Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[CH3:25][O:26][CH2:27][CH2:28][OH:29]>C1(C)C=CC=CC=1>[C:1]([O:29][CH2:28][CH2:27][O:26][CH3:25])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCCO
Reactant: O=CC=Cc1ccccc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: COCCOC(=O)C=Cc1ccccc1
Yield: 93 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), 2-methoxyethanol (25 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of basic alumina (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with ethylacetate (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. 2-Methoxyethyl cinnamate (from formula I where X1═H, X2═H, X3═H, X4═H, X5═H, R═C3H7O) is isolated in 93% yield. 1H-NMR (CDCl3, 300 MHz) δ7.51 (1H, d, J=16.55 Hz), 7.28 (2H, m), 7.15 (3H, m), 6.28 (1H, d, J=16.55 Hz), 4.16 (2H, t), 3.44 (2H, t), 3.18 (3H, s); 13C-NMR (CDCl3, 75.4 MHz) δ166.6, 144.8, 134.3, 130.2, 128.8, 117.8, 70.4, 63.4, 58.7.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.[CH3:11][NH:12][C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([O:28]CCC)=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[CH3:11][N:12]([C:8](=[O:10])[CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1)[C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3
Reactant: Cc1nc(CC(=O)O)cs1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: Cc1nc(CC(=O)N(C)[C@@H]2CCc3c(CC(=O)O)c4ccccc4n3C2)cs1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2-methyl-1,3-thiazol-4-yl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 398.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][C@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>ClCCl>[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][C@H:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][CH2:11]2)=[O:16])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCC[C@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.1 %

Procedure:
To a solution of cis-tert-butyl 3-(1-(3,4-dichlorophenyl)piperazine-4-carbonyl)cyclohexylcarbamate (640 mg) in dichloromethane (10 mL) was added TFA (10 mL). The resulting solution was allowed to stir at rt. for 2 h. After this time, the solvent was removed by rotary evaporation to provide an oil which was partitioned between dichloromethane and 1 N NaOH. The dichloromethane extract was washed with water, dried over MgSO4 and then evaporated to provide the title compound (590 mg) as an oil.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[C:11]([O:14][CH2:15][CH:16]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:17][CH2:18]I)(=[O:13])[CH3:12]>>[C:11]([O:14][CH2:15][CH:16]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH2:17][CH2:18][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:13])[CH3:12]
Reactant: CC(=O)OCC(CCI)COC(C)=O
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCC(COC(C)=O)COC(C)=O)OCC

Procedure:
Triethyl phosphite (6.58 g, 6.8 ml, 39.67 mmol) and 4-acetoxy-3-(acetoxymethyl)butyl iodide (5 g, 15.87 mmol) were stirred at 130° C. for 9 hours. The reaction mixture was then allowed to cool and the excess of triethyl phosphite was evaporated under reduced pressure. The product distilled at 235° C./0.3 mm Hg, yield 4.6 g, 75%. 1HNMR: δH (CDCl3) 1.33 (6H, t, J=7Hz, (OCH2CH3)2, 1.74 (5H, m, CHCH2CH2P), 2.06 (6H, s, 2xCOCH3), 4.12 (8H, m, (OCH2CH3)2, 2xCH2OAc). Found: C,47.29; H,7.83%. C13H25O7P 0.25 H2O requires C,47.48; H,7.81%.
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([N+]([O-])=O)[CH3:14])=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[O:18]1CCCC1>[Fe]>[CH:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](=[O:18])[CH3:14])=[CH:8][CH:7]=1)([CH3:4])[CH3:3]
Reactant: CC(=Cc1ccc(OC(C)C)cc1)[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [Fe]
Agent: Cl
Product: CC(=O)Cc1ccc(OC(C)C)cc1

