Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].C(N(C(C)C)C(C)C)C.Cl.[C:34]([O:38][C:39](=[O:43])[C@@H:40]([CH3:42])[NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:41][C@@H:40]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:43])[CH3:42])=[O:19])=[C:5]2[OH:23]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 54.9 %

Procedure:
Ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (705 mg, 2093 μmol, prepared in Example 1 A-C) was dissolved in 1,4-dioxane (2093 μL) and N-ethyl-N-isopropylpropan-2-amine (1094 μL, 6280 μmol). D-Alanine tert-butyl ester hydrochloride (570 mg, 3140 μmol) was added, and the reaction mixture was heated to 80° C. for 24 hours. The resulting mixture was then diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 75 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (501 mg) after flash chromatography. MS (m/z)=436 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:13]([Zn]CC)[CH3:14]>O1CCOCC1>[CH2:13]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:14]
Reactant: CCOC(=O)c1cccnc1Cl
Reactant: CC[Zn]CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cccnc1CC
Temperature: 70 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of ethyl 2-chloropyridine-3-carboxylate (15 g, 81 mmol) in anhydrous 1,4-dioxane (150 mL) at room temperature was added (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (1.3 g, 1.6 mmol) followed by a diethylzinc solution (75 mL, 83 mmol, 1.1 M solution in toluene). The mixture was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction was quenched with MeOH. Ethyl acetate (200 mL) was added. The mixture was extracted with 0.2 N HCl (200 mL). The organic layer was recovered. The pH of the aqueous phase was brought around 6 with 2 N NaOH. The mixture was extracted with EtOAc (1×100 mL). The combined organic extracts were dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-20% ethyl acetate/hexane), affording ethyl 2-ethylpyridine-3-carboxylate (8.8 g, 61% yield)
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH:6]1([N:12]=[C:13]=[N:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH2:1]([NH:5][C:13]([NH:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[N:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCNC(=NC1CCCCC1)NC1CCCCC1
Yield: 99 %

Procedure:
A mixture of 15.69 g of N-butylamine (0.214 mol) and 22.13 g of dicyclohexylcarbodiimide (0.107 mol) is heated at reflux for 2 h. GC analysis then shows a conversion of the dicyclohexylcarbodiimide of greater than 99.6%. The final colorless mixture is concentrated at 60° C. under 1 mbar for 2 h to give 29.7 g of a colorless, virtually odorless and moderately viscous liquid corresponding to the expected guanidine 2 (99% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([CH:26]([OH:30])[C:27]([NH2:29])=[O:28])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:16])[N:9]=2)[C:3]2[CH:35]=[CH:36][CH:37]=[CH:38][C:2]1=2.IC1C=CC=CC=1C(O)=O>CS(C)=O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:12]=[CH:11][N:10]([C:13]3[N:34]=[CH:33][CH:32]=[CH:31][C:14]=3[C:15]([NH:17][CH:18]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:16])[N:9]=2)[C:3]2[CH:35]=[CH:36][CH:37]=[CH:38][C:2]1=2
Reactant: NC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCOc3ccccc32)n1
Agent: O=C(O)c1ccccc1I
Solvent: CS(C)=O
Product: NC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1ccc(CN2CCOc3ccccc32)n1
Yield: 105.1 %

Procedure:
Oxidation of 2-(3-((2H-benzo[b][1,4]oxazin-4(3H)-yl)methyl)-1H-pyrazol-1-yl)-N-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-yl)nicotinamide (210 mg, 0.410 mmol) in DMSO (6 mL) with 2-iodobenzoic acid as described for example 2.4 gave 220 mg of a yellow solid, which was purified by chromatography over silica gel (eluent CH2Cl2+0-15% methanol). After concentration the obtained solid was recrystallized from 2-propanol to give 78 mg of the title compound as an amorphous solid; ESI-MS [M+H]+: 511.2. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.97 (m, 1H), 8.55 (m, 1H), 8.29 (m, 1H), 8.09 (m, 1H), 7.84 (m, 1H), 7.70 (m, 1H), 7.44 (m, 1H), 7.31 (m, 4H), 7.22 (m, 1H), 6.82 (m, 1H), 6.70 (m, 1H), 6.61 (m, 1H), 6.50 (m, 1H), 6.34 (m, 1H), 5.44 (m, 1H), 4.26 (d, 1H), 4.20 (d, 1H), 4.12 (m, 2H), 3.25 (m, 3H), 2.88 (dd, 1H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][C:15](=[O:17])[NH:14][CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].CN(C)C=O.[H-].[Na+].Cl[CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][C:15](=[O:17])[N:14]([CH2:43][C:44]([N:46]([CH3:48])[CH3:47])=[O:45])[CH2:13][CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)C(=O)CCl
Reactant: O=C1NCC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)CN1CC(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)OC1=O
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
To a solution of 243 mg (0.5 mmol) 9-(3,5-bis-trifluoromethyl-benzoyl)-5-phenyl-1-oxa-3,9-diaza-spiro[5.5]undecan-2-one in dimethylformamide 24 mg (0.5 mmol) of a 55% sodium hydride suspension in mineral oil was added at room temperature under argon. After 15 min, 126 mg (0.8 mmol) of 2-chloro-N,N-dimethylacetamide was added. The reaction mixture was stirred at 80° C. under argon overnight. After evaporation of the solvent in vacuum water (1 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was dried over (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2, Hexane/ethylacetate=1:1) to yield 154 mg (54%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:24]3[CH:45]=[CH:44][C:27]([C:28]([NH:30][C@H:31]([C:39]([O:41]CC)=[O:40])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:29])=[CH:26][CH:25]=3)[CH2:15][C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[CH:8]=2)[N:3]=1.[OH-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][C@H:31]([C:39]([OH:41])=[O:40])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])=[CH:44][CH:45]=3)[CH2:15][C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(Cc2ccc3nc(N)nc(O)c3c2)Cc2c[nH]c(=O)[nH]c2=O)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(O)c2cc(CN(Cc3c[nH]c(=O)[nH]c3=O)c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)ccc2n1
Reaction time: 1.5 h

Procedure:
Diethyl N-(4-(N-(2-amino-4-hydroxy-6-quinazolinyl)methyl-N-(5-uracilyl)methyl-amino)benzoyl)-L-glutamate (0.327 g) was suspended in a mixture of water (7 ml) and ethanol (2 ml) and treated with 1N NaOH aq. (6 mol. eq.) Vigorous shaking gave a solution within 30 min. After a further 1.5 hr. the solution was clarified by filtration and the pH brought to 4.0 using 1N HCl aq. A particulate precipitate of the product resulted. It was freed from inorganic ions by three cycles of suspension-centrifugation-decantation. The amorphous white solid was dried at 40° C. in vacuo, to yield the pure diacid, N-(4-(N-(2-amino-4-hydroxy-6-quinazolinyl)methyl-N-(5-uracilyl)methyl-amino)benzoyl)-L-glutamic acid (CB 3743), as its dihydrate (68%), m.p. 250°-255° C. The structure was confirmed by elemental analysis (C,H,N) and by uv spectroscopy (spectrum determined in 0.1N NaOH aq.). λ(nm) (ε) maxima: 310 (29,200), 276.5(22,000), 230 (50,700); minima: 282.5 (21,500), 251.5 (11.600).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:11](/[CH:20]=[CH:21]/[C:22]#N)[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:41]CC1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:11](/[CH:20]=[CH:21]/[CH:22]=[O:41])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: N#C/C=C/n1c(C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: O=C/C=C/n1c(C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1

Procedure:
From (E)-3-[4,5-bis(4-fluorophenyl)-2-trifluoromethyl-1H-imidazol-1-yl]-2-propenenitrile (484 mg) and diisobutylaluminum hydride (2.2 ml) in dry THF (15 ml) by the process as described for the preparation of Intermediate (4a) to afford a brown gum (0.53 g) which was purified by FCC eluting with System A (1:4) to afford the title compound (263 mg) as a yellow solid. νmax (Nujol) 1692 cm-1 (C=O).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([O:12][C:13](=[O:16])[NH:14][NH2:15])([CH3:11])([CH3:10])[CH3:9]>O>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][NH:15][NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:16])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)NN
Solvent: O
Product: CCOC(=O)CNNC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Ethyl bromoacetate 3 (6.97 mL, 62.8 mmol) was added to a stirred solution of tert-butylcarbazate 2 (24.9 g, 188.6 mmol) in water (25 mL) at room temperature. The mixture was stirred for 30 min. Water layer was then extracted with ethyl acetate (3×). Ethyl acetate extracts were pooled together and washed with brine. Ethyl acetate was evaporated under vacuum to get crude product which was purified by flash column chromatography using hexane:ethyl acetate (70:30) as an eluent (yield 70%). 1H NMR (500 MHz, CDCl3) 1.28 (3H, CH2—CH3, t), 1.45 (9H, C—CH3, s), 3.64 (2H, NH—CH2—CO, s), 4.20 (2H, CH2CH3, q); MS Anal. Mol. Wt. 218.25 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=1.Cl.[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([NH2:31])[CH3:30])=[N:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][N:3]=2)[CH3:30])=[N:27][CH:28]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
A mixture of 2-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyrimidin-4-amine (Intermediate 30, 1.0 g) and [(1S)-1-(5-fluoropyridin-2-yl)ethyl]amine hydrochloride (Intermediate 5, 0.8 g) in n-BuOH (5 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 1.0 g of the title compound. MS (electrospray): 403 (M+1) for C17H19FN8O3. 1H NMR (300 MHz, CD3OD) δ ppm 9.10 (s, 1H) 8.50 (s, 1H) 7.60 (m, 1H) 7.40 (m, 1H) 5.80 (s, 1H) 5.20 (m, 1H) 4.70 (m, 2H) 1.60 (d, 3H) 1.40 (d, 6H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[N:8]=[C:7]([N:22]2[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[N:23]2)[N:6]=1>C1COCC1>[CH3:1][N:2]([CH3:3])[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=2)[N:8]=[C:7]([N:22]2[CH:26]=[C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:24]=[N:23]2)[N:6]=1
Reactant: CNC
Reactant: CCOC(=O)c1cnn(-c2nc(Cl)c3ccc(Oc4ccccc4)cc3n2)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(-c2nc(N(C)C)c3ccc(Oc4ccccc4)cc3n2)c1
Reaction time: 1 h
Yield: 62 %

Procedure:
A THF solution of dimethylamine (2M, 0.44 mL, 0.88 mmol) was added to a solution of the above ethyl 1-(4-chloro-7-phenoxyquinazolin-2-yl)-1H-pyrazole-4-carboxylate (70 mg, 0.18 mmol) and THF (1.4 mL). The mixture was stirred 1 h, and then concentrated. The residue was triturated with ethanol, providing the titled compound (45 mg, 63%). MS (ESI/CI): mass calcd. for C22H21N5O3, 403.1; m/z found, 404.3 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.02 (s, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.12 (s, 1H), 7.53 (dd, J=11.1, 4.8 Hz, 2H), 7.32 (t, J=7.4 Hz, 1H), 7.27-7.21 (m, 2H), 7.18 (dd, J=9.3, 2.7 Hz, 1H), 6.96 (d, J=2.7 Hz, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.46 (s, 6H), 1.30 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([CH2:19][C:20]3([OH:26])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][CH:14]=2)=[N:8]1.[Cl:29][C:30]1[C:31]([F:39])=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34].O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:29][C:30]1[C:31]([F:39])=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33]([N:23]1[CH2:22][CH2:21][C:20]([CH2:19][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:12][C:9]3[CH:10]=[CH:11][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:27])([CH3:1])[CH3:28])[N:8]=3)[N:18]=2)([OH:26])[CH2:25][CH2:24]1)=[O:34]
Reactant: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CC3(O)CCNCC3)n2)n1
