Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Br:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCO
Product: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(Cn5cccn5)cc4)nc23)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.050 g, 0.126 mmol, 1 eq), EtOH (2.2 mL), and DMF (0.3 mL), 4-(1H-pyrazol-1-ylmethyl)-benzaldehyde (0.026 g, 0.14 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 mL, 0.38 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8). The title compound was obtained as a solid after trituration with diethyl ether (0.008 g, 12%); 1H-NMR (500 Mz, DMSO-d6): 2.55-2.62 (m, 4H, piperazine N(CH2)2), 3.53 (s, 2H, NCH2), 3.61-3.67 (m, 4H, piperazine N(CH2)2), 3.68 (s, 3H, imidazole Me), 5.41 (s, 2H, NCH2), 6.30 (t, J=2.0 Hz, 1H, pyrazole H-4), 6.81 (s, 1H, imidazole H-4), 7.34 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.49 (d, J=1.5 Hz, 1H, pyrazole H-3), 7.58 (s, 1H, imidazole 2-H), 7.85 (d, J=2.0 Hz, 1H, pyrazole H-3), 8.13 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 2.71 min—532/534 [(M+H)+], Br isotopic pattern]. ESI-HRMS: Found: 532.1567, calculated for C25H27BrN9 (M+H)+: 532.1573.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:14][C:15](=[O:41])[C@@H:16]([C@@H:21]([C:31](=[O:40])[NH:32][O:33]C1CCCCO1)[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:12])=O)(C)(C)C.[ClH:46]>O1CCOCC1.C(OCC)C>[ClH:46].[NH2:8][CH2:9][CH2:10][C:11]([N:13]([CH2:42][CH:43]([CH3:45])[CH3:44])[NH:14][C:15](=[O:41])[C@@H:16]([C@@H:21]([C:31](=[O:40])[NH:32][OH:33])[CH2:22]/[CH:23]=[CH:24]/[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:12]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCNC(=O)OC(C)(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)CCN)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
A solution of 0.47 g of (E)-2′-(N-tert.-butoxycarbonyl-β-alanyl)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)-carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of 4M hydrogen chloride in dioxan was stirred for 2 hours at room temperature and diluted with diethyl ether. The solid was filtered off, washed with diethyl ether and dried to give 0.29 g of (E)-2′-(β-alanyl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide hydrochloride in the form of a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10]C)[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=2)[CH2:13]1)[CH3:2].Cl.[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:32][CH2:33][O:34][C:35]2[CH:43]=[CH:42][C:38]([CH2:39][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:37][CH:36]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)c1ccc(OCCN2CCCCCC2)cc1
Agent: Cl
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1NCCCc1ccc(OCCN3CCCCCC3)cc1)C2
Yield: 59 %

Procedure:
Synthesized from ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (400 mg) and 4-(2-azepan-1-ylethoxy)benzoyl chloride hydrochloride (530 mg) according to an analogous synthetic method to Example 187, the title compound (390 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([O:10][CH2:11][CH:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][OH:14])[C:6]=2[CH:23]=1.[CH:24](OC(=O)C)=[O:25]>C(Cl)Cl>[C:19]([O:18][C:16]([NH:15][CH:12]([CH2:13][OH:14])[CH2:11][O:10][C:7]1[C:6]2[CH:23]=[C:2]([NH:1][CH:24]=[O:25])[CH:3]=[CH:4][C:5]=2[O:9][N:8]=1)=[O:17])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(=O)OC=O
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(N)cc12
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(NC=O)cc12

