Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:32][C@H:33]([C:35]([OH:37])=[O:36])[CH3:34])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:15]1([N:4]2[C@H:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:7][CH2:8][C@H:2]([NH:1][C:35](=[O:36])[C@H:33]([CH3:34])[NH:32][C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[CH:23]=3)[C:3]2=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH:15]1([N:4]2[C@@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:7][CH2:8][C@@H:2]([NH:1][C:35](=[O:37])[C@H:33]([CH3:34])[NH:32][C:30](=[O:31])[CH2:29][C:24]3[CH:25]=[C:26]([F:28])[CH:27]=[C:22]([F:21])[CH:23]=3)[C:3]2=[O:20])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: N[C@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1CC=C[C@H](c2ccccc2)N(C2CCCC2)C1=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CC=C[C@@H](c2ccccc2)N(C2CCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of crude (3S,7S)-3-amino-1-cyclopentyl-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (8d) (40 mg) in DCM (3 ml) at RT under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (36 mg), HOBt (40 mg), EDAC.HCl (42 mg), and N-methylmorpholine (15 mg). The reaction was stirred at RT overnight., then diluted with DCM (10 ml) and washed with 1N HCl, 1N K2CO3, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as a 70:30 mixture with N1-[(3R,7R)-1-cyclopentyl-2-oxo-7-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yl]-N2-[(3,5-difluorophenyl)acetyl]-L-alaninamide as an off white solid (55 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 1.17-2.21 (m, 12H), 2.79-2.87 (m, 1H), 3.55 (s, 2H), 5.44-5.52 (m, 1H), 5.80-5.84 (m, 1H), 5.90-5.93 (s, 1H), 6.26-6.35 (m, 2H), 6.69-6.86 (m, 3H), 7.19-7.46-(m, 6H). MS APCI, m/z=496 (M+1), LC/MS, 2.65 min.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=1.C(N(CC)CC)C.[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>CN(C=O)C.O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:33][O:32][C:28](=[O:31])[CH:29]=[CH:30][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:3]=1
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc([N+](=O)[O-])ccc21
Reactant: C=CC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1nn(C(=O)OC(C)(C)C)c2ccc([N+](=O)[O-])cc12
Temperature: 50 °C
Yield: 36.6 %

Procedure:
A solution of tert-butyl 3-iodo-5-nitro-1H-indazole-1-carboxylate (Intermediate 44, 4.6 g; 11.8 mmol) in DMF (76 ml) and water (12 ml) was treated with triethylamine (12 ml; 86 mmol), methyl acrylate (10.4 ml; 115 mmol) and tetrabutyl ammonium iodide (8.6 g; 23 mmol). The mixture was degassed and then dichlorobis(triphenylphosphine)palladium (II), (1.68 g; 2.4 mmol) was added. The mixture was heated to 50° C. for 18 hours and the volatile solvent removed in vacuo. The mixture was poured into water (600 ml) and extracted with EtOAc. The combined organic extracts were washed with water, dried over sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give tert-butyl 3-(3-methoxy-3-oxoprop-1-enyl)-5-nitro-1H-indazole-1-carboxylate as a light brown solid (1.5 g, 37%). A solution of this residue (200 mg; 0.58 mmol) in methanol (100 ml) was treated with palladium (100mg, 5% on C). The mixture was stirred under hydrogen for 18 hours, filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=1[NH2:12].C(N(C(C)C)CC)(C)C>C(O)CCC>[CH3:11][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].[Cl:1][C:2]1[N:7]=[C:6]([NH:12][C:11]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:10]=2[Br:9])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1ccc(N)c(Br)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)C
Product: Cc1ccc(Nc2ccnc(Cl)n2)c(Br)c1
Temperature: 120 °C

