Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:27])=[O:4].O[Li].O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1.CCN(C(C)C)C(C)C>CO.O.C(Cl)Cl>[C:23]([O:22][C:20](=[O:21])[NH:19][C@H:17]([C:11]1[N:12]([CH:14]2[CH2:15][CH2:16]2)[C:13]2[C:5]([C:3]([N:55]3[CH2:60][CH2:59][O:58][CH2:57][CH2:56]3)=[O:4])=[C:6]([F:27])[CH:7]=[CH:8][C:9]=2[N:10]=1)[CH3:18])([CH3:25])([CH3:26])[CH3:24]
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(C3CC3)c12
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c(C(=O)N3CCOCC3)c2n1C1CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
A solution of 2-((S)-1-tert-butoxycarbonylaminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester (441 mg, 1.17 mmol) and LiOH.H2O (196 mg, 4.67 mmol) in MeOH (20 mL) and water (2 mL) was heated at 90° C. for 4 h. Additional LiOH.H2O (196 mg) was added and the mixture heated at 90° C. for 48 h. After cooling to RT, the organic solvent was removed in vacuo and the pH of the mixture adjusted to 3 by addition of 1M HCl(aq). The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (Na2SO4) and concentrated in vacuo. A mixture of this residue (349 mg), HATU (401 mg, 1.06 mmol), morpholine (125 μL, 1.44 mmol) and DIPEA (335 μL, 1.92 mmol) in DCM (10 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and a saturated solution of NaHCO3. The organic layer was dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (380 mg, 75% over 2 steps) as a pale yellow oil. LCMS (Method C): RT 2.64 min [M+H]+ 433.25
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].C([O-])(O)=O.[Na+]>CO>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24]
Reactant: COC(=O)[C@H](N)COCc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](COCc1ccccc1)Nc1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 22.1 %

Procedure:
To a solution of O-benzyl-D-serine methyl ester (3,13 g, 14.96 mmol) in MeOH, was added 2-fluoronitrobenzene (1.6 mL, 15.08 mmol) and NaHCO3 (1.3 g, 15.48 mmol), and the resulting solution was brought to a reflux for approximately one day. The reaction mixture was then cooled, filtered, concentrated and chased with benzene (4×50 ml). The residue was re-dissolved in EtOAc, cooled to 0° C. and HCl gas was bubbled into the resulting solution until it reached a pH of ˜4. The reaction mixture was allowed to warm to room temperature and stirred for 5 hours. Upon completion, the reaction mixture was washed with saturated NaHCO3 (3×50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to silica gel chromatography eluting with 8%-30% EtOAc in Hexanes to give 1.09 g (3.30 mmol) of N-(2-nitrophenyl)-O-benzyl-D-serine methyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]([CH2:4][OH:3])=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1onc(-c2ccc(Cl)cc2)c1CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (373 mg, 1.4 mmol) in THF (17.9 mL) was added portionwise lithiumaluminiumhydride (29.6 mg, 0.78 mmol) at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The mixture was then cooled to 0° C. and water (29.0 μL) added followed by sodium hydroxide (15% solution, 29.0 μL) and then again water (84.0 μL) and the mixture then stirred overnight at room temperature. The precipitate was then filtered off and washed with THF. The combined washings and filtrate were then evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (204 mg, 65%) which was obtained as a white solid. MS: m/e=224.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH2:15])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH:15][S:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:26])=[O:25])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Nc1nc2c(s1)CCc1ccc([N+](=O)[O-])cc1-2
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)-c1nc(NS(=O)(=O)c3ccccc3)sc1CC2

Procedure:
The title compound was prepared from 8-nitro-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (100 mg, synthesized according to METHOD I from 7-nitrotetralone) and benzenesulfonyl chloride (85 mg) as described in the synthetic METHOD A to give a yellow powder (12 mg) with a purity of >90%: MS-ES (neg) m/z 386.3.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[OH:15])#[N:4].IC.[CH3:18]COC(C)=O.O>CN(C=O)C>[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[O:15][CH3:18])#[N:4]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C#N)c(OC)c1
Reaction time: 2 h

Procedure:
Sodium hydride (9 g, 0.24 mol as 60% wt. disp. mineral oil) was added to a solution of the phenol from Step C (36.1 g, 204 mmol) in 400 mL of dry DMF at room temperature. Iodomethane was added (14 mL. 0.22 mol) was added, and the reaction was stirred for 2 hours. The mixture was poured into EtOAc/water, and the organic layer was washed with water and brine (4×), dried (Na2SO4), and concentrated in vacuo to provide the titled.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: C1CNCCN1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)N4CCNCC4)cc3C)cc12