Procedure:
To a solution of 0.59 g of 5-amino-3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-1,2-benzoisoxazole in 12 ml of methylene chloride is added 0.17 g of acetic formic anhydride at 5°-10° C., and they are subjected to reaction at 20°-25° C. for one hour. The solvent is removed from the reaction mixture by distillation under reduced pressure, and the residue obtained is crystallized from n-hexane, after which the crystals are collected by filtration, to obtain 0.52 g of colorless, crystalline 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-formylamino-1,2-benzoisoxazole having a melting point of 104°-105° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.O=S(Cl)[Cl:13]>O1CCOCC1>[Cl:13][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(CCl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
110 mmol 4-methoxybenzyl alcohol was dissolved in 60 ml dioxane and 150 mmol SOCl2 was slowly dropped into the solution. The solution was stirred for 3 h at 60° C. and evaporated under reduced pressure. EtOAc was added and the resulted solution was washed with water. The separated organic layer was dried and evaporated to give 107 mmol 1-(chloromethyl)-4-methoxybenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)=[O:18])=[O:10])=[N:6][CH:7]=1.N[C:28]1[CH:33]=CC(Cl)=[CH:30][N:29]=1.C[Al](C)C.Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[N:29]([CH3:30])[CH2:28][CH2:33][N:26]=3)=[CH:23][CH:24]=2)=[O:18])=[O:10])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccsc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: Nc1ccc(Cl)cn1
Agent: C[Al](C)C
Agent: Cl
Product: CN1CCN=C1c1ccc(C(=O)Nc2ccsc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
Preparation of methyl 3-[(4-cyanophenyl)carbonylamino]thiophene-2-carboxylate A mixture of 4-cyanobenzoyl chloride (1.0500 g, 6.4 mmol), methyl 3-aminothiophenecarboxylate (1.0000 g, 6.4 mmol), and triethylamine (1 mL, 7.0 mmol) in dichloromethane was stirred at room temperature for 18 hours. The mixture was poured into a separatory funnel and washed by 1 N HCl. The organic layers were combined, dried over MgSO4, concentrated in vacuo, and chromatographed through a silica gel column to give the title compound 1.6588 g (91%). ES-MS 287 (M+1). Preparation of N-{2-[N-(5-chloro(2-pyridyl))carbamoyl](3-thienyl)}(4-cyanophenyl)carboxamide A portion of 2-amino-5-chloropyridine (68.6 mg, 0.5 mmol) was treated with AlMe3 (0.8 mL, 1.6 mmol), followed by adding the product from step A (160 mg, 0.5 mmol). The mixture was stirred at room temperature for 18 hours. The excess of AlMe3 was killed by 1N HCl solution. The organic layers were combined, dried over MgSO4, concentrated in vacuo, and chromatographed through a silica gel column to give the title compound 0.1528 g (80%). ES-MS 383 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:10]([NH:16][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCN
Reactant: OCc1ccccc1Br
Product: CCCCCCNc1ccccc1CO
Yield: 81 %

Procedure:
Using the general procedure, 2-bromobenzyl alcohol (187 mg, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol) at 90° C. for 22 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (6:1) as eluent afforded the desired product as a colorless liquid (168 mg, 81% yield). Rf=0.7 (hexane/ethyl acetate=2:1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][CH2:8][C:9]([O:11]CC)=[O:10])=[CH:2]1.[OH-].[Na+].C(O)(=O)C>C(O)C>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:2]1
Reactant: CCOC(=O)COCc1ccsc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(O)COCc1ccsc1
Yield: 96.9 %

Procedure:
0.9 g of the resulting ether compound was dissolved in 10 ml of ethanol, and an aqueous solution(10 ml) of 1.44 g of sodium hydroxide was added. The mixture was refluxed for 4 hours, and then acetic acid was added to the solution to acidify it. The solvent was evaporated, and ethyl acetate and water were added. The organic layer separated was worked up in a customary manner to give 0.75 g of the captioned compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[CH3:11][O:10][C:6]1[CH:5]=[C:4]([CH2:3][CH2:2][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:9]=[CH:8][CH:7]=1
Reactant: COc1cccc(CCCl)c1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: COc1cccc(CCn2ccnc2)c1
Yield: 62.3 %

Procedure:
A mixture of 67 g of 1-(2-chloroethyl)-3-methoxybenzene, 53.1 g of 1H-imidazole, 99 g of sodium carbonate, 500 ml of 4-methyl-2-pentanone and a few crystals of potassium iodide was stirred for 48 hours at reflux temperature. After cooling, the reaction mixture was diluted with water and extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated and the residue was destilled (13.3 Pa; 160° C.), yielding 49.5 g (62.8%) of 1-[2-(3-methoxyphenyl)ethyl]-1H-imidazole (interm. 10).
Reaction SMILES: C(C1C=CC2C(C)(C)CCC(C)(C)C=2C=1)=O.O[CH:18]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1.S(Cl)([Cl:43])=O>>[Cl:43][CH:18]([P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])[C:19]1[CH:28]=[CH:27][C:26]2[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=2[CH:20]=1
Reactant: CCOP(=O)(OCC)C(O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: O=S(Cl)Cl
Agent: CC1(C)CCC(C)(C)c2cc(C=O)ccc21
Product: CCOP(=O)(OCC)C(Cl)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 88 %

