Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4].[CH2:22](Br)[CH:23]([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]2[N:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C@@H:15]([CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:14][S:13]2)=[C:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(N=C2N[C@@H](CC(C)C)CS2)c(C)c1
Reactant: CC(C)CBr
Product: COC(=O)c1ccc(N=C2SC[C@H](CC(C)C)N2CC(C)C)c(C)c1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methyl butylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-(Methoxycarbonyl)-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-(methoxycarbonyl)-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O.O>CCCCCC>[OH:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(C(=O)OC)c1O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCC
Product: COC(=O)c1cc([N+](=O)[O-])cc(C(=O)OC)c1O
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Dimethyl 2-hydroxyisophthalate (1.5 g) was added to a mixture of 69% nitric acid (5 ml) and concentrated sulfuric acid (5 ml) and the mixture was stirred in an ice bath for 0.5 hours. After pouring into iced water, the reaction mixture was extracted with ethyl acetate. The extract was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford a yellow solid. To the solid was added hexane and the mixture was filtered to give the desired compound (1.6 g, yield 89%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]([CH2:15][CH2:16][CH:17]=O)=[CH:13][C:12]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:17][CH2:16][CH2:15][C:14]2[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[N:11]=[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH:13]=2)[CH2:32][CH2:31]1
Reactant: CCCCc1cc(CCC=O)n(-c2cccc([N+](=O)[O-])c2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2cccc([N+](=O)[O-])c2)n1

Procedure:
218 mg (66.2%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(3-nitrophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (213 mg, 0.707 mmol), 1-(2-fluorophenyl)piperazine (167 mL, 1.060 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.[H-].[Na+].CC1C=CC(S(O[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]3[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[CH:25][CH:24]=2)(=O)=O)=CC=1>O1CCCC1>[Br:36][C:34]1[CH:33]=[CH:32][C:31]([Cl:37])=[C:30]([CH:35]=1)[CH2:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][O:6][C@H:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[CH:28][CH:27]=1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cc3cc(Br)ccc3Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Br)cc1Cc1ccc(OCCO[C@H]2CCOC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of (R)-tetrahydrofuran-3-ol (320 mg, 3.63 mmol) in dry tetrahydrofuran (10 mL) was added sodium hydride (145 mg, 3.63 mmol, 60%) slowly under 0° C. The reaction was stirred at this temperature for 30 min and then 2-(4-(5-bromo-2-chlorobenzyl)phenoxy)ethyl 4-methylbenzenesulfonate (intermediate AB) (300 mg, 0.61 mmol was added. The reaction was warmed to room temperature and then heated to reflux overnight. The reaction was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to a yellow oil. The crude oil was purified by flash chromatography to get 200 mg of colorless oil (80% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].S(Cl)(Cl)=O.[CH3:17]O>>[CH3:17][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Bromo-4-fluorophenylacetic acid (2.078 g, 8.92 mmol) and thionyl chloride (1.3 mL, 17.84 mmol) were combined in MeOH (20 mL) and stirred at room temperature for 10 minutes. The mixture was concentrated, and the residue was worked up with CH2Cl2 and 1N aqueous NaOH. The organic layer was dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=O.[Cl:10][C:11]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:12]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[O:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[CH:17][CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][N:23]1[CH2:24][CH2:25][O:26][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:12]3[C:11]([Cl:10])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: Clc1cccc(Cl)c1COc1ccc(C2CNCCO2)cc1
