Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:23]O>>[CH3:23][O:14][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([C:6]2[N:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2)nn1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(-c2ccc(OC)nn2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(6-methoxy-pyridazin-3-yl)-benzoic acid (5.02 g, 21.8 mmol) (reference example 11f) in methanol (75 mL) is added slowly conc. H2SO4 (3.75 mL). The resulting solution is heated to 50° C. and stirred for 1 hour. The solution is then concentrated to one third volume, cooled to 0°-5° C., adjusted to pH 6 with sat NaHCO3 soln and extracted into ethyl acetate. The organic layer is washed with brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 20% ethyl acetate in dichloromethane) to give 4.26 g of title compound as a white crystalline solid. 1H NMR (DMSO) δ 3.90 (s, 3H), 4.10 (s, 3H), 7.38 (d, J=9 Hz, 1H), 8.10 (d, J=9 Hz, 2H), 8.25 (m, 3H). MS (EI) m/z 244 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:28]=[CH:27][C:13]([C:14]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:15])=[CH:12][CH:11]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>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.C(O)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][C:14](=[O:15])[C:13]1[CH:12]=[CH:11][C:10]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:28][CH:27]=1)[CH3:26]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccsc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccc(-c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
To a mixture of 3-thiophene boronic acid (383 mg, 3 mmol) and bromoester 49d (1.03 g, 3 mmol) were added anhydrous toluene (30 mL) and ethanol (1.5 mL) (20:1, c=1.0M) followed by 2M K2CO3 aqueous solution (3 mL, 6 mmol). The reaction mixture was stirred under nitrogen for 30 minutes and then Pd(PPh3)4 (191 mg, 5 mol %, 0.16 mmol) was quickly added. After 24 hours of reflux, the mixture was cooled to room temperature, filtered through a pad of Celite and rinsed with ethyl acetate (50 mL). The organic solution was washed with brine (30 mL), dried (MgSO4), and concentrated. Purification by flash silica gel chromatography (10% methanol in dichloromethane) followed by crystallization from ethyl acetate afforded the corresponding ester 115 (210 mg, 20% yield) as a white solid.
Reaction SMILES: C([N:8]1[CH2:14][C:13]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([N+:15]([O-])=O)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].BrCC(OC(C)(C)C)=O>C(#N)C>[CH2:18]([C:13]1([NH2:15])[CH2:14][NH:8][CH2:9][CH2:10][NH:11][CH2:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])C1(Cc2ccccc2)CN(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC1(Cc2ccccc2)CNCCNC1
Temperature: 60 °C
Yield: 139.9 %

Procedure:
In a 50 mL round-bottom flask the amine 5 (1.65 g 4.7 mmol) was dissolved in acetonitrile (15 ml) and K2CO3 (5.16 g, 37 mmol) was added. t-Butyl bromoacetate (4.55 g, 23.4 mmol) was slowly dropped into the stirred heterogeneous mixture, while maintaining the temperature <10° C. (ice bath). After the addition the mixture was heated at 60° C. with stirring until TLC showed complete conversion. The precipitate was filtered and washed with dichloromethane; the filtrate and the washings were combined and evaporated in vacuo to give the crude product. The semisolid residue was purified by silica gel chromatography (petroleum ether/ethyl acetate 9.3/0.7), obtaining pure 6 as pale yellow oil (1.35 g, 36%). ESI-MS: 832 (MNa+), 810 (MH+); (Calc. for C46H87N3O8: 809 u.m.a.).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][C:31]([C:34]#[N:35])=[CH:32][N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.CCN(C(C)C)C(C)C.[CH3:45][S:46]([CH2:49][CH2:50]OS(C)(=O)=O)(=[O:48])=[O:47]>C(Cl)Cl>[C:8]1([C:14]2[N:19]=[C:18]([CH:20]3[CH2:21][CH2:22][N:23]([CH2:50][CH2:49][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:24][CH2:25]3)[CH:17]=[CH:16][C:15]=2[NH:26][C:27]([C:29]2[NH:30][C:31]([C:34]#[N:35])=[CH:32][N:33]=2)=[O:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: N#Cc1cnc(C(=O)Nc2ccc(C3CCNCC3)nc2C2=CCCCC2)[nH]1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CCN1CCC(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)n2)CC1
Reaction time: 8 h
Yield: 42 %