Procedure:
216 g (1 mole) of 2-formyl-5,6,7,8-tetrahydro5,5,8,8-tetramethylnaphthalene were converted to 251 g (71%) of diethyl 1-hydroxy-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-yl)-methylphosphonate of melting point 93°-95° C., and 188.4 g (88%) of the title compound were obtained from 203 g (0.57 mole) of the lastmentioned compound and 287 ml of thionyl chloride. Since the material decomposes during distillation, the working up procedure was modified as follows. The crude product obtained after removal of the thionyl chloride was dissolved in toluene, and the solution stirred with 5 g of potassium carbonate for 20 minutes. The solid was filtered off, the solvent was removed and the solidified mass was comminuted in a mortar. The material thus obtained (m.p. 65°-66° C.) was about 85% pure according to the H-NMR spectrum. General method for the preparation of monoarylacetylenes.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11](=O)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.C(OC([NH:26][CH2:27][C:28]([NH:30][C@H:31]1[CH2:35][N:34](C(OC(C)(C)C)=O)[C@H:33]([C:43](O)=[O:44])[CH2:32]1)=[O:29])=O)(C)(C)C>>[NH2:26][CH2:27][C:28]([NH:30][C@H:31]1[CH2:35][NH:34][C@H:33]([C:43]([NH:1][C:2]2[NH:3][C:4]3[CH:10]=[C:9]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:44])[CH2:32]1)=[O:29]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)Nc2nc3ccc(Cc4ccccc4)cc3[nH]2)C1

Procedure:
2-Amino-5-benzoylbenzimidazole(J. Med. Chem., 1984, 27, 914-917) was reduced according to Compounds M73(A,B), coupled with trans-4-(N-tert-butoxycarbonylglycyl)amino-N-tert-butoxycarbonyl-L-proline and deprotected according to Compound M1.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:37]4[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][C:29]([OH:31])=[O:30])=[CH:35][CH:36]=4)[CH:18]=[CH:19][CH:20]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]2=[O:28])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1N(c2ccccc2)C(c2cccc(Br)c2)CN1S(=O)(=O)c1ccccc1
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCc1ccc(-c2cccc(C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccccc3)c2)cc1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-phenyl-imidazolidin-2-one (example 5, step 2) was reacted with 4-(2-carboxyethyl)benzeneboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 3-[3′-(1-benzenesulfonyl-2-oxo-3-phenyl-imidazolidin-4-yl)-biphenyl-4-yl]-propionic acid as an off-white solid. MS: 525.1 ([M−H]−)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@H]1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C(=O)CCC1C(=O)OCc1ccccc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
A suspension containing (2S)5-oxo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (10.00 g, 0.044 mol, 1.0 equivalent), benzyl bromide (7.88 g, 0.046 mol, 1.05 equivalents), and potassium carbonate (15.20 g, 0.11 mol, 2.5 equivalents) in DMF (200 ml) was allowed to stir at 65° C. overnight. The reaction was allowed to cool to room temperature and the mixture was filtered through Celite. The solid was rinsed with ethyl acetate (100 ml) and the resulting filtrate was partitioned between ethyl acetate and saturated brine solution. The organic layer was washed with saturated brine (3×100 ml), dried over anhydrous Na2SO4 and concentrated in vacuo. The crude, colorless oil was chromatographed on silica to afford 5-oxo-pyrrolidine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester as a colorless oil (8.20 g, 0.026 mol, 59% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.36 (5H, broad s), 5.20 (2H, d), 4.64 (1H, dd), 2.44–1.96 (4H, m), 1.41 (9H, s). MS (LC-MS): Calculated for C17H21NO5 319.14, found 320.19 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)COc1ncncc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)COc1ncncc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of 0.9 g of 5-benzyloxy-4-(methoxycarbonyl)methoxypyrimidine, 10% palladium/carbon and ethyl acetate was stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated to obtain 0.574 g of 5-hydroxy-4-(methoxycarbonyl)methoxypyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:29])[C:5]2=[C:6]([CH2:8][C@H:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3Br)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][C@H:16]([OH:20])[C:17]([NH2:19])=[O:18])[N:7]=1.B1([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[N:45]=2)OCCN(C2C=CC=CC=2)CCO1.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]=[C:4]([CH3:29])[C:5]2=[C:6]([CH2:8][C@H:9]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[C:44]3[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH3:51])[N:45]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][C@H:16]([OH:20])[C:17]([NH2:19])=[O:18])[N:7]=1
Reactant: COc1cccc(B2OCCN(c3ccccc3)CCO2)n1
Reactant: Cc1nc(N)nc2c1/C(=N/OCC[C@H](O)C(N)=O)N[C@@H](c1ccc(F)cc1Br)C2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCC[C@H](O)C(N)=O)N2)n1
Temperature: 85 °C
Yield: 22.7 %