Procedure:
2,4-Dichloropyrimidine (1 g, 6.71 mmol), 2-bromo-4-methylaniline (1.25 g, 6.71 mmol) and di-isopropylethylamine (1.29 ml, 7.38 mmol) were dissolved in n-butanol (5 ml). The reaction mixture was heated at 120° C. for 12 hours, cooled and evaporated onto silica (5 ml). The residue was purified by column chromatography and eluted with EtOAc (30%):isohexane to give the title product as a solid on evaporation (1.01 g). NMR (300 MHz): 2.31 (s, 3H), 6.50 (d, 1H), 7.22 (dd, 1H), 7.36 (d, 1H), 7.55 (s, 1H), 8.09 (d, 1H), 9.61 (s, 1H); m/z: (ES+) 298.1 (MH+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[C]=[O:19].CO.C1[CH2:26][O:25][CH2:24]C1>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:24]([O:25][CH3:26])=[O:19])=[N:3][C:4]=1[O:9][CH3:10]
Reactant: COc1nc(Br)cnc1N
Reactant: [C]=O
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cnc(N)c(OC)n1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-3-methoxypyrazin-2-amine (2.80 g, 13.7 mmol, 1 eq.; Jiang, B. et al. Bioorg. Med. Chem. (2001), 9, 1149-1154), [1,1,-Bis-(diphenylphosphino)ferrocen]palladium(II)-dichlorid (2.24 g, 2.75 mmol, 0.2 eq) and triethylamine (2.10 mL, 15.1 mmol, 1.1 eq) was placed in 600 mL autoclave and dissolved in 135 mL methanol/THF (10/1). The autoclave was flushed with carbon monoxide (3×) and was then pressurized with carbon monoxide to 9 bar. After 30 min at r.t. no conversion was obtained. The autoclave was again pressurized with carbon monoxide to 9 bar and subsequently heated to 100° C. In the course of the reaction, carbon monoxide consumption was observed (decrease of CO pressure). The autoclave was cooled to r.t., flushed with inert gas and the reaction mixture was filtered through a small pad of Celite. LC-MS analysis showed full conversion. The volatile components were removed in vacuo and the material observed this way (1.8 g, 62%) contained the title compound in 92% purity (UPLC-MS, area-%) and was used in the following without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.CCN(CC)CC.[C:41]([O:46][CH2:47]Cl)(=[O:45])[CH:42]([CH3:44])[CH3:43]>CN(C=O)C>[C:41]([O:46][CH2:47][N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)(=[O:45])[CH:42]([CH3:44])[CH3:43]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(C)C(=O)OCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(COC(=O)C(C)C)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
To a mixture of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (0.1 g, 0.2 mmol) and Et3N (57 μL, 0.4 mmol) in DMF (1 mL) was added chloromethyl isobutyrate (34 mg, 0.25 mmol) at rt. The reaction was stirred at rt for 16 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=4/1 to 3/1) to afford the title compound as a white solid (45 mg, 37.5%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH2:1]([CH:4]1[N:7]([C:8]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6](=[O:38])[CH:5]1[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH:2]=C.FC(F)(F)C(O)=O.O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C>[CH2:39]([CH:5]1[C:6](=[O:38])[N:7]2[CH:4]1[CH2:1][CH:2]=[C:8]2[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: C=CCC1C(Cc2ccccc2)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1=CCC2C(Cc3ccccc3)C(=O)N12
Reaction time: 0.5 h

Procedure:
A solution of 4-allyl-3-benzyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidine-2-one (36) (0.38 g) in ethyl acetate (20 ml) was treated with trifluoroacetic acid (1.0 ml). The solution was cooled to -78° and ozone passed through it until it just became blue in colour. The excess ozone was blown off in a stream of argon and a solution of triphenylphosphine (0.16 g) in ethyl acetate (2 ml) was then added. The reaction solution was purged with argon for the next 30 minutes and the reaction flask was then transferred to an ice bath. Saturated aqueous sodium bicarbonate (30 ml) was added with vigorous stirring and after a further 30 minutes the ethyl acetate solution was separated, washed with brine and dried over sodium sulphate. Column chromatography on silica gel 60 (<230 mesh) eluting with ethyl acetate/60°-80° petroleum ether 3:7 gave benzyl 6-benzyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate as the trans isomer (37) (0.09 g. 42%). It was a colourless gum; νmax (CHCl3) 3020, 2960, 1785, 1725 and 1610 cm-1 ; τ (CDCl3) 2.6-3.0 (10H, m, phenyls), 3.66 (1H, t, J 3 Hz, C3-H), 4.80 (2H, s, benzyl CH2 -O), 6.02 (1H, td, J 81/2 and 3 Hz, C5-H), 6.60 (1H, ddd, J 9, 6 and 3 Hz, C6-H), 6.88 (1H, d, J 6 Hz, inner signal of ABX for PhCH2 -C6), 6.97 (1H, d, J 9 Hz, inner signal of ABX for PhCH2 -C6), 7.29 and 7.32 (2H, each a dd, J 81/2 and 3 Hz, inner signals of AB for C4-H2).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)O1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH:28]=[C:27](OS(C(F)(F)F)(=O)=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:25][CH:26]=[C:27]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)[CH2:28][CH2:29]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2)CC1

