Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.CN(C([O:26][N:27]1N=N[C:29]2[CH:30]=[CH:31]C=[N:33][C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(P1(N(C)CCCN1)=NC(C)(C)C)CC.CC1ON=C(N)C=1>C1COCC1.CN(C=O)C>[CH3:31][C:30]1[O:26][N:27]=[C:28]([NH:33][C:16]([C:14]2[CH:13]=[CH:12][C:10]3[CH:11]=[C:3]4[C:2](=[O:1])[NH:8][CH2:7][CH2:6][CH2:5][N:4]4[C:9]=3[N:15]=2)=[O:18])[CH:29]=1
Reactant: O=C(O)c1ccc2cc3n(c2n1)CCCNC3=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN(CC)P1(=NC(C)(C)C)NCCCN1C
Agent: Cc1cc(N)no1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)c2ccc3cc4n(c3n2)CCCNC4=O)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a solution of 6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate E, 100 mg, 0.41 mmol) in THF (2 mL) and DMF (0.5 mL) is added HATU (171 mg, 0.45 mmol). The mixture is stirred at room temperature for 1 h, after which 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polystyrene (556 mg, 1.22 mmol) is added. The mixture is stirred at room temperature for 10 min and 5-methyl-3-aminoisoxazole (120 mg, 1.22 mmol) is added. The reaction is stirred at 60° C. for 16 h and is then cooled to room temperature. The mixture is filtered, washing with methanol and the filtrate is concentrated under reduced pressure. The residue is purified via preparative HPLC using a gradient elution from 10-90% acetonitrile/H2O with 0.1% TFA to afford the title compound (11 mg, 8%). LCMS: 326.20 (M+H+). (System V-med polar)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([Br:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:34][Si:35]([CH2:38][CH2:39][O:40][CH2:41]Cl)([CH3:37])[CH3:36]>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:41][O:40][CH2:39][CH2:38][Si:35]([CH3:37])([CH3:36])[CH3:34])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([Br:33])=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1Br
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1Br
Reaction time: 0.33 h
Yield: 94 %

Procedure:
To a mixture of compound 34B (0.815 g, 1.5 mmol) and SEMCl (0.318 mL, 1.8 mmol) in THF (6 mL) was added TEA (0.65 mL, 4.5 mmol) at rt. The reaction mixture was stirred for 20 minutes, concentrated under reduced pressure, and purified by column chromatography on silica gel eluting with 3:1/hexanes:EtOAc to provide 0.95 g of the desired product as a mixture of two inseparable isomers: MS (ESI(+)): m/z 657 (M+H).
Reaction SMILES: [NH2:1][C:2]([O:9][CH2:10][CH3:11])=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(OCC)C.[O:17]([C:24]([N:26]=[C:27]=[S:28])=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.OO>C(O)C>[CH2:10]([O:9][C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:27]([NH:26][C:24](=[O:25])[O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[S:28][N:1]=1)[CH3:11]
Reactant: O=C(N=C=S)Oc1ccccc1
Reactant: CCOC(=O)C=C(N)OCC
Agent: OO
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1c(OCC)nsc1NC(=O)Oc1ccccc1
Yield: 38.8 %