Procedure:
To a slurry of 5-cyano-1H-imidazole-2-carboxylic acid (6-cyclohex-1-enyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinyl-5-yl)-amide trifluoroacetic acid salt (57 mg, 0.11 mmol) in 5 mL of DCM was added DIEA (50.4 μL, 0.290 mmol) followed by 30.5 mg (0.150 mmol) of methanesulfonic acid 2-methanesulfonyl-ethyl ester (as prepared in Example 40, step (a)). The reaction was allowed to stir overnight, diluted with 20 mL of DCM, washed with satd aq NaHCO3 (1×20 mL) and dried over Na2SO4. Purification by preparative TLC (silica gel, 40% EtOAc-hexanes) afforded 22.3 mg (40%) of the title compound as a white solid. 1H-NMR (DMSO; 400 MHz): δ 10.02 (s, 1H), 8.24 (s, 1H), 8.11 (d, 1H, J=8.4 Hz), 7.18 (d, 1H, J=8.4 Hz), 5.96 (s, 1H), 3.04 (s, 3H), 3.02-2.99 (m, 3H), 2.73 (t, 2H, J=2.7 Hz), 2.39-2.37 (m, 2H), 2.11-2.05 (m, 4H), 1.85-1.64 (m, 10H). Mass Spectrum (ESI, m/z): Calcd. for C24H31N6O3S, 483.2 (M+H). found 483.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[C:8](=[O:25])[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:6]=2[S:5][C:4]=1[C:26]([N:28]([CH3:40])[CH2:29][CH2:30][CH2:31][NH:32]C(=O)OC(C)(C)C)=[O:27].C(OC(=O)C)C.[ClH:47]>C(OCC)(=O)C>[ClH:47].[NH2:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:40])[C:26]([C:4]1[S:5][C:6]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]([CH2:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8](=[O:25])[C:7]=2[C:3]=1[O:2][CH3:1])=[O:27]
Reactant: COc1c(C(=O)N(C)CCCNC(=O)OC(C)(C)C)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1c(C(=O)N(C)CCCN)sc2c1c(=O)n(CC(=O)c1ccccc1)c1ccccc21
Yield: 54 %

Procedure:
A solution of the obtained tert-butyl {3-[{[3-methoxy-4-oxo-5-(2-oxo-2-phenylethyl)-4,5-dihydrothieno[3,2-c]quinolin-2-yl]carbonyl}(methyl)amino]propyl}carbamate (230 mg) and 4N hydrogen chloride ethyl acetate solution (8 mL) in ethyl acetate (15 mL) was stirred at room temperature for 2 hr. The obtained precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (216 mg, 54%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.C(O)C.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=Cc1ccc(Cl)cn1
Yield: 39.8 %

Procedure:
5-Chloro-pyridine-2-carboxylic acid ethyl ester (146 mg, 76.3%) was obtained obtained as described in Example 11 from 5-chloro-pyridine-2-carboxylic acid (200 mg, 1.03 mmol) with ethanol (3 mL) and 4M HCl in dioxane (0.5 mL) at 90° C. for 20 h. 5-Chloro-pyridine-2-carbaldehyde (58 mg, 52%) was obtained as described in Example 11 from 5-chloro-pyridine-2-carboxylic acid ethyl ester (146 mg, 0.786 mmol) with 1 M DIBAL in toluene (1.74 mL, 1.74 mmol) in dichloromethane (4.0 mL) 20 min. GC-MS (M+): 141
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14]1[O:18][C:17]([C:19]([NH:21][C:22]2[CH:38]=[CH:37][C:25]([O:26][C@H:27]3[CH2:32][CH2:31][C@H:30]([C:33]([O:35]C)=[O:34])[CH2:29][CH2:28]3)=[CH:24][CH:23]=2)=[O:20])=[N:16][N:15]=1.O.CO>C1COCC1>[F:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:6]=1[NH:13][C:14]1[O:18][C:17]([C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][C@H:27]3[CH2:28][CH2:29][C@H:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[CH:37][CH:38]=2)=[O:20])=[N:16][N:15]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O[C@H]2CC[C@H](C(=O)O)CC2)cc1)c1nnc(Nc2cc(F)c(F)cc2F)o1
Temperature: 35 °C
Reaction time: 1 h

Procedure:
Lithium hydroxide monohydrate (104 mg, 2.48 mmol) was added in one portion to a solution of methyl trans-4-{4-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)-amino]phenoxy}cyclohexanecarboxylate (Example 449, 125 mg, 0.25 mmol) in a mixture of THF (2 mL), H2O (2 mL) and MeOH (4 mL) and the reaction mixture was stirred at 35° C. for 1 h. The reaction mixture was concentrated in vacuo and citric acid (15 mL) was added. The resulting mixture was filtered, washed with H2O and the white solid was then triturated with hot MeOH and filtered to give the title compound (93 mg, 79%) as a solid. The compound may be recrystallised from a 4:6:1 mixture of EtOH:MeOH:H2O; melting point 263-265° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[Li]CCCC.CCCCCC.CN([CH:26]=[O:27])C>C1COCC1>[CH2:10]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH:26]=[O:27])[CH3:11]
Reactant: CN(C)C=O
Reactant: CCc1cc(Br)ccc1OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cc(C=O)ccc1OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 42.4 %