Procedure:
The title compound was prepared by Suzuki coupling of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine with 4-trifluoromethanesulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (Synthesis, 993, (1991)) according to the procedure in Example 35, step (b). Mass spectrum (ESI, m/z): Calcd. for C16H22N2O2, 275.2 (M+H). found 275.1.
Reaction SMILES: [SH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH2:12]([O:19][C:20]([NH:22]/[C:23](=[CH:28]\[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>CO>[CH2:12]([O:19][C:20]([NH:22][CH:23]([CH:28]([S:1][CH2:2][CH2:3][NH:4][C:5]([O:6][C:7]([CH3:8])([CH3:10])[CH3:9])=[O:11])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)/C(=C/c1ccccc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(NC(=O)OCc1ccccc1)C(SCCNC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Using a method similar to that described in Example 1, part b (Method B) a solution of tert-butyl N-(2-mercaptoethyl)carbamate (2.4 mL), methyl (2Z)-2-{[(benzyloxy)carbonyl]amino}-3-phenylprop-2-enoate (0.87 g), triethylamine (0.39 mL) and methanol (15 mL) was stirred at RT for 3 days. Removal of the solvent and chromatograpy of the resultant crude oil on silica gel (10% to 25% ethyl acetate/hexanes) returned the title compound as a viscous oil (1.22 g, 90%). The proton NMR displayed a mixture of diastereomers of approximate ratio 7:3; the major diastereomer is reported. 1H NMR (300 MHz, CDCl3) δ 1.41 (s, 9H), 2.48 (t, 2H), 3.19 (br, 2H), 3.65 (s, 3H), 4.12 (q, 1H), 4.35 (t, 1H), 4.73 (t, 2H), 5.09 (d, 2H), 7.27-7.34 (m, 10H). MS APCI, m/z=389(M−t-BuOCO)+. HPLC Method A: 3.47 min.
Reaction SMILES: [CH:1]1([CH:7](O)[C:8]2[CH:9]=[C:10]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH2:19])=[O:18])[O:11][C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[C:17]([C:16]1[CH:15]=[C:14]([C:10]2[O:11][C:12]([CH3:13])=[C:8]([CH:7]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:41])[CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=3)[CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:18])[NH2:19]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1oc(-c2cccc(C(N)=O)c2)cc1C(O)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1oc(-c2cccc(C(N)=O)c2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 53.2 %

Procedure:
A mixture of 3-{4-[cyclohexyl(hydroxy)methyl]-5-methylfuran-2-yl}benzamide (0.6 g), ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.7 g), sodium carbonate (0.3 g) and sodium iodide (0.6 g) in N,N-dimethylacetamide (20 mL) was stirred at 80° C. for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (50% ethyl acetate/hexane to 100% ethyl acetate/hexane). To the residue were added ethanol (3 mL), tetrahydrofuran (3 mL) and 1N lithium hydroxide (2.5 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (527 mg, 54%).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.C1(P(=C[C:32]([O:34][CH2:35][CH3:36])=[O:33])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37]1(C)C=CC=CC=1>>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[CH2:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: Cc1ccccc1
Reactant: COc1cccc(C=O)c1F
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=C(C(=O)OCC)c1cccc(OC)c1F
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 2-fluoro-3-methoxybenzaldehyde (2.00 g) in toluene (50 mL) was added ethyl (triphenylphosphoranylidene)acetate (4.50 g), and the mixture was stirred at 110° C. for 4 hr. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.50 g) as a colorless oil.
Reaction SMILES: CI.[N+:3]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][NH:11][CH2:12][C@H:13]2[CH2:17][CH2:16][CH2:15][O:14]2)=[CH:8][CH:7]=1)([O-:5])=[O:4].[C:20](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:20][N:11]([CH2:10][C:9]1[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:19][CH:18]=1)[CH2:12][C@H:13]1[CH2:17][CH2:16][CH2:15][O:14]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(CNC[C@H]2CCCO2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccc([N+](=O)[O-])cc1)C[C@H]1CCCO1

Procedure:
Methyl iodide (0.728 mL, 11.7 mmol) was added to (4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 10a2 (1.84 g, 7.80 mmol) and potassium carbonate (3.23 g, 23.4 mmol) in DMF (30 mL). After 4 hrs the reaction was diluted with water and extracted with ethyl ether. The combined extracts were washed with water, dried over MgSO4, and evaporated down to give 1.43 g of methyl-(4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 10a3. Using the procedure of Example 21, Compound 10a3 was used in place of Compound 21a2 and carried forward to prepare 4-({methyl-[(2R)-tetrahydro-furan-2-ylmethyl]-amino}-methyl)-phenylamine Compound 10a.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]2[C:19]#[N:20])=[O:8])=[CH:5][CH:4]=1.C(=O)(O)[O-:26].[Na+].OO>CC(C)=O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]2[C:19]([NH2:20])=[O:26])=[O:8])=[CH:21][CH:22]=1
Reactant: N#CC1C=Cc2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)C1C=Cc2ccccc2N1C(=O)c1ccc(C(F)(F)F)cc1
Yield: 40.8 %

