate of 4-nitroso-N,N-bis-(β-hydroxyethyl) aniline formed was dried in a vacuum desiccator overnight. The dried product, amounting to 25.0 g was suspended in 150 ml. isopropanol and reduced on a Parr hydrogenator over Pt/C. When the loss in pressure approached theoretical, the mixture was filtered into a flask containing 200 ml. isopropanol saturated with HCl gas. A stream of HCl gas was passed through the filtrate during the filtration and for about 20 minutes after the filtration was complete. The white precipitate of N,N-bis-(β-hydroxyethyl)-p-phenylenediamine hydrochloride was collected and weighed. Yield 19.8 g.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:3][CH2:2]1.[H][H]>CO.O.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([CH2:9][CH2:10][N:11]([C:13]([O:15][C@@H:16]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]([OH:19])=[O:18])=[O:14])[CH3:12])=[O:8])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CN(CCC(=O)N1CCOCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CN(CCC(=O)N1CCOCC1)C(=O)O[C@@H](Cc1ccccc1)C(=O)O
Yield: 98.4 %

Procedure:
A solution of benzyl 2(S)-[N-(2-morpholinocarbonyl-ethyl)-N-methylaminocarbonyloxy]-3-phenylpropionate (726 mg) in methanol (150 ml) and water (10 ml) was hydrogenated over 10% palladium on carbon (80 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give 2(S)-[N-(2-morpholinocarbonylethyl)-N-methylaminocarbonyloxy]-3-phenylpropionic acid (573 mg).