Procedure:
A solution of 4-bromo-2-ethyl-1-methoxybenzene (J. Chem. Soc., Perkin Trans. 1, 1987, 1423; 2.13 g, 9.9 mmol) in THF (30 ml) was cooled to −78° C. A 1.6M solution of n-BuLi in hexane (7.42 ml, 11.9 mmol) was added slowly and the mixture was stirred for 1.5 h. at −78° C. The mixture was warmed slowly to −10° C. and subsequently again cooled to −78° C. DMF (2.29 ml, 29.7 mmol) was added slowly and the mixture was stirred for 1 h. at −78° C. and for 1 h. at 0° C. The reaction mixture was poured into ice-cold 3M HCl and extracted with diethyl ether. The organic phase was dried and filtered, and the filtrate was concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 8:1=>2:1). There were obtained 690 mg (42%) of 3-ethyl-4-methoxy-benzaldehyde as a yellowish liquid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:15]=2)=[CH:8][CH:7]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:20]([C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:4]2[CH2:5][C@H:3]2[NH:2][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:11][CH:10]=1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(Cc3ccccc3)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1cccc(Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]-3-benzylbenzamide hydrochloride (69.6 mg) in methanol (1.5 mL) were added benzaldehyde (19 μL) and sodium hydrogen carbonate (23.2 mg). The mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (10.4 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and crystallized (hexane/ethyl acetate) to give the title compound (29.7 mg).
Reaction SMILES: [N+](=[CH2:3])=[N-].[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:36][OH:37])[C:11]([NH:13][CH:14]2[C:34](=[O:35])[N:16]3[C:17]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=4)=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1>C(OCC)C.CO>[NH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](=[N:36][O:37][CH3:3])[C:11]([NH:13][CH:14]2[C:34](=[O:35])[N:16]3[C:17]([C:21]([O:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=4)=[O:22])=[CH:18][CH2:19][S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: Nc1nc(C(=NO)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1

Procedure:
A solution of diazomethane in diethyl ether was added little by little to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.3 g.) in methanol (30 ml.) until the reaction terminated. The resultant solution was concentrated under reduced pressure, and the residue was pulverized with diethyl ether, collected by filtration and dried to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer: 0.26 g.) This product was identified with the authentic sample.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][CH:26]([NH2:28])[CH3:27]>>[OH:24][CH2:25][CH:26]([NH:28][C:20]([C:17]1[NH:18][N:19]=[C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])[CH3:27]
Reactant: CC(N)CO
Reactant: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)O)[nH]n1
Product: Cc1onc(-c2ccc(F)cc2)c1/C=C/c1cc(C(=O)NC(C)CO)[nH]n1
Yield: 41 %

Procedure:
As described for example 132, 5-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-vinyl}-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1-methylethylamine instead of morpholine, to the title compound (14 mg, 41%) which was obtained as an off white solid. MS: m/e=371.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[C:58]([CH3:63])=[N:59][O:60][C:61]=1[CH3:62])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[C:58]([CH3:63])=[N:59][O:60][C:61]=2[CH3:62])=[O:56])[CH2:51][CH2:52]1
Reactant: Cc1noc(C)c1N=C=O
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1NC(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 4-isocyanato-3,5-dimethylisoxazole as the starting materials in 50% yield. LCMS for C30H34ClN8O3 (M+H)+: m/z=589.1.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.N#N.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1OCc1ccccc1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1O
Reaction time: 3 h