Procedure:
(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)(piperazin-1-yl)methanone was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and piperazine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.66 (s, 1H), 8.55 (s, 1H), 8.19 (d, 1H), 7.38 (s, 1H), 7.21-7.23 (m, 2H), 7.10-7.15 (m, 2H), 3.66 (br, 6H), 3.08-3.18 (m, 6H), 2.45 (s, 3H), 2.30 (s, 3H). LRMS [M+H]=440.2
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[C:6]1([S:12]Cl)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[C:6]1([S:12][C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClSc1ccccc1
Reactant: c1cc[nH]c1
Solvent: CCOCC
Product: c1ccc(Sc2ccc[nH]2)cc1
Yield: 5.7 %

Procedure:
Pyrrole (2.0 g., 30 mmoles) was dissolved in 20 ml. of ether. Benzenesulfenyl chloride (4.5 g., 30 mmoles) was added dropwise at such a rate that the purple color of the reagent was discharged. A slightly exothermic reaction was noted. After addition was complete (10 minutes), the reaction was evaporated to an oil (5.7 g.). The oil was chromatographed on approximately 180 ml. of silica gel, eluted with ethyl acetate-1/hexane-7. Middle fractions, evaporated to dryness, afforded 2-phenylthiopyrrole (300 mg.).
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[O:13])[CH2:10][CH2:9][S:8][CH2:7][CH2:6]1)=[O:4].Cl>C1COCC1.[OH-].[Na+].CO>[F:34][C:32]([F:33])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:22]=[CH:23][C:14]=2[C:12]([NH:11][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][S:8][CH2:9][CH2:10]2)=[O:13])=[CH:31][CH:30]=1
Reactant: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCc2ccc(C(F)(F)F)cc2)CCSCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CCSCC1)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Yield: 93.9 %

Procedure:
126 mg 4-{[1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-tetrahydro-thiopyran-4-carboxylic acid methyl ester in 2.5 ml THF, 0.25 ml 2 M sodium hydroxide and 0.25 ml methanol were reacted at room temperature for 16 h. The reaction was then acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated to yield 115 mg of 4-{[1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-tetrahydro-thiopyran-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=[O:6].O=[C:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18](OC)=[O:19].[O-]S([O-])(=O)=O.[Mg+2]>CO.Cl>[O:19]=[C:18]1[C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:13]2[CH2:17][CH2:16][CH2:15][C:14]1=2
Reactant: COC(=O)c1cccc(N)c1
Reactant: COC(=O)C1CCCC1=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: O=C(O)c1cccc2[nH]c3c(c(=O)c12)CCC3
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To the solution of methyl 3-aminobenzoate (302 mg, 2.0 mmol) and methyl 2-oxocyclopentanecarboxylate (284 mg, 2.0 mmol) in MeOH (10 mL) were added MgSO4 (240 mg) and concentrated HCl (2 drops), the mixture was heated to 60° C. for 4.0 h. After cooling to room temperature, the solvent was evaporated in vacuum. The mixture was filtered and washed with EtOAc (15 mL), the solvent was evaporated and used for the next step without further purification. The crude mixture was dissolved in PPA (4.0 mL), and was stirred in 130° C. for 3 h. After cooling to the room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The organic layers were combined, dried over Na2SO4, and concentrated to afford the mixture, which was purified on Pre-HPLC to afford 9-oxo-2,3,4,9-tetrahydro-1H-cyclopenta[b]quinoline-8-carboxylic acid as a white solid. MS (ESI) m/e [M+1]+230.0
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:16])OC(C)(C)C.[F:17][C:18]([F:27])([F:26])[C:19](=O)C(OCC)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:8][C:5]1[CH:4]=[C:3]2[C:2]([N:1]=[C:19]([C:18]([F:27])([F:26])[F:17])[C:10]([OH:16])=[N:9]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1N
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1nc2cc(F)ccc2nc1C(F)(F)F
Temperature: 63 °C
Yield: 83 %