Procedure:
Concentrated hydrochloric acid (90 ml) was added dropwise, over 45 minutes, to a stirred mixture of iron powder (17.5 g) and 1-(4-isopropoxyphenyl)-2-nitroprop1-ene (16.0 g) in tetrahydrofuran (50 ml) at reflux. The mixture was heated under reflux for a further hour, cooled, filtered through diatomaecous earth and the tetrahydrofuran removed under reduced pressure. The residue was diluted with water, extracted with diethyl ether, washed with brine, dried (magnesium sulphate), filtered and evaporated to dryness. Distillation of the residue gave the title compound, bp 120°-6°/1.5 mm.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:27]=[CH:26][C:10]([O:11][C:12]3[C:17]4[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=4[CH:15]=[C:14]([C:23](O)=[O:24])[CH:13]=3)=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH2:34])=[N:30]1>>[CH3:28][N:29]1[CH:33]=[CH:32][C:31]([NH:34][C:23]([C:14]2[CH:13]=[C:12]([O:11][C:10]3[CH:9]=[CH:8][C:7]([C:5]([N:1]4[CH2:2][CH2:3][CH2:4]4)=[O:6])=[CH:27][CH:26]=3)[C:17]3[CH2:18][C:19]([CH3:21])([CH3:22])[O:20][C:16]=3[CH:15]=2)=[O:24])=[N:30]1
Reactant: CC1(C)Cc2c(Oc3ccc(C(=O)N4CCC4)cc3)cc(C(=O)O)cc2O1
Reactant: Cn1ccc(N)n1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 15, from 4-[4-(azetidine-1-carbonyl)-phenoxy]-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (35c) (598 mg, 1.63 mmol) and 1-methyl-3-aminopyrazole (236 mg, 2.43 mmol) to give a white solid (315 mg, 41% yield). 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1 H) 7.65 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 7.28 (d, J=2.27 Hz, 1 H) 7.02 (dd, J=9.85, 1.26 Hz, 2 H) 6.98 (ddd, J=9.22, 2.78, 2.40 Hz, 2 H) 6.78 (d, J=2.02 Hz, 1 H) 4.30-4.40 (m, 2 H) 4.19-4.30 (m, 2 H) 3.81 (s, 3 H) 2.89 (s, 2 H) 2.32-2.40 (m, 2H) 1.49 (s, 6 H); LCMS for C25H26N4O4 m/z 447.20 (M+H)+; Anal. Calcd. for C25H26N4O4.0.31 H2O: C, 65.38; H, 6.02; N, 12.20. Found: C, 65.37; H, 5.85; N, 12.38.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl.C(OCC)(=O)C>[CH2:32]([NH:34][C:35](=[O:36])[NH:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:33]
Reactant: NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Reactant: CCN=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCNC(=O)NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.28 mmol) in CH2Cl2 (5 mL) was added ethyl isocyanate (0.05 mL, 0.63 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours and then diluted with ethyl acetate. The organic fraction was washed with sat. NaHCO3, and then brine and dried over Na2SO4. The solvent was removed and the crude was purified by HiTOPs to provide N-((1-((1-(3-ethylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[N:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:22][NH2:23].Cl.CN(C)CCCN=C=NCC>ClCCl>[F:17][C:18]([F:31])([F:32])[C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[CH2:22][NH:23][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][N:14]=[CH:15][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:16]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1cnccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1-c1cnccc1C(=O)NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 12 h
Yield: 42.4 %

Procedure:
To a solution of 0.28 g (1.17 mol) 3-o-tolyl-isonicotinic acid and 0.34 g (1.40 mmol) 3,5-bis(trifluoromethyl)benzylamine in 10 ml dichloromethane 0.38 ml N-methylmorpholine and 0.27 g (1.40 mmol) N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride were added and the mixture stirred for 12 h. The phases were separated, the water phase extracted with three portions of dichloromethane. The combined organic phases were dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 0.26 g (51%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[C:10]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:12]([C:15]([O:17]C)=[O:16])=[CH:13][CH:14]=1.[OH-].[K+].Cl>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(-c2cc(F)ccc2F)c(C(=O)OC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)ccc1-c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 100 %