Procedure:
A mixture of 66.1 g of ethyl 3-amino-3-ethoxyacrylate and 300 ml of diethyl ether was stirred in a 500 ml flask during the addition of 60.5 g of phenoxycarbonylisothiocyanate. A solution of 38.3 ml of 33% hydrogen peroxide (11.5 g of active H2O2) in 300 ml of ethanol was added to the reaction mixture at a rate sufficient to maintain uniform reflux. The reaction mixture was allowed to stand at ambient temperature over a weekend. The precipitate was collected by filtration and dried. The filter cake was recrystallized from 1400 ml of 1:1 acetonitrile:water to yield 44.1 g of phenyl (3-ethoxy-4-ethoxycarbonyl-5-isothiazolyl)carbamate, mp 130° (decomposes). The ir spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][C:15]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][NH:21][C:17]=2[CH:16]=1.[NH2:24][CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](Cl)=[C:30]([CH3:35])[CH:29]=1)=O>C(Cl)Cl>[NH:19]1[C:18]2[CH:22]=[CH:23][C:15]([N:14]3[CH:26]([C:28]4[CH:29]=[C:30]([CH3:35])[CH:31]=[CH:32][CH:33]=4)[CH2:25][NH:24][C:2]3=[O:3])=[CH:16][C:17]=2[N:21]=[CH:20]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(C(=O)CN)ccc1Cl
Reactant: Nc1ccc2nc[nH]c2c1
Solvent: ClCCl
Product: Cc1cccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The compound was synthesized as hydrochloride salt by the following procedure. 4-Nitrophenyl chloroformate (0.564 g, 3.5 mmol) was dissolved CH2Cl2, cooled down to 0° C. and 5-aminobenzimidazole (0.466 g, 3.5 mmol) was added slowly. The mixture was kept at 0° C. for 30 min and then the mixture was allowed to adapt ambient temperature. The mixture was stirred at ambient temperature for 2 h. The resulted solid was withdrawn by suction, dried and taken up in a small amount of DMF. To the solution aminomethyl-(4-chloro-3-methylphenyl)ketone (0.774, 3.5 mmol) and TEA (1.46 ml, 10.5 mmol) was added. The mixture was kept at 40° C. for 2 h. The solvent was removed and purified by means of preparative HPLC. The remains were re-dissolved in MeOH and a small amount of HCl was added (1-2%). The solution was subjected to hydrogenation (PdC, 10% on charcoal, 4 bar, 60° C.) for 4 h. The catalyst was removed by filtration through a pad of CELITE® and the solvent was removed and purified by means of preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].S(C1C=CC(C)=CC=1)(O[CH2:15][C@H:16]1[CH2:19][CH2:18][N:17]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O>CN(C=O)C>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][C@@H:16]1[CH2:15][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: Oc1cncc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCN2C(=O)OC(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cncc(Cl)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
To a solution of 5-chloro-3-hydroxypyridine (0.3 g, 2.6 mmol) in DMF was added KOH (0.2 g, 3.8 mnol) at room temperature. 1-t-Butoxycarbonyl-2-(R)-azetidinylmethyl tosylate (0.8 g, 2.4 mmol, from example 10d) was then added, and the reaction mixture was stirred at 80° C. for 16 hours. The DMF was removed by washing with H2O/brine (1:1) in EtOAc. The organic layer was dried, concentrated and chromatographed (silica gel; hexane/EtOAc, 5:1 to 1:1) to afford an oil (0.6 g, 87%): 1H NMR (CDCl3, 300 MHz) δ 1.43 (s, 9H), 2.21-2.40 (m, 2H), 3.89 (t, 2H, J=8 Hz), 4.12 (m, 1H), 4.36 (m, 1H), 4.52 (m, 1H), 7.29 (m, 1H), 8.20 (d, 1H, J=2 Hz), 8.25 (d, 1H, J=3 Hz); MS (CI/NH3) m/z 299 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([NH2:28])[C:24]=1[C:25]([OH:27])=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:28][C:23]1[C:24](=[C:19]([Cl:18])[CH:20]=[CH:21][CH:22]=1)[C:25]([OH:27])=[O:26])=[O:6]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1C(=O)O)c1cccc(F)c1
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
15.9 parts of 3-fluorobenzoyl chloride and 10.1 parts of triethylamine are introduced simultaneously, from 2 feeds, into a solution of 17.1 parts of 6-chloroanthranilic acid in 200 parts of methylene chloride at from 25° to 30° C. The reaction mixture is subsequently stirred for 30 minutes, and is extracted once with 1 N hydrochloric acid and then with water. The organic solution is dried and concentrated, giving 29 parts of N-(3'-fluorobenzoyl)-6-chloroanthranilic acid of melting point 216°-219° C.; yield: 98.6% of theory.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][CH:24]1[N:29]([CH3:30])[CH2:28][CH2:27][N:26]([C:31]2[N:36]=[CH:35][C:34]([C:37](OC)=[O:38])=[CH:33][N:32]=2)[CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:37]([C:34]3[CH:33]=[N:32][C:31]([N:26]4[CH2:27][CH2:28][N:29]([CH3:30])[CH:24]([CH3:23])[CH2:25]4)=[N:36][CH:35]=3)=[O:38])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COC(=O)c1cnc(N2CCN(C)C(C)C2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
Trimethylaluminium (2M in toluene, 1.31 ml, 2.62 mmol) was added dropwise to a suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (260 mg, 1.05 mmol) and methyl 2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxylate (263 mg, 1.05 mmol) in toluene (5.26 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was poured into methanol (50 mL) and acidified with HCl (2M aqueous solution, to obtain a clear freely stirring solution). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane. Fractions containing product were evaporated to dryness to give material that was still impure. The residue was repurified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (175 mg, 36%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH:13][C:14]([C:16]2[CH:17]=[C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:20][C:21]=2[F:22])=[O:15])[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][C:3]([OH:29])=[O:2])=[CH:7][C:8]=1[NH:13][C:14]([C:16]1[CH:17]=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][C:21]=1[F:22])=[O:15]
Reactant: COC(=O)C=Cc1ccc(Cl)c(NC(=O)c2cc(-c3ccccc3)ccc2F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=Cc1ccc(Cl)c(NC(=O)c2cc(-c3ccccc3)ccc2F)c1
Reaction time: 3 h