Reactant: COC(=O)C(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)C(C)(C)CN1CCOC(c2ccc(OCc3c(Cl)cccc3Cl)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a solution of 2,2-dimethyl-3-oxo-propionic acid methyl ester (WHSS0374-001) (0.90 g; 5.44 mmol) in 1,2-dichloroethane (20 mL) was added 2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholine (0.91 g, 2.7 mmol) and NaBH(OAc)3 (1.62 g; 7.62 mmol). The resulting mixture was stirred overnight at RT, and subsequently treated with 5% aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (3×30 ml). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O/hexanes 1:1) to afford 3-{2-[4-(2,6-dichloro-benzyloxy)-phenyl]-morpholin-4-yl}-2,2-dimethyl-propionic acid methyl ester (1.12 g) as a clear colourless oil. The required 2,2-dimethyl-3-oxo-propionic acid methyl ester was prepared as follows: To a solution of 2,2-dimethyl-3-hydroxypropionic acid methyl ester (10.00 g; 75.7 mmol) in CH2Cl2 (200 mL) was added pyridinium chloroformate (28.54 g; 132.4 mmol) in small portions, at 0° C. The reaction mixture was allowed to slowly warm to RT and stirred overnight. Subsequently, the mixture was diluted with CH2Cl2, filtered over kieselguhr, and concentrated in vacuo. The remaining oil was purified by column chromatography (SiO2, hexanes/Et2O 7:3) to afford 2,2-dimethyl-3-oxo-propionic acid methyl ester (5.59 g)
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:7]=[CH:6][C:5]1=[O:16]>C(O)(=O)C>[Br:1][C:6]1[C:5](=[O:16])[N:4]([CH3:3])[CH:9]=[C:8]([C:10]2[CH:15]=[N:14][CH:13]=[CH:12][N:11]=2)[CH:7]=1
Reactant: Cn1cc(-c2cnccn2)ccc1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cn1cc(-c2cnccn2)cc(Br)c1=O
Reaction time: 8 h

Procedure:
2.5 ml of bromine are added to a solution of 1-methyl-5-(2-pyrazinyl)-2-pyridone (3.5 g) in glacial acetic acid (150 ml). The reaction mixture is filtered and the filtered solid washed with glacial acetic acid. The filtrate is evaporated in vacuum and the oily residue treated with aqueous sodium bisulfate. The filtered solid is suspended in 250 ml of distilled H2O to which has been added 7 g of sodium bisulfate. A solution of saturated potassium carbonate is added to the suspension to bring the pH back to 6.4. The resulting solid is filtered, washed with H2O and air dried. The same sodium bisulfate procedure is followed with the oily residue obtained from the evaporated filtrate. The solids are combined, recrystallized from isopropanol with decolorizing charcoal added and filtered off hot. The recrystallized solid is suspended in 50 ml of H2O containing 10 g of sodium bisulfate and stirred overnight. The suspended solid is filtered and washed with distilled H2O, recrystallized from isopropanol, filtered, washed with ether and air dried, resulting in the desired 3-bromo-1-methyl-5-(2-pyrazinyl)-2-pyridone, M.P. 196°-197° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:34](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:35]([C:37]([OH:39])=[O:38])[CH3:36].[NH:57](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:58]([C:83]([OH:85])=[O:84])[CH2:59][CH2:60][CH2:61][NH:62][C:63](=[NH:82])[NH:64]S(C1C(C)=C2C(OC(C2)(C)C)=C(C)C=1C)(=O)=O.C1(CCCCC(O)=O)C=CC=CC=1>>[NH2:34][C@H:35]([C:37]([OH:39])=[O:38])[CH3:36].[NH2:57][C@H:58]([C:83]([OH:85])=[O:84])[CH2:59][CH2:60][CH2:61][NH:62][C:63](=[NH:64])[NH2:82]
Reactant: C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CCCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N)C(=O)O
Product: N=C(N)NCCC[C@H](N)C(=O)O
Reaction time: 0.5 h

Procedure:
An analogous procedure to that described in Example 2.6 was used, except that the whole of the peptide assembly was performed manually using HBTU/DIPEA activation, coupling Fmoc-Papa-OH, Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-IIb-OH and 5-phenylvaleric acid in the appropriate order. The peptide was cleaved from the resin using a similar procedure to that described in Example 2.6. The product was purified using preparative RP-HPLC in a similar manner to that described for Example 1.4, eluting with a gradient of acetonitrile-water containing 0.1% TFA (15-30% acetonitrile) over 90 minutes at a flow rate of 10 ml/minute. The product was characterised by HPLC, mass spectroscopy and amino acid analysis in a similar manner to that described for Example 1.4; RP-HPLC (eluting with acetonitrile and water containing 0.1% TFA, using a 15-30% acetonitrile gradient over 30 minutes, flow rate 1.0 ml/minute) retention time=20.02 minutes; mass spectrometry, m/e (ES+) 1061.6 (MH+), 531.4 (M+2H++); amino acid analysis gave Ala 4.16, Arg 2.00, IIb present.