Reactant: O=C(O)c1cccc(Cl)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc(Nc2cccc(CC3(O)CCN(C(=O)c4cccc(Cl)c4F)CC3)n2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 204 mg of 4-((6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridin-2-yl)methyl)piperidin-4-ol in 10 ml of chloroform were added 132 mg of 3-chloro-2-fluorobenzoic acid, 116 mg of hydroxybenzotriazole hydrate and 194 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature, followed by stirring the reaction mixture at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The resulting chloroform layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=10/1 to ethyl acetate) to give the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[CH2:4][C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([F:15])=[N:10][C:11]=2[NH2:14])[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([CH2:4][C:3]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:2]=3[Br:1])[N:6]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:11]([NH2:14])[N:10]=1
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(Br)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2Br)nc2c(N)nc(F)nc21

Procedure:
A solution of 8-(2-bromo-4,5-dimethoxy-benzyl)-2-fluoroadenine (13 mg, 0.034 mmol), Cs2CO3 (11 mg, 0.034 mmol), pent-4-ynyl tosylate (10 mg, 9 L, 0.044 mmol) in anhydrous DMF (80 L) was stirred at 60° C. for 30 min. Following solvent removal, the product (8.2 mg, 53.6%) was collected through silica gel column purification (CHC13:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1HNMR (400 MHz, CDC13) 7.06 (s, 1H), 6.67 (s, 1H), 5.92 (bs, 2H), 4.31 (s, 2H), 4.14 (t, J=7.4 Hz, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 2.25-2.20 (m, 2H), 1.99 (t, J=2.6 Hz, 1H), 1.96-1.89 (m, 2H); 13C NMR (100 MHz, CDC13) 160.0, 158.3, 156.7, 153.4, 151.3, 149.4, 127.2, 117.3, 115.9, 114.5, 113.2, 82.7, 70.2, 56.62, 56.56, 42.7, 34.3, 30.1, 28.5, 16.3; MS m/z 447.9 (M+H)+. HPLC: (a) 99.0% (60% water-40% acetonitrile); (b) 98.8% (35% to 55% acetonitrile).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].C(N(C(C)C)C(C)C)C.[CH3:14][S:15][C:16](=[O:30])[CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:20]([OH:22])=[O:21].[Cl-].[NH4+]>CS(C)=O>[CH3:14][S:15][C:16](=[O:30])[CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:20]([O:22][CH2:2][C:3]#[N:4])=[O:21]
Reactant: N#CCBr
Reactant: C=CCCC(=O)N[C@@H](CCC(=O)SC)C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCC(=O)N[C@@H](CCC(=O)SC)C(=O)OCC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2-Bromoacetonitrile (3.60 ml, 52.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.297 ml, 2.86 mmol) were added to a solution of (S)-5-(methylthio)-5-oxo-2-(pent-4-enamido)pentanoic acid (Compound 1f-IIA) (673 mg, 2.60 mmol) in DMSO (5.5 ml), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution (3 ml) was added to the reaction mixture, after which the mixture was extracted with ethyl acetate and the organic layer was washed with water. The organic extract was then dried over magnesium sulfate. Following concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→30/70) to afford (S)-cyanomethyl 5-(methylthio)-5-oxo-2-(pent-4-enamido)pentanoate (Compound 1g-IIA) (772 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-])=O)[CH:10]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:12]([CH2:15][C:16](=[O:17])[NH:19]2)=[CH:13][CH:14]=1
Reactant: COc1ccccc1-c1ccc(CC(=O)O)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Temperature: 100 °C
Yield: 66.2 %

Procedure:
Iron powder (5 g) was added in one portion to 9.8 g of 2′-methoxy-3-nitrobiphenyl-4-acetic acid in 50 mL of glacial acetic acid was heated to 100° C. for 3 hours. The reaction mixture was concentrated to dryness, sonicated in ethyl acetate and filtered to remove the insolubles. The filtrate was washed twice with 1N hydrochloric acid, water and then brine, dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on silica gel in ethyl acetate:hexane (1:2) to give 5.4 g of 6-(2-methoxyphenyl)-2-oxindole as a rose colored solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[N:4]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].CCN(C(C)C)C(C)C.[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC#N.O>[CH2:12]([N:4]1[C:5]2[C:10](=[CH:9][N:8]=[CH:7][CH:6]=2)[CH2:11][CH:2]([NH:1][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[C:3]1=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NC1Cc2cnccc2N(Cc2ccccc2)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cnccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a suspension of 1G (140 mg, 0.55 mmol) in CH3CN (4 mL) at RT was added DIPEA (153 μL, 0.88 mmol), followed by benzenesulfonyl chloride (84 μL, 0.66 mmol). After addition, the reaction was stirred at RT for 30 min. The reaction was diluted with H2O and extracted with EtOAc (20 mL×3). The combined organics were washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel (12 g) column chromatography eluting with a gradient of EtOAc (20-100%) in hexane to give the title compound as a white solid (182 mg, 84%). LC/MS (method A): retention time=2.10 min, (M+H)+=394. 1H-NMR (DMSO6, 400 MHz): δ 8.25-8.36 (m, 3H), 7.85-7.90 (m, 2H), 7.52-7.70 (m, 3H), 7.15-7.30 (m, 5H), 6.93 (d, J=4 Hz, 1H), 5.04 (dd, J1=28.6 Hz, J2=16.3 Hz 2H), 4.35-4.46 (m, 1H), 2.90-3.15 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:20]([CH3:21])=[CH:19][C:8]2[N:9]3[CH2:14][CH2:13][CH:12](CC([O-])=O)[C:10]3=[N:11][C:7]=2[C:6]=1[N+:22]([O-:24])=[O:23])(=[O:3])[CH3:2].C([O-])([O-])=[O:26].[K+].[K+]>CO>[C:1]([NH:4][C:5]1[C:20]([CH3:21])=[CH:19][C:8]2[N:9]3[CH2:14][CH2:13][CH:12]([OH:26])[C:10]3=[N:11][C:7]=2[C:6]=1[N+:22]([O-:24])=[O:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C)cc2c(nc3n2CCC3CC(=O)[O-])c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1c(C)cc2c(nc3n2CCC3O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 205 mg (0.61 mmol) of 15b in 10 mL of dry methanol was added 88 mg of K2CO3. The reaction was stirred at room temperature for 20 min and then concentrated in vacuo. The black residue was flash chromatographed on silica gel using a chloroform/methanol (98:2) mixture as the eluant. The yellow-colored product was recrystallized by dissolving it in a minimum amount of (4:1) chloroform/methanol, adding hexane, and then chilling: 141 mg (78%) yield: dec pt 259° C.; TLC (chloroform:methanol[20:80]) Rf =0.35, IR(KBr pellet) 3237, 3181, 3065, 1741, 1700, 1667, 1632, 1574, 1532, 1404 cm-1 ; 1H NMR (dimethyl sulfoxide-d6) δ9.67 (1 H, s, amide proton), 7.66 (1 H, s, C(8) proton), 5.97 (1 H, d, J= 5.3 Hz, hydroxyl proton), 5.09 (1 H, m, C(3) proton), 4.22 and 4.05 (2 H, 2×m, C(1) diastereomeric methylene), 2.90 and 2.37 (2 H, 2×m, C(2) diastereomeric methylene), 2.27 (3 H, s, 7-methyl proton), 1.97 (3 H, s, acetamido methyl); mass spectrum (EI mode) m/z, 290(P+), 272(P+ -H2O), 248 (P+ -ketene) 244 (P+ -NO2) Anal. Calcd for C13H14N4O4.0.75H2O: C, 51.39; H, 5.13; N, 18.44. Found: C, 51.75; H, 4.77; N, 18.45.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][N:12]3[C:16](=[O:17])[CH2:15][S:14][C:13]3=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:19](=O)[CH2:20][CH2:21][CH3:22].N1CCCCC1>C(O)C>[CH:19](=[C:15]1[S:14][C:13](=[O:18])[N:12]([CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:16]1=[O:17])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1CSC(=O)N1CSc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.41 g (5.1 mmol) of 3-(imidazo[1,2-a]pyridin-5-ylthio)methylthiazolidine-2,4-dione and 0.46 ml (5.1 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.06 ml (0.6 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/2) to yield 1.26 g (74.8%, yellow oily substance) of the desired product.