Procedure:
To a solution of (S)-4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanamide (51 mg, 0.11 mmol) in DMA was added 6-methoxypyridine-2-boronic acid N-phenyldiethanolamine ester (130 mg, 0.44 mmol), Pd(dppf)2Cl2 (9 mg, 0.011 mmol), and 2N Na2CO3 (273 μL, 0.55 mmol). The resultant mixture was degassed with N2 for 5 min then heated in a sealed tube at 85° C. for 14 h. The reaction was allowed to cool to r.t. and filtered through a pad of Celite topped with anhydrous Na2SO4, rinsing with EtOAc and CH3OH. The filtrate was concentrated to provide a brown residue which was purified by preparative HPLC eluting with TFA/ACN/H2O. The solvent was removed on a rotary evaporator and the sample was dried under high vacuum to yield (S)-4-((Z)—((R)-2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)-2-hydroxybutanamide (12.6 mg, 0.025 mmol). 1H NMR (400 MHz, MeOD) δ 1.76-1.93 (m, 1H), 2.16-2.35 (m, 1H), 2.80 (s, 3H), 3.18 (dd, J=16.80, 9.22 Hz, 1H), 3.32-3.42 (m, 1H), 3.90 (s, 3H), 4.10 (dd, J=8.72, 3.16 Hz, 1H), 4.13-4.31 (m, 2H), 5.07 (dd, J=9.09, 4.04 Hz, 1H), 6.79 (d, J=8.08 Hz, 1H), 7.12 (d, J=7.33 Hz, 1H), 7.15-7.28 (m, 2H), 7.66 (dd, J=8.59, 5.56 Hz, 1H), 7.71-7.83 (m, 1H). [M+H] calc'd for C24H26FN7O4, 496. found, 496.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:44][CH2:45][CH3:46])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[C:33]([S:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].Cl.C(OCC)(=O)C>CO.C1COCC1.[OH-].[Li+]>[CH3:1][O:2][C:3]1[C:4]([CH2:44][CH2:45][CH3:46])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[C:33]([S:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCOc2ccc(-c3c[nH]c(SCc4ccccc4)n3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(-c3c[nH]c(SCc4ccccc4)n3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2

Procedure:
The compound of Example 7 (12.0 mg, 18.6 μmol) in 1.0 ml of 4:1 methanol/THF and 40 ml of 1N lithium hydroxide was stirred at room temperature for 2.5 hours. The reaction mixture was poured into 0.5N hydrochloric acid/ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated under vacuum. Flash chromatography of the residue using 3:1 to 1:1 hexane/ethyl acetate (1% acetic acid) as eluant gave the product; melting point 92-97° C. High resolution mass spectrum, m/e 586.2868 (Calculated for C35H42O4N2S (M-CO2), 586.2865).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:30][N:31]1[C:39]2[C:34](=[C:35]([NH2:40])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:40][C:35]3[CH:36]=[CH:37][CH:38]=[C:39]4[C:34]=3[CH:33]=[CH:32][N:31]4[CH3:30])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Reactant: Cn1ccc2c(N)cccc21
Product: CCOC(=O)c1cnn2c(Nc3cccc4c3ccn4C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 89.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 1-methyl-4-aminoindole (0.076 g, 0.52 mmol), the title compound (0.169 g, 90%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](OS(C(F)(F)F)(=O)=O)=[C:9]([C:21]([O:23]CC)=O)[C:8]2=[O:26])=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][C:10]3[N:32]4[CH2:33][CH2:34][NH:29][C:30](=[O:35])[C:31]4=[C:21]([OH:23])[C:9]=3[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: O=C1CNCCN1
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CCN(Cc2ccc(F)cc2)C1=O
Solvent: CO
Product: O=C1NCCn2c3c(c(O)c21)C(=O)N(Cc1ccc(F)cc1)CC3
Temperature: 180 °C

Procedure:
A mixture of ethyl 1-(4-fluorobenzyl)-2-oxo-4-{[(trifluoromethyl)-sulfonyl]oxy}-1,2,5,6-tetrahydropyridine-3-carboxylate (0.67 g, 1.58 mmol) and piperazin-2-one (0.63 g, 6.3 mmol) was heated in a sealed tube at 180° C. in a microwave reactor for 10 minutes with stirring. The resultant solution was diluted with methanol and was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided a semi-purified sample of title compound. Further purification of the product was achieved through formation of the corresponding tosylate. To a solution of the semipurified product (0.1 g, 0.30 mmol) and triethylamine (63 μL, 0.46 mmol) in dichloromethane (2 mL) at room temperature, toluenesulfonyl chloride (58 mg, 0.30 mmol) was added. The resultant solution was stirred at room temperature for two hours. The product was isolated and purified. A solution of the resultant tosylate (30 mg, 0.06 mmol) and sodium methoxide (10 mg, 0.18 mmol) in anhydrous methanol (0.5 mL) was heated at 60° C. for 1 hour. The resultant solution was concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.