Procedure:
To a stirred solution of 83.27A (0.800 g, 2.6 mmol) in THF (7.00 mL) and MeOH (7.00 mL) at 0° C. was slowly added potassium hydroxide (1.4 mL, 2.9 mmol) to maintain the temperature below 6° C. The reaction mixture was then allowed to warm to room temperature and stirred for 19 hours. The reaction was then acidified with 1N HCl and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure to yield 83.27B as a colorless solid (0.76 g, 100% yield).
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH2:28][OH:29])=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[C:10]([CH3:33])=[C:11]([C:15]3[C:27]4[C:26]5[C:21](=[CH:22][C:23]([CH:28]=[O:29])=[CH:24][CH:25]=5)[NH:20][C:19]=4[C:18]([C:30]([NH2:32])=[O:31])=[CH:17][CH:16]=3)[CH:12]=[CH:13][CH:14]=2)=[O:7])=[CH:34][CH:35]=1
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(CO)ccc3c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(C=O)ccc3c12
Reaction time: 2 h
Yield: 85.2 %

Procedure:
Step 1 A solution of 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 31-4, 0.54 g, 1.155 mmol) in THF (38.5 mL) was treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (Dess-Martin periodinane, 0.784 g, 1.848 mmol) at rt and the mixture was stirred for 2 h. The mixture was partitioned between NaHCO3 (aq) and EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was triturated with methanol and the solid was collected by filtration and dried to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-formyl-9H-carbazole-1-carboxamide as an orange solid (458 mg, 85%). 1H NMR (400 MHz, DMSO-d6) δ 11.98 (1H, s), 10.16 (1H, s), 10.03 (1H, s), 8.23-8.32 (2H, m), 8.05-8.14 (3H, m), 7.60 (1H, br. s.), 7.49-7.55 (1H, m), 7.39-7.49 (2H, m), 7.32-7.39 (2H, m), 7.21-7.27 (1H, m), 7.09 (2H, t, J=8.1 Hz), 1.88 (3H, s). Mass spectrum m/z 466.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH:6]=[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]([C:13]([F:16])([F:15])[F:14])[O:9]2)=[CH:4][CH:3]=1.[Cl:22]Cl>CC(O)=O>[Cl:22][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([CH3:12])[C:2]=1[CH3:1])[O:9][CH:8]([C:13]([F:16])([F:14])[F:15])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:6]2
Reactant: CCOC(=O)C1=Cc2ccc(C)c(C)c2OC1C(F)(F)F
Reactant: ClCl
Solvent: CC(=O)O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C)c(C)c2OC1C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of ethyl 7,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylat (4.0 g, 13.3 mmol) in 75 mL HOAc was added Cl2 until the solvent was saturated as indicated by the greenish chlorine cloud above the solvent. After 2 h, the reaction was flushed with N2 and subsequently treated with excess Zn dust for 1.5 h. The reaction mixture was decanted from the Zn and concentrated under vacuum. The resulting residue was dissolved in 300 mL of EtOAc and washed with 100 mL 1 M KHSO4 and 100 mL brine. The organic layer was dried over MgSO4, filtered and concentrated under vacuum. The yield of ethyl 6-chloro-7,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylate was 5.2 g.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:35])[C@@H:14]([NH:24]C(OCC2C=CC=CC=2)=O)[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:35])[C@@H:14]([NH2:24])[CH2:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCOC(=O)N1CCN(C(=O)[C@@H](N)CCC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 15.8 g 4-((S)-2-Benzyloxycarbonylamino-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid propyl ester in 100 ml ethyl acetate were added 0.4 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite, washed with ethanol and concentrated to give the crude product which was used in the subsequent reaction. Yield: 10.2 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][C:6]([NH:8][C@H:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7]>CCO.[Pd]>[NH2:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C@@H:9]([NH:8][C:6](=[O:7])[CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:32])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:22][CH:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc([N+](=O)[O-])c2)cc1)NC(=O)CCC(=O)OC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(N)c2)cc1)NC(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 91.6 %