Procedure:
tert-Butyl 2-amino-5-fluorophenylcarbamate (30.5 g), toluene (300 mL), triethylamine (34.1 g) and ethyl 3,3,3-trifluoro-2-oxopropanoate (69.5 g) were charged into a reactor and warmed to 63° C. for 14 h, then cooled to ambient temperature. A 5% aq. NaOH solution (390 mL) was added, stirred, settled, and then the lower layer was separated. The organic layer extracted with another charge of 5% aq. NaOH solution (130 mL). To the combined aq. NaOH layers was charged 2-methyl-THF (390 mL) and concentrated HCl (77.9 g), keeping the temperature below 25° C. The layers were mixed, settled and separated. The acidic aq. layer was separated, and the organic layer was extracted with water (260 mL). The layers were separated and the organic layer was filtered to remove insoluble material. The product was isolated by switching the solvent to toluene by distillation (a total of 1.1 L toluene used). The final slurry was briefly warmed to 80° C. and then cooled −10° C. and filtered. The cake was washed with toluene (128 mL), then dried under vacuum at 60° C. To the crude solid was added ethanol (350 mL) and warmed to reflux to dissolve the solids. The solution was cooled to room temperature and concentrated to approximately 270 mL total volume by distillation. Water (250 g) was then added over 30 min. The slurry was filtered and washed with cold (1:1) ethanol: water (2×60 mL). The solid was dried under vacuum at 60° C. (26.1 g, 83% yield).
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([S:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:6]
Reactant: O=C(O)CCC(F)(F)Cl
Reactant: SCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CCC(F)(F)Cl)SCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4.0 g of 4-chloro-4,4-difluorobutyric acid are added dropwise over the course of 45 minutes to a solution of 4.5 g of N,N'-carbonyldiimidazole in 30 ml of dimethylformamide at 0° C. After the solution has been stirred at 0° C. for 2 hours, 2.82 g of benzyl mercaptan are added and the mixture is allowed to warm to room temperature over the course of 17 hours. Then 100 ml of ethyl acetate are added and the organic solution is washed with saturated sodium chloride solution. The organic phase is dried over MgSO4 and evaporated. The resulting crude product is purified by chromatography on silica gel (mobile phase: hexane/ethyl acetate 9:1). This results in 4.0 g of S-benzyl 4-chloro-4,4-difluorothiobutyrate as an oil, nD20 : 1.5220.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:12]1([S:11][CH2:10][C@@H:9]([C:18]([O:20][CH3:21])=[O:19])[NH2:8])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](CSc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)CSc1ccccc1

Procedure:
A mixture of Example 133A in 1:1 dioxane/4M HCl at room temperature was stirred for 3 hours, poured into saturated Na2CO3 (400 mL), and extracted with ethyl acetate (3×300 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to provide the desired product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13](CC3C=C(F)C=CC=3Br)[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.[Cl:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Br>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:27]=3[Cl:26])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2Br)c1=O
Product: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccc(F)cc2Cl)c1=O

Procedure:
The title compound was prepared from compound 1 using the same procedures as described the preparation of compound 10, except that 2-chloro-4-fluoro-benzyl bromide was used in the place of 2-bromo-5-fluoro-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.15 (dd, J=8.211, 2.400 Hz, 1H), 6.95-7.06 (m, 2H), 5.40 (s, 1H), 5.09-5.18 (ABq, J=37.7, 15.9 Hz, 2H), 3.33-3.39 (m, 1H), 3.30 (s, 3H), 3.23-3.29 (m, 1H), 2.98 (bd, J=12.9 Hz, 1H), 2.79 (t, J=10.4 Hz, 1H), 2.55-2.66 (t, J=11.2 Hz, 1H), 2.13 (m, 1H), 1.78-1.88 (m, 1H), 1.55-1.65 (m, 2H). MS (ES) [m+H] calc'd for C17H21ClFN4O2, 367.1; found 367.1.
Reaction SMILES: [F:1][C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[C:3]([F:14])([F:13])[C:4]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([CH3:12])[NH:6][N:5]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:42][C:39]1[CH:38]=[CH:37][C:36]([N:33]2[CH2:32][CH2:31][N:30]([C:28](=[O:29])[CH2:27][N:6]3[C:7]([CH3:12])=[C:8]([N+:9]([O-:11])=[O:10])[C:4]([C:3]([F:13])([F:14])[C:2]([F:1])([F:19])[C:15]([F:17])([F:18])[F:16])=[N:5]3)[CH2:35][CH2:34]2)=[CH:41][CH:40]=1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c([N+](=O)[O-])c(C(F)(F)C(F)(F)C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4, Rf=0.81) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): δ 6.92–7.02 (m, 2H), 6.82–6.9 (m, 2H), 5.04–5.14 (m, 2H), 3.64–3.82 (m, 4H), 3.06–3.18 (m, 4H), 2.6–2.66 (d, 3H). 13C NMR (400 MHz, CDCl3): 160.4, 146, 144.2, 119.2, 118.2, 52, 50.8, 50.6, 46, 42, 12.2.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]([C:16]#[N:17])=[C:12]2[C:7]([C:8](=O)[CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[Na]>C1COCC1>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]([C:16]#[N:17])=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc2c(c(C#N)c1=O)CCCC2=O
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCn1cc2c(c(C#N)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.1 %