Procedure:
The ester (51) (124 mg, 0.21 mmol) was hydrolysed using Method C, except that MeOH (1.25 mL), THF and 1M NaOH (1.25 mL) were used, and the reaction was stirred for 3 hours. The solvent was removed under a stream of nitrogen gas and the residue acidified with 1N HCl. The solid was filtered and dried to give the title compound. Yield: 91 mg, 76%; LC-MS tr 2.28 min; HPLC Purity: 94%; MS (ES+) m/z 396 (M÷H); 1H NMR (400 MHz; DMSO): δ 6.60 (d, 1H), 7.45-7.75 (m, 7H), 7.80 (d, 2H), 7.95 (m, 1H), 8.10 (d, 1H), 8.15 (s, 1H), 10.25 (s, 1H), 12.55 (br. s, 1H)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][C:15]=1[F:27].[CH2:28]1[O:30][CH2:29]1>C1COCC1>[Br:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([NH:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[C:16]([CH2:28][CH2:29][OH:30])[C:15]=1[F:27]
Reactant: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccc(Br)c(F)c1CCO
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (6.2 mL, 44 mmol) in THF (200 mL) was treated with n-butyllithium (17.4 mL, 44.0 mmol) at 0° C. The solution was stirred for 30 min before being cooled to −78° C. Next, a solution of 4-bromo-N-tert-butyl-3-fluorobenzamide (4.8 g, 17 mmol) in THF (100 mL) was added. The solution was then warmed to −40° C. and maintained there for 1 h. Next, ethylene oxide (10 mL, 200 mmol) was added and the solution warmed to 0° C. After 1 h, the ice bath was removed and the solution was allowed to warm to rt. LC/MS indicated desired product present. The solution was quenched with MeOH, diluted with brine (200 mL), and extracted with EtOAc (300 mL). The organic layer was removed, dried over MgSO4, filtered and concentrated. The crude product was purified using a 340 g Biotage SNAP (0-60% Hexanes: EtOAc) cartridge to yield the title compound: LC-MS: m/z 319.98 (M+H)+.
Reaction SMILES: [Cl:1][C:2](=[N:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:18])[C:3]([O:5][CH3:6])=[O:4].OO.C(=O)(O)[O-:28].[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2](=[N:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH2:16][C:17]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH2:18])=[O:28])[C:3]([O:5][CH3:6])=[O:4]
Reactant: O=C([O-])O
Reactant: C=C(CSc1ccccc1NN=C(Cl)C(=O)OC)c1ccccc1
Agent: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: C=C(CS(=O)c1ccccc1NN=C(Cl)C(=O)OC)c1ccccc1
Reaction time: 5 h