Procedure:
The title compound was prepared by the procedure described in step 2 of Example 1 using 20.0 g of 1-(4-Trifluoromethylbenzoyl)-1,2-dihydro-quinoline-2-carbonitrile, 10.0 g of sodium bicarbonate, 500 mL of acetone, and 250 mL of 30% hydrogen peroxide solution. Crystallization from acetonitrile afforded the title compound (8.6 g) as a white solid, m. p. 158-160° C.
Reaction SMILES: [N+:1](=[C:3]([C:18](=[O:20])[CH3:19])[C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)=[N-:2].[CH2:21]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:22]>C(#N)C>[N+:1](=[C:3]([C:18](=[O:20])[CH3:19])[C:4](=[O:17])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)=[N-:2].[CH2:21]([NH+:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:22]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)O)cc1
Reactant: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(=O)CCc1ccc(S(=O)(=O)[O-])cc1
Product: CC[NH+](CC)CC
Reaction time: 2 h

Procedure:
To a solution of 4-(4-diazo-3,5-dioxohexyl)benzenesulfonic acid (890 mg, 30 mmol) obtained in Example 4 in acetonitrile (5 ml), triethylamine (3 ml) was added dropwise at 5°-10° C., and stirring was continued for 2 h at the same temperature. Then the mixture was evaporated under reduced pressure, the residue was washed thrice with ethyl ether and evaporated to dryness under reduced pressure to give the title compound as a slightly yellow viscous oil; yield: 700 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)(=[O:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:30]([C:29]2[CH:33]=[CH:34][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=2)=[O:31])=[CH:20][CH:21]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccc(C(C)=O)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) and commercially available 4-acetylbenzoic acid (46 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (87 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was then purified in the same manner as described in Example 50 to obtain 43 mg of the title compound (yield: 53%).
Reaction SMILES: C([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([NH2:27])=[N:21][C:22]=3Cl)[O:12][C@@H:11]1[CH2:28][O:29]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.Cl.[NH:39]1[CH2:42][CH2:41][CH2:40]1.C(N(CC)CC)C.C[O-].[Na+].C(O)(=O)C>C(O)C>[NH2:27][C:20]1[N:19]=[C:18]2[C:23]([N:24]=[CH:25][N:17]2[C@@H:13]2[O:12][C@H:11]([CH2:28][OH:29])[C@@H:10]([OH:9])[C@:14]2([F:16])[CH3:15])=[C:22]([N:39]2[CH2:42][CH2:41][CH2:40]2)[N:21]=1
Reactant: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cnc2c(Cl)nc(N)nc21
Reactant: C1CNC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@]1(F)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N3CCC3)nc(N)nc21
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
To a 350 mL of dry seal pressure flask (Chemglass) were added (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(benzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl benzoate (12, 3.6 g, 6.85 mmol) and 150 mL of absolute ethanol. Azetidine hydrochloride (2.56 g, 27.4 mmol) was added and then followed by triethylamine (4.16 g, 41.1 mmol). The suspension was stirred and heated to 70° C. while sealed for 5 hours. All the starting material was consumed but the benzoyl groups remained as shown by TLC. Sodium methoxide (7.8 mL, 34.3 mmol, 25% solution in methanol) was added to the mixture and heated at 50° C. The reaction was complete after 3.5 h. The reaction mixture was allowed to cool to room temperature and neutralized by addition of glacial acetic acid (0.41 g, 6.85 mmol). The mixture was concentrated under reduced pressure and then the residue was triturated with ethyl acetate. The resulting solid was removed by filtration and the solid was washed with EtOAc (2×15 mL). The filtrate was concentrated under reduced pressure and the residue was purified via column chromatography (Analogix, 120 g cartridge, gradient of 0 to 15% MeOH in DCM). The pure product containing fractions were combined, concentrated under reduced pressure and dried (50° C., 0.2 mmHg, 17 h) to a light pink colored foam solid (2.15 g, 6.35 mmol, 93%).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]([C:26](O)=[O:27])[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:30]1[C:34](=O)[CH2:33][CH2:32]C1=O.C1CCC([N:43]=C=NC2CCCCC2)CC1>CN(C=O)C>[NH2:43][CH:32]([C:26](=[O:27])[C@H:10]([CH2:9][S:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:11][C:12](=[O:25])[C:13]([CH3:24])([CH3:23])[CH2:14][S:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:33][CH2:34][NH2:30]
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(CSCc1ccccc1)C(=O)N[C@@H](CSCc1ccccc1)C(=O)C(N)CCN
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
To a stirred solution of S-benzyl-N-(3-benzylthio-2,2-dimethylpropionyl)-L-cysteine (2.04 g) and N-hydroxysuccinimide (0.563 g) in DMF (5 ml), DCC (1.11 g) dissolved in DMF (5 ml) was added dropwise. The mixture was stirred for 0.5 hr. under ice cooling and for 0.5 hr. at room temperature, and filtered. To the filtrate, 1,3-diaminopropane (1.09 g) dissolved in DMF (30 ml) was added dropwise with stirring. The mixture was stirred for lhr and water was added to the mixture, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 1.6 g (69%) of the titled compound.