Procedure:
2-Butyl-3,8-dioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-011) (100 mg, 0.41 mmol) was dissolved in THF (7 mL) and to the reaction mixture were added boron trifluoride diethyl ether complex (0.21 mL, 1.64 mmol) and sodium cyanoborohydried (90 mg, 1.44 mmol), and the reaction mixture was stirred at room temperature for 30 min. To the reaction mixture was added an saturated aqueous solution of sodium hydrogencarbaonate (30 mL) and the reaction mixture was extracted with ethyl acetate (60 mL), washed with brine (30 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (toluene/ethyl acetate) to give 2-butyl-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-012) (70 mg, 75%) as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[C:10]1[NH:11][CH:12]=[N:13][CH:14]=1)(=O)=O>C(#N)C>[CH:14]1[N:13]=[CH:12][N:11]2[CH2:6][CH2:7][O:8][CH:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)[C:10]=12
Reactant: CS(=O)(=O)OCCOC(c1ccc(C#N)cc1)c1cnc[nH]1
Solvent: CC#N
Product: N#Cc1ccc(C2OCCn3cncc32)cc1
Temperature: 25 °C

Procedure:
A solution of 1.20 mmol of 2-[(4-cyanophenyl)-(3H-imidazol-4-yl)methoxy]ethyl methanesulphonate in 10 ml of acetonitrile is heated to reflux for 24 hours. The reaction mixture is cooled to room temperature and evaporated. The title compound is obtained as a white solid from the residue by flash chromatography (SiO2 60F). Rf=0.14 (dichloromethane -2M ammonia in ethanol 95:5); Rt=4.29.
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:20]([NH:22][C@H:23]([C:27]([OH:29])=O)[CH:24]([CH3:26])[CH3:25])=[O:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:44][C@H:45]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49]>>[C:1]([O:18][CH:19]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:20]([NH:22][C@H:23]([C:27]([NH:44][C@H:45]([C:58]([O:60][CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)=[O:59])[CH2:46][CH2:47][C:48]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)=[O:49])=[O:29])[CH:24]([CH3:25])[CH3:26])=[O:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Yield: 90.4 %

Procedure:
Starting from N-(2-hexadecanoyloxyhexadecanoyl)-L-valine (2.4 g) prepared by the method of Preparation B-2 and dibenzyl L-glutamate (1.26 g), dibenzyl N-[N-(2-hexadecanoyloxyhexadecanoyl)-L-valyl]-L-glutamate (3.2 g) was obtained as crystals according to a similar manner to that of Example 2. M.p. 65° C.
Reaction SMILES: [CH2:1]([C@:8]1([C:23]([NH:25][CH2:26][C:27](=O)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:24])[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(=O)([O-])O.[Na+]>[CH2:1]([C@:8]1([C:23]2[O:24][C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:26][N:25]=2)[O:12][C:11](=[O:13])[N:10]([C@@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1C(=O)O[C@](Cc2ccccc2)(C(=O)NCC(=O)c2ccccc2)C1=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: C[C@H](c1ccccc1)N1C(=O)O[C@](Cc2ccccc2)(c2ncc(-c3ccccc3)o2)C1=O
Reaction time: 16 h

Procedure:
To the product of Step B (40 mg, 0.088 mmol) was added concentrated sulfuric acid (0.5 mL, 9.38 mmol) and the mixture stirred for 16 h. Ice was added followed by saturated aqueous sodium hydrogen carbonate (30 mL) and the mixture was extracted with ethyl acetate (3×10 mL). The combined organic fractions were washed with saturated aqueous brine (1×15 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The yellow oil was purified by reverse phase HPLC(YMC Pro-C 18 column, gradient elution, 20% to 100% acetonitrile/water with 0.1% TFA) to afford the title compound as a colorless amorphous solid. LC/MS 439.1 (M+1). IC50 value=C rating
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[CH:20]=O>>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cc(Br)ccc3F)CC2)nc[nH]1

Procedure:
6-[4-(5-Bromo-2-fluoro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 5-bromo-2-fluorobenzaldehyde. Mass spectrum (ES) MH+=367.