Reaction SMILES: [CH2:1]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([CH2:22][C:23]([NH:25]N)=[O:24])=[C:12]1[CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>CCO.[Ni]>[CH2:1]([N:11]1[C:19]2[C:14](=[CH:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([CH2:22][C:23]([NH2:25])=[O:24])=[C:12]1[CH3:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCn1c(C)c(CC(=O)NN)c2cc(OC)ccc21
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCn1c(C)c(CC(N)=O)c2cc(OC)ccc21
Yield: 68.8 %

Procedure:
Approximately 1.5 g of Raney Ni was added to 1.5 g (4.0 mmol) of 1-decyl-5-methoxy-2-methyl-1H-indole-3-acetic acid hydrazide in 250 mL of EtOH and the mixture heated at reflux for 3 hours. After cooling the mixture was filtered and the filtrate concentrated at reduced pressure. The residue was crystallized from EtOAc/hexane to give 0.987 g (69% yield) of 1-decyl-5-methoxy-2-methyl-1H-indole-3-acetamide, mp, 110-111° C.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1>>[CH2:1]([C:9]1[N:13]=[C:12]([CH2:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH2:30][C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=3)=[CH:18][CH:17]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCc1noc(CCc2ccc(CN)cc2)n1
Product: CCCCCCCCc1noc(CCc2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 65 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-[2-(3-octyl-1,2,4-oxadiazol-5-yl)ethyl]benzylamine and 4-(trifluoromethyl)benzaldehyde gave the title compound as a pale yellow oil (65%). 1H NMR (CDCl3, 300 MHz) δ 7.60 (d, 2H, J=8.3 Hz), 7.51 (d, 2H, J=8.3 Hz), 7.30 (d, 2H, J=7.9 Hz), 7.18 (d, 2H, J=7.9 Hz), 3.86 (s, 2H), 3.78 (s, 2H), 3.12 (m, 4H), 2.70 (t, 2H, J=7.7 Hz), 1.73 (m, 2H), 1.28 (m, 10H), 0.88 (t, 3H, J=6.6 Hz). M+(LC/MS(ESI)): 474. HPLC (Condition A), Rt: 4.31 min (HPLC purity: 97.9%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH3:24])[N:19]=[CH:18]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:24][N:20]1[C:21]2[C:17](=[CH:16][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: Cn1ncc2cc(Br)ccc21
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(cnn3C)c2)C1=O
Yield: 32.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5649 mmol) was reacted with 5-bromo-1-methyl-1H-indazole (142 mg, 0.6794 mmol), 1,4-dioxane (15 mL), copper iodide (10 mg, 0.0526 mmol), trans-L2-diamino cyclohexane (19 mg, 0.1666 mmol) and potassium phosphate (36 mg, 1.698 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 57 mg of the product (32.94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[H][H]>C(OCC)(=O)C.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: O=c1c2cc(F)ccc2nc(C=Cc2ccccn2)n1-c1ccccc1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cl
Product: O=c1c2cc(F)ccc2nc(CCc2ccccn2)n1-c1ccccc1Cl
Reaction time: 3 h

Procedure:
A solution of 1.00 gram (2.65 mmol) of 3-(2-Chloro-phenyl)-6-fluoro-2-(2-pyridin-2-yl-vinyl)-3H-quinazolin-4-one in about 100 mL of ethyl acetate was treated with 0.5 gram of 10% Pd/C and the resulting mixture was hydrogenated at about 2 cm of Hg for two hours at which time uptake of hydrogen had ceased. The catalyst was filtered off with the aid of supercel (filteraid) and the ethyl acetate was removed by evaporation. The residues were dissolved in diethyl ether and treated with excess of a solution of HCl gas in diethyl ether. The product precipitated immediately and was allowed to stir for 3 hours at which time it was separated by filtration and dried in a stream of dry nitrogen. The product was 1.15 g (100%) of 3-(2-chloro-phenyl)-6-fluoro-2-(2-pyridin-2-yl-ethyl)-3H-quinazolin-4-one hydrochloride, an amorphous white solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]2[NH:34][C:33](=[O:35])[N:32]([CH:36]3[CH2:41][CH2:40][N:39]([C:42]4[N:47]=[CH:46][N:45]=[C:44]([C:48]([OH:50])=O)[CH:43]=4)[CH2:38][CH2:37]3)[CH2:31][CH2:30][C:29]=2[CH:51]=1.Cl.Cl.[CH3:54][C:55]1([CH3:64])[CH2:60][NH:59][CH2:58][C:57]2[CH:61]=[N:62][NH:63][C:56]1=2.C(N(CC)CC)C>CN(C=O)C>[CH3:54][C:55]1([CH3:64])[CH2:60][N:59]([C:48]([C:44]2[N:45]=[CH:46][N:47]=[C:42]([N:39]3[CH2:40][CH2:41][CH:36]([N:32]4[CH2:31][CH2:30][C:29]5[CH:51]=[C:25]([O:24][CH3:23])[CH:26]=[CH:27][C:28]=5[NH:34][C:33]4=[O:35])[CH2:37][CH2:38]3)[CH:43]=2)=[O:50])[CH2:58][C:57]2[CH:61]=[N:62][NH:63][C:56]1=2
Reactant: CC1(C)CNCc2cn[nH]c21
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5cn[nH]c5C(C)(C)C4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
105 mg (0.28 mmol) TBTU were added to 100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 80.0 mg (0.36 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC, the product fractions were combined and then lyophilised.
Reaction SMILES: C([O:3][C:4](=O)[N:5]([C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[C:16]([NH2:24])[C:15]=1[N+:25]([O-])=O)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)C>C(O)(=O)C.[Pd]>[NH2:24][C:16]1[C:15]2[NH:25][C:4](=[O:3])[N:5]([CH2:6][C:7]3[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[C:14]=2[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=1
Reactant: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C(F)(F)F)nc(N)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(Cn2c(=O)[nH]c3c(N)nc(C(F)(F)F)cc32)cn1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
(2-Amino-3-nitro-6-trifluoromethyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (27 mg, 0.07 mmol) was stirred in glacial acetic acid (5 ml) and the solution stirred at ambient temperature, 40 psi H2, in the presence of 10% Pd/C (5.4 mg, 20% wt) for 4 h. The suspension was filtered through an Arbocel pad, washed with 2×3 ml AcOH and the filtrate concentrated in vacuo. Acetonitrile (5 ml) was added to the residue and the material triturated, the resulting solid removed by filtration and dried in vacuo to afford 10.6 mg of the title compound as a white solid. 1H NMR (d6-DMSO): δ 8.45(s, 1H), 7.57-7.55(d, 1H), 7.20-7.18(d, 1H), 7.10(s, 1H), 6.20(bs, 2H), 5.01(s, 2H), 2.40(s, 3H); LRMS (APCI) m/z 324 [MH]+
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:6](=O)[O:7]C1C=CC=CC=1.[NH2:20][NH2:21].O>C(O)C>[NH2:20][N:21]1[CH2:2][CH2:3][CH2:4][N:5]([CH2:15][C:16]([F:19])([F:18])[F:17])[C:6]1=[O:7]
Reactant: O=C(Oc1ccccc1)N(CCCCl)CC(F)(F)F
Reactant: NN
Solvent: O
Solvent: CCO
Product: NN1CCCN(CC(F)(F)F)C1=O
Temperature: 90 °C
Reaction time: 5 h

Procedure:
Into a 100-mL round-bottom flask, was placed phenyl N-(3-chloropropyl)-N-(2,2,2-trifluoroethyl)carbamate (1.4 g, 4.73 mmol, 1.00 equiv), NH2NH2.H2O (6 mL), ethanol (40 mL). The resulting solution was stirred for 5 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of H2O. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×30 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (crude) of 1-amino-3-(2,2,2-trifluoroethyl)-1,3-diazinan-2-one as a light yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9].[I-:28].[Na+]>CC(C)=O>[I:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([S:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)[C:8]#[N:9]
Reactant: COc1ccc(C(C#N)(CCCCCCl)Sc2ccc(C)cc2)cc1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(C(C#N)(CCCCCI)Sc2ccc(C)cc2)cc1OC
Yield: 96.7 %

Procedure:
A mixture of 0.86 g of α-(5-chloropentyl)-3,4-dimethoxy-α-[(4-methylphenyl)thio]benzeneacetonitrile, 3.2 g of sodium iodide, and 10 mL of acetone is heated to reflux overnight, protected from light. The volatiles are removed in yacuo and 30 mL of diethyl ether is added to the residue. The insolubles are collected and the volatiles removed in vacuo. The residue is purified via column chromatography using hexane/ethyl acetate (2:1) to afford 1.02 g of the desired product as a clear oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[O:18][CH2:17]1)[C:10]([O:12]CC)=[O:11].C(O)(=O)C>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C@H:9]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([OH:27])=[O:26])[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[O:18][CH2:17]1)[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)[C@H](CCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NCCCCC[C@H](N[C@H]1COc2ccccc2N(CC(=O)O)C1=O)C(=O)O
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
A solution of 3(S)-[6-amino-1(S)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.35 g) in 1N sodium hydroxide solution (10 ml) is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2.5 ml), the mixture is subjected to Amberlite XAD-2 column chromatography eluting with methanol-water (1:10). The eluate is concentrated under reduced pressure and lyophilized to yield 3(S)-[6-amino-1(S)-carboxyhexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.17 g) as colorless powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[S:8][C:7]=1[NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH:22]=1)=O)C.O.[NH2:35][NH2:36]>C(O)C>[CH2:31]([N:28]([CH2:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[C:20]([NH:19][C:7]1[S:8][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:10]([CH3:11])[C:6]=1[C:4]([NH:35][NH2:36])=[O:3])=[O:33])[CH2:29][CH3:30])[CH3:32]
Reactant: CCOC(=O)c1c(NC(=O)c2cccc(CN(CC)CC)c2)sc(CN2CCCCC2)c1C
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCN(CC)Cc1cccc(C(=O)Nc2sc(CN3CCCCC3)c(C)c2C(=O)NN)c1
Reaction time: 12 h

Procedure:
Subsequently, 2-(3-diethylaminomethyl-benzoylamino)-4-methyl-5-piperidin-1-ylmethylthiophene-3-carboxylic acid ethyl ester (79 mg) was dissolved in ethanol (10 ml), hydrazine monohydrate (2 ml) was added dropwise to the solution at room temperature, and a reaction was then allowed to proceed at that temperature for 12 hr. After the completion of the reaction, the reaction system was concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 3-diethylaminomethyl-N-(3-hydrazinocarbonyl-4-methyl-5-piperidin-1-ylmethylthiophen-2-yl)-benzamide as a useful intermediate (30 mg, yield 38%).