Procedure:
The compound of Step B (5 g) was stirred with occasional warming in acetic acid (45 ml) and treated with 30% aqueous hydrogen peroxide (2.0 ml). After stirring for 5 h, water (200 ml) was added and the P.h. was adjusted to 6 with sodium bicarbonate. Saturated sodium bisulfite solution (3 ml) was added and the mixture was extracted with dichloromethane (200 ml). The organic layer was dried and evaporated to give the title compound (4.9 g).
Reaction SMILES: C(=O)([O-])[O-].[Li+].[Li+].Cl[CH2:8][C:9]1[O:13][N:12]=[C:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=2)[N:10]=1.[OH:22][C:23]1[C:28]([CH3:29])=[C:27]([OH:30])[CH:26]=[CH:25][C:24]=1[C:31](=[O:33])[CH3:32].C1C2C(C3ON=C(N)N=3)CN(C2)C1>CN(C)C=O.O>[OH:22][C:23]1[C:28]([CH3:29])=[C:27]([O:30][CH2:8][C:9]2[O:13][N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=3)[N:10]=2)[CH:26]=[CH:25][C:24]=1[C:31](=[O:33])[CH3:32]
Reactant: ClCc1nc(Cc2cccc(I)c2)no1
Reactant: CC(=O)c1ccc(O)c(C)c1O
Agent: Nc1noc(C2CN3CCC2C3)n1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2nc(Cc3cccc(I)c3)no2)c(C)c1O
Temperature: 60 °C
Yield: 53.8 %

Procedure:
Add lithium carbonate (49 mg, 0.66 mmol) and 5-chloromethyl-3-(3-iodo-benzyl)-[1,2,4]oxadiazole (200 mg, 0.60 mmol) to a solution of 1-(2,4-dihydroxy-3-methyl-phenyl)-ethanone (110 mg, 0.66 mmol) in anhydrous dimethylformamide (20 mL) 4]oxadiazole (200 mg, 0.60 mmol). Heat the reaction mixture at 60° C. overnight. Cool the reaction mixture to RT, pour into H2O, and extract with diethyl ether (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate to provide the title compound (150 mg). LC-MS (m/e): 463 (M−1).
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:30][CH2:31][CH2:32][CH3:33])[N:26]([CH2:27][CH2:28][NH2:29])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1>>[NH2:13][C:14]1[C:23]2[N:24]=[C:25]([CH2:30][CH2:31][CH2:32][CH3:33])[N:26]([CH2:27][CH2:28][NH:29][C:1](=[O:12])[CH2:2][CH:3]([CH3:4])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])[C:22]=2[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: CC(C)=CCCC(C)CC(=O)O
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)CC(C)CCC=C(C)C
Yield: 67.4 %

Procedure:
Using the general method of Example 97 citronellic acid (0.3 g, 1.7 mmole) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,7-dimethyl-6-octenamide as a white whispy solid, m.p. 163-164° C. Analysis: Calculated for C25H36N6O: % C, 68.77; % H, 8.31; % N, 19.25; Found: % C, 68.84; % H, 8.14; % N, 19.58. HRMS (EI) calcd for C25H36N6O (M+) 436.2950 found 436.2952.
Reaction SMILES: CN(C=O)C.[CH2:6]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]Br)=[CH:20][CH:19]=[CH:18][C:17]=2[C:31]([F:34])([F:33])[F:32])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]3([CH3:57])[NH:54][C:53](=[O:55])[NH:52][C:51]3=[O:56])=[CH:49][C:44]=2[O:43][CH2:42]1>O>[O:41]1[C:45]2[CH:46]=[CH:47][C:48]([C:50]3([CH3:57])[NH:54][C:53](=[O:55])[N:52]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][O:23][C:22]4[C:21]5[C:16](=[C:17]([C:31]([F:34])([F:33])[F:32])[CH:18]=[CH:19][CH:20]=5)[N:15]=[CH:14][C:13]=4[CH2:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:51]3=[O:56])=[CH:49][C:44]=2[O:43][CH2:42]1
Reactant: CC1(c2ccc3c(c2)OCO3)NC(=O)NC1=O
Reactant: FC(F)(F)c1cccc2c(OCCCCCCBr)c(Cc3ccccc3)cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(c2ccc3c(c2)OCO3)NC(=O)N(CCCCCCOc2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)C1=O
Reaction time: 8 h
Yield: 121 %