Procedure:
A suspension of (R)-ethyl 3-(4-methoxy-4-oxobutanamido)-4-(3′-nitrobiphenyl-4-yl)butanoate (123 mg, 0.278 mmol) and Pd/C (59.2 mg, 0.028 mmol) in EtOH (2 ml) is allowed to stir under hydrogen at room temperature for 5.5 hours. The reaction mixture is filtered, and the solution is concentrated to give (R)-ethyl 4-(3′-aminobiphenyl-4-yl)-3-(4-methoxy-4-oxobutanamido)butanoate (105 mg); HPLC retention time=0.84 minutes (condition B); MS (m+1)=413.1; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (t, J=7.2 Hz, 3H) 2.41-2.65 (m, 6H) 2.85-3.00 (m, 2H) 3.67 (s, 3H) 4.11-4.22 (m, 2H) 4.46-4.54 (m, 1H) 6.31 (br d, J=8.8 Hz, 1H) 6.71-6.74 (m, 1H) 6.95-7.02 (m, 2H) 7.21-7.25 (m, 3H) 7.48-7.50 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.Cl.C(O[CH:25](OCC)[CH2:26][NH:27][C:28]#[N:29])C>COCCOC.O>[NH:29]1[CH:25]=[CH:26][N:27]=[C:28]1[NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[N:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3c[nH]nn3)CS[C@H]12
Reactant: CCOC(CNC#N)OCC
Agent: Cl
Solvent: COCCOC
Solvent: O
Product: O=C(O)C1=C(CSc2c[nH]nn2)CS[C@@H]2C(Nc3ncc[nH]3)C(=O)N12
Temperature: 51 °C
Yield: 10 %

Procedure:
To a suspension of 7-amino-3 (1H-1,2,3-triazol-4-yl)thiomethylceph-3-em-4-carboxylic acid (31.3 g., 0.1 moles) in a mixture of 1,2-dimethyoxyethane (250 ml.) and concentrated HCl (12 ml., 0.138 moles) in water (50 ml.) was added 2,2-diethoxyethylcyanamide (52.05 g., 0.3 moles). The mixture was stirred and heated at 51° C. for 4 hours and the resulting solution was evaporated under reduced pressure to remove the 1,2-dimethoxyethane. The residual oil was diluted with water (250 ml.), the pH of the resulting suspension was adjusted to 4.8 using sodium bicarbonate and then filtered. The filtrate was applied to a column of "Amberlite" XAD-2 (500 ml.) ("Amberlite" is a Trade Mark). The resin was first washed with water (2000 ml.) and then eluted with 40% v/v aqueous methanol. The required fractions were combined and evaporated to dryness to give 7-(imidazol-2-yl)amino-3-(1H-1,2,3-triazol-4-yl)thiomethylceph-3-em-4-carboxylic acid (3.79 g., 10%) having an n.m.r. spectrum identical to the product of Example 5.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([C:19]1([CH2:23][OH:24])[CH2:22][O:21][CH2:20]1)[CH3:18].O>CS(C)=O>[CH2:17]([C:19]1([CH2:23][O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:22][O:21][CH2:20]1)[CH3:18]
Reactant: CCC1(CO)COC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCC1(COc2ccc([N+](=O)[O-])cc2)COC1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
To a solution of 4-fluoronitrobenzene (3.76 mL, 35.4 mmol) in DMSO (35 mL) at room temperature was added cesium carbonate (7.09 mL, 89.0 mmol) followed by 3-ethyl-3-oxetanemethanol (4.48 mL, 42.5 mmol). The mixture was heated to 70° C. for 2 hours. After cooling water was added and the resulting precipitate was filtered, washed with water, and dried in a vacuum oven to provide the title compound (8.28 g, 98% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([N:9]([C@@H:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:28])[C:22]=3[C:23]([O:25]CC)=[O:24])=[CH:14][CH:13]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].O>C1COCC1>[Cl:2][C:3]1[C:4]([N:9]([C@@H:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:28])[C:22]=3[C:23]([OH:25])=[O:24])=[CH:16][CH:17]=2)=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1c(-c2ccc(C(=O)N(c3ncccc3Cl)[C@@H]3CCCNC3)cc2)cnn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ncc(-c2ccc(C(=O)N(c3ncccc3Cl)[C@@H]3CCCNC3)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.1 %