Procedure:
To compound (3R)-1-[(1R,2R)-2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (35.0 g, 75.8 mmol) was added methanol (150 mL). This solution was transferred to a Parr bottle and Pd/C (10% wt/wt on activated carbon) was added portion-wise while maintaining a N2 atmosphere through the reaction mixture. Hydrogen pressure (60 psi) was then applied and the vessel shaken for 3 hours, after which HPLC showed complete consumption of the starting material. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give (3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol as a colorless syrup. The crude product was dissolved in 1 M aqueous HCl solution (450 mL) and washed with chloroform (8×250 mL). The aqueous layer was then saturated with solid NaCl (100 g) and the solution was extracted with dichloromethane (8×200 mL). The combined dichloromethane extracts were dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to give 3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol as a colorless syrup; 1H NMR (400 MHz, D2O) δ 7.01 (d, H, J=8.0), 6.86-6.83 (m, 2H), 4.42-4.36 (m, 1H), 4.02 (overlapping dt, 1H, J=5.2, J=10.1), 3.85 (s, 3H), 3.67-3.55 (m, 1H), 3.46-2.81 (m, 7H), 2.77-2.70 (m, 1H), 2.34-2.27 (m, 1H), 2.11-1.74 (m, 5H), 1.41-1.10 (m, 4H); IR: 3439 (O—H stretch), 1592, 1510, 1098, 1022 cm−1; MS (ESI) 336.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][CH:10]([CH3:31])[C:11]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:12].[OH:32]O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([CH:10]([CH3:31])[C:11]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:12])=[O:32]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(C)Sc3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Reactant: OO
Solvent: CC(=O)O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)C(C)S(=O)c3ccc(Cl)cc3Cl)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 250 mg of 5'-[2(RS)-(2,4-dichlorophenylthio)propionamido]-2',5'-dideoxy-5-ethyluridine in 10 ml of acetic acid was cooled to 0° C. and 60 ml of 30% hydrogen peroxide were added. The mixture was stirred at 0° C. for 0.5 hour and then at room temperature overnight. An additional 60 mg of 30% hydrogen peroxide were added and the mixture was stirred for 24 hours. An additional 30 mg of 30% hydrogen peroxide were added and the mixture was stirred for an additional 4 hours and then evaporated to dryness. The residue was triturated with methanol and the resulting solid was removed by filtration and recrystallized from methanol to give 90 mg of 5'-[2(RS)-(2,4-dichlorophenylsulphinyl)propionamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 208°-209° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=[O:20].O=[C:22]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([OH:25])=[O:24].C([BH3-])#N.[Na+]>>[C:17]([CH:9]([N:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:2]([NH:1][CH:22]([C:23]([OH:25])=[O:24])[CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:3]1=[O:20])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:19])=[O:18]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@H]1CCCCN(C(Cc2ccccc2)C(=O)O)C1=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@H]1CCCCN(C(Cc2ccccc2)C(=O)O)C1=O

Procedure:
Methyl 2-oxo-3-phenylpropionate and α-t-Boc-L-lysine are condensed in the presence of sodium cyanoborohydride as described in Example 19. Subsequent ring closure to 3-(S)-t-butoxycarbonylamino-1-[1-carbomethoxy-2-phenylethyl]perhydroazepin-2-one is carried out as described in Example 3. Saponification of the methyl ester followed by removal of the t-butoxycarbonyl group affords 3-(S)-amino-1-[1-carboxy-2-phenylethyl]perhydroazepin-2-one. The caprolactam and 2-oxo-4-phenylbutyric acid are condensed in the presence of sodium cyanoborohydride to yield 1-[1-carboxy-2-phenylethyl]-3-(S)-[(1-carboxy-3-phenylpropyl)amino]perhydroazepin-2-one.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])(=[O:9])=[O:8].C([Li])CCC.[CH3:29][C:30]([CH3:32])=[O:31].FC(F)(F)C(O)=O>C1COCC1.CCCCCC.C(OCC)(=O)C.O>[OH:31][C:30]([CH3:32])([CH3:29])[C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)([S:7]([NH2:6])(=[O:8])=[O:9])[CH3:11]
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)C(C)c2ccccc2)c(OC)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(O)C(C)(c1ccccc1)S(N)(=O)=O
Reaction time: 0.08 h

Procedure:
Under inert gas, 330 mg of N-(2,4-dimethoxybenzyl)-1-phenylethanesulfonamide were initially charged in 5 ml of THF, and then, at a temperature of −78° C., 1.41 ml of a 1.6 N butyllithium solution in hexane were added dropwise and the mixture was stirred for 5 minutes. Subsequently, 0.22 ml of acetone was added, the mixture was stirred briefly and, after the addition of 1 ml of trifluoroacetic acid, the reaction solution was allowed to come to room temperature. The reaction mixture was admixed with 50 ml of water and 50 ml of ethyl acetate, and the aqueous phase was reextracted with 50 ml of ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation, and the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (113 mg) with a molecular weight of 243.3 g/mol (C11H7NO3S).
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.Cl.[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH2:18])[CH3:14].C(N(CC)CC)C>CN(C=O)C.O>[CH2:13]([O:15][C:16](=[O:19])[CH2:17][NH:18][CH2:10][C:5]1[C:6]([NH2:9])=[N:7][CH:8]=[C:3]([Br:2])[CH:4]=1)[CH3:14]
Reactant: Nc1ncc(Br)cc1CBr
Reactant: CCOC(=O)CN
Agent: Br
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNCc1cc(Br)cnc1N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.8 %

Procedure:
A solution of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (6.00 g, 17.3 mmol) and glycine ethyl ester hydrochloride (2.41 g, 17.3 mmol) in DMF (200 mL) was treated with triethylamine (7.8 mL, 56 mmol). After stirring at room temperature for 3.5 h, the cloudy mixture was diluted with H2O (300 mL) and then extracted with EtOAc (2×300 mL). The combined organic layers were washed with H2O (3×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (2.83 g, 57%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.3 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 5.56 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.71 (s, 2H), 3.38 (s, 2H), 1.73 (s, 1H), 1.30 (t, J=7.2 Hz, 3H); MS (ESI) m/e 288 (M+H)+.