Procedure:
A DMF (0.1 mL) solution of 3-benzyl-4-(6-bromohexyloxy)-8-(trifluoromethyl)quinoline (12.5 mg, 0.03 mmol) was added with potassium carbonate (9 mg, 0.06 mmol) and 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazolidine-2,4-dione (46.8 mg, 0.20 mmol), and stirred overnight. The reaction solution was added with water, extracted with ethyl acetate, subsequently dried using anhydrous sodium sulfate and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane:ethyl acetate), and the title compound (22.5 mg, yield 49%) was obtained as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:42]([NH:52][C@H:53]([C:61](O)=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].N>ClCCl.CO>[C:42]([NH:52][C@H:53]([C:61]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:62])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 53 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-L-phenylalanine. Yield 53%. Rf 0.29 (dichloromethane/methanol/conc. ammonia 15:1:0.1).
Reaction SMILES: [Li+].[OH-].O.C([O:6][C:7](=[O:19])[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[C:11]([NH2:16])=[C:10]([CH3:17])[C:9]=1[OH:18])C>C(O)C.O>[NH2:16][C:11]1[C:12]([C:14]#[N:15])=[CH:13][C:8]([C:7]([OH:19])=[O:6])=[C:9]([OH:18])[C:10]=1[CH3:17]
Reactant: CCOC(=O)c1cc(C#N)c(N)c(C)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(N)c(C#N)cc(C(=O)O)c1O
Temperature: 80 °C
Yield: 98.9 %

Procedure:
To a solution of LiOH×H2O (8.4 g, 0.2 mol) in ethanol/water (1:1, 300 mL) was added compound 74 (22 g, 0.1 mol) at RT and the reaction mixture was refluxed at 80° C. for 4 h. The reaction mixture was concentrated under vacuum, the obtained residue was diluted with water (100 mL), washed with pet. ether/ethyl acetate (1:1, 2×200 mL). The aqueous layer was separated, acidified to pH=5 using 1.5N HCl and the obtained solid product was filtered off. The aqueous layer was further extracted with ethyl acetate (2×300 mL), dried and concentrated to give more product. The combined products was washed with 5% ethyl acetate in pet. ether to give the pure title compound (19 g, >95%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:13][C:14]1[N:19]=[N:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])=[O:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C:10]([NH:13][C:14]2[N:19]=[N:18][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:27])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH2:24][CH2:25]3)=[CH:16][CH:15]=2)=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: O=C(O)CCCC1CCCCC1
Product: O=C(CCCC1CCCCC1)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 2, making variations only as required to use 4-cyclohexylbutyric acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (18% yield). 1H NMR (300 MHz, CDCl3) δ 9.04, 8.32, 7.68, 7.56, 7.49, 7.30, 7.04-7.00, 3.99-3.23, 2.40, 1.89-1.83, 1.69-0.84.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])=[O:10].CO.O>C(O)(CC)(C)C>[OH:15][CH2:14][CH:13]1[CH2:12][NH:11][C:9](=[O:10])[CH2:8][O:16]1
Reactant: O=C(CCl)NCC(O)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCC(C)(C)O
Product: O=C1COC(CO)CN1
Reaction time: 1 h
Yield: 91.8 %

Procedure:
To a stirred solution of potassium tert-butoxide (23.4 g, 299.4 mmol) in 200 mL tert-amyl alcohol at room temperature was added 2-chloro-N-(2,3-dihydroxypropyl) acetamide (Step-1 of Intermediate-9) (20 g, 119.6 mmol) in 460 mL tert-amyl alcohol for 2 h under nitrogen atmosphere. After one hour, MeOH (100 mL) and H2O (3 mL) were added and further stirred for 20 min. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel with MeOH/EtOAc (20:80) to give the title compound as a white solid (14.4 g). m/z 132.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23](C5NN=CC=5)=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[F:77][C:78]([F:94])([F:93])[C:79]1[C:83](B2OC(C)(C)C(C)(C)O2)=[CH:82][NH:81][N:80]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:83]5[C:79]([C:78]([F:94])([F:93])[F:77])=[N:80][NH:81][CH:82]=5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(-c5ccn[nH]5)ccc4c3=O)cc2)CCC1
Reactant: CC1(C)OB(c2c[nH]nc2C(F)(F)F)OC1(C)C
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(-c5c[nH]nc5C(F)(F)F)cccc4c3=O)cc2)CCC1
Yield: 64 %

Procedure:
Following the procedure of (1-{4-[4-oxo-2-phenyl-7-(2H-pyrazol-3-yl)-4H-chromen-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 3-(trifluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester to give the title compound as a white solid (35 mg, 64%). LCMS (Method G): RT=4.15 min, [M+H]+=602.