Procedure:
EXAMPLE 6 Ethyl 4-(4-{(3-chloropyridin-2-yl)[(3R)-piperidin-3-yl]carbamoyl}phenyl)-1-methyl-1H-pyrazole-5-carboxylate hydrochloride salt (7.65 g, 15.2 mmol) was slurried in 50 mL THF followed by the addition of aqueous NaOH (1 mol/L, 50 mL, 50 mmol). Another 23 mL of water was added and the reaction stirred at room temperature for 1.5 h. THF solvent was removed in vacuo, then pH of residual aqueous phase was adjusted to pH 7 with 1 M aqueous HCl, resulting in precipitation of solids. The solids were collected via filtration and after drying afforded the hydrochloride salt of the title compound as an off-white solid (6.49 g, 97%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[N:6][CH:5]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[Cl:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[N:6][CH:7]=1
Reactant: COC(=O)c1cncc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OCc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
To a solution of 5-chloro-nicotinic acid methyl ester (17.2 g, 101 mmol) in methanol (230 mL) and DCM (230 mL) at 0° C. was added sodium borohydride (16.4 g, 434 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (300 mL) and extracted with AcOEt (3×300 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography to afford (5-chloro-pyridin-3-yl)-methanol (7.8 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.52 (m, 2 H), 7.83 (s, 1 H), 5.45 (t, J=5.8 Hz, 1 H), 4.55 (t, J=5.7 Hz, 2 H). MS m/z 144.1
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18](I)=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([N:10]2[CH2:13][CH:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:28]4[CH:29]=[C:24]([O:23][CH3:22])[CH:25]=[CH:26][C:27]=4[O:30][CH3:31])=[CH:17][N:16]=3)[CH2:11]2)=[O:9])[N:2]=1
Reactant: O=C(Nc1cccnn1)N1CC(Oc2ccc(I)cn2)C1
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: COc1ccc(OC)c(-c2ccc(OC3CN(C(=O)Nc4cccnn4)C3)nc2)c1
Yield: 83 %

Procedure:
This compound was prepared by the method outlined for example 5 step 6. Thus 3-(5-Iodo-pyridin-2-yloxy)-azetidine-1-carboxylic acid pyridazin-3-ylamide (100 mg, 0.25 mmol) was reacted with 2,5-Dimethoxybenzeneboronic acid (Cas. No 107099-99-0, 69 mg, 0.38 mmol) to afford title compound (84 mg, 83%) as an off-white powder. LCMS: (Method B) RT=1.19 min; m/z=408 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:26][C:27]1[CH:28]=[CH:29][C:30](F)=[N:31][CH:32]=1.O>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][N:31]=2)[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: Fc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Reaction time: 1.5 h
Yield: 65.6 %

Procedure:
A solution of 1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (6.09 g) in tetrahydrofuran (14 ml) was added dropwise to a tetrahydrofuran solution (32 ml) of 1.0M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (39.8 ml) at −78° C., and stirred at the same temperature for 1.5 hours. Next, a solution of 5-bromo-2-fluoropyridine (5.0 g) in tetrahydrofuran (14 ml) was added dropwise and stirred at the same temperature for 0.5 hour and at room temperature for an hour. After completion of the reaction, water was added to the reaction solution and extracted with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (6.9 g) as a colorless oil.