Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C1(C(=[N:15][CH:16]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=2)[C:17]([O:19]C(C)(C)C)=[O:18])C2C=CC=CC=2)C=CC=CC=1>>[ClH:1].[NH2:15][CH:16]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=1)[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(OC(F)(F)F)cc1)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Product: NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Temperature: 25 °C
Yield: 91 %

Procedure:
A 6 N hydrochloric acid (1 mL) solution of tert-butyl 2-[(diphenylmethylene)amino]-3-[4-(trifluoromethoxy)phenyl]propanoate (64 mg, 0.136 mmol) prepared in Reference Example 1 (1a) was heated under reflux for 6 hours and then cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the residue was washed with diethyl ether to give 35 mg of the title compound (white powder, yield: 91%).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[C:20]1[S:24][C:23]([NH2:25])=[N:22][N:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:18][C:3]([F:2])([F:17])[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:20]2[S:24][C:23]([NH2:25])=[N:22][N:21]=2)[CH2:9][CH2:8]1
Reactant: FC(F)(F)c1ccccc1OC1CCNCC1
Reactant: Nc1nnc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[2-(trifluoromethyl)phenoxy]piperidine hydrochloride (5.5 g, 2.2 mmol) in DMF (50 mL) was added 5-bromo-1,3,4-thiadiazol-2-amine (3.3 g, 2.2 mmol) and K2CO3 (9.1 g, 6.6 mmol). The reaction was heated at 80° C. with stirring overnight. After cooling, the salt was removed by filtration and the filtrate was evaporated in vacuo. The residue was triturated with EtOAc to afford the title compound.
Reaction SMILES: CC(O[C:6]([NH:8][C@@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])C=O)=[O:7])(C)C.CC(OC([NH:23][C@@H:24]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:25]=[O:26])=O)(C)C>>[CH:9]1([NH:8][C:6](=[O:7])[CH:25]([OH:26])[C@@H:24]([NH2:23])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: CCCC[C@@H](C=O)NC(=O)OC(C)(C)C
Product: CC(C)C[C@H](N)C(O)C(=O)NC1CCCC1
Yield: 34 %

Procedure:
The same procedure as in Reference Example 11 was repeated except that the (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]hexanal was replaced by 18.64 g of (S)-2-[N-(2-methyl-2-propyloxycarbonyl)amino]-4-methylpentanal, whereby 6.72 g of the captioned (2RS,3S)-N-cyclopentyl-3-amino-2-hydroxy-5-methylhexanamide was obtained in a yield of 34%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH:23]4[CH2:25][CH2:24]4)=[CH:21][C:20]([CH:26]4[CH2:28][CH2:27]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:29]([N:32]1[CH2:36][CH2:35][NH:34][C:33]1=[O:37])(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:36][CH2:35][N:34]([C:2]2[CH:3]=[CH:4][C:5]([C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([CH:23]5[CH2:25][CH2:24]5)=[CH:21][C:20]([CH:26]5[CH2:28][CH2:27]5)=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:6]([CH3:8])[N:7]=2)[C:33]1=[O:37])(=[O:31])[CH3:30]
Reactant: Cc1nc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)c(C)n2)C1=O
Yield: 87.1 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (221 mg) described in Preparation Example 251 and 1-acetylimidazolidin-2-one (77 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (213 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH2:20][OH:21])[CH2:17][CH2:16][C:14]=3[CH:15]=2)[CH:6]=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>C(Cl)Cl>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH:20]=[O:21])[CH2:17][CH2:16][C:14]=3[CH:15]=2)[CH:6]=[CH:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OCC1=Cc2sc(COc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CC1=Cc2sc(COc3ccc(-c4ccccc4)c(C(F)(F)F)c3)cc2CC1
Reaction time: 3 h
Yield: 34.7 %

Procedure:
To a solution of [2-({[2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-4,5-dihydro-1-benzothien-6-yl]methanol (1.0 g) in DCM (20 mL) were added PDC (1.36 g) and MS4 Angstrom (1.36 g) at 25° C. The reaction liquid was stirred for 3 hours, and then filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 80:20) to obtain 2-({[2-(trifluoromethyl)biphenyl-4-yl]oxy}methyl)-4,5-dihydro-1-benzothiophene-6-carbaldehyde (345 mg) as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:17]=[C:18](O)[CH:19]=[N:20][CH:21]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:17]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 85.8 %

Procedure:
To a solution of [1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methanol (1.39 g, 6.9 mmol, 1.5 equiv.), 5-bromo-3-pyridinol (796 mg, 4.6 mmol) and Ph3P (1.80 g, 6.9 mmol, 1.5 equiv.) in anhydrous THF (35 mL) was added diethyl azodicarboxylate (1.09 mL, 6.9 mmol, 1.5 equiv.) dropwise at 0° C. under Ar protection. After stirring at rt for 120 h, the solvent was removed under reduced pressure. The mixture was diluted with hexane/EtOAc 4:1, and the solution was washed with brine and dried over Na2SO4. After evaporation, the residue was purified by CC (SiO2, hexane/EtOAc 4:1, then 1:1) to afford 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]methoxy]pyridine (1.41 g, 86%) as a pale yellow oil, which solidified upon storage at room temperature.
Reaction SMILES: [CH3:1][S:2]([CH:5]([C:11]1[S:12][C:13]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:14]=2[N:15]=1)C(OCC)=O)(=[O:4])=[O:3].NN>CCO>[CH3:1][S:2]([CH2:5][C:11]1[S:12][C:13]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:14]=2[N:15]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)C(c1nc2ccc(-c3ccccc3)cc2s1)S(C)(=O)=O
Agent: NN
Solvent: CCO
Product: CS(=O)(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
To a solution of Compound 89a (100 mg, 0.27 mmol) in EtOH (8 mL) was added hydrazine (0.13 mL, 4.0 mmol) and the reaction mixture stirred at rt for 1 h, then at 50° C. for 1 h. The reaction mixture was allowed to cool, concentrated under reduced pressure and the residue suspended in DCM, filtered and dried under vacuum to give Compound 89b (22 mg, 23% yield). RT=1.65 min using analytical method (Q), 361.9 (M+H). 1H NMR (500 MHz, DMSO-d6) δ 8.51-8.45 (m, 1H), 8.15 (d, J=8.5 Hz, 1H), 7.87 (dd, J=8.5, 1.9 Hz, 1H), 7.77 (d, J=7.4 Hz, 2H), 7.53-7.49 (m, 2H), 7.44-7.38 (m, 1H), 5.80 (s, 1H), 3.24 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].[Na+]>C1COCC1>[CH2:24]([NH:31][CH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[C:14]([NH:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CCl)c1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(CNCc2ccccc2)c1
Yield: 58.2 %

Procedure:
3-((Benzylamino)methyl)-N-(2-(5-chloro-1H-indol-3-yl)ethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-(chloromethyl)benzamide (0.050 g; 0.144 mmol), benzylamine (0.055 mL; 0.5 mmol), and sodium iodide (0.015 g; 0.1 mmol) in THF (3 mL), under a microwave irradiation at 150° C. for 5 minutes. Flash chromatography on silica gel (eluent 2 to 10% methanol in dichloromethane) furnished 0.035 g (58%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[Mg].[F:11][C:12]([F:19])([F:18])[C:13](OCC)=[O:14].CC(C)=O.C(=O)=O>CCOCC>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][C:13](=[O:14])[C:12]([F:19])([F:18])[F:11])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: O=C=O
Agent: [Mg]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=C(Cc1ccc(Cl)cc1)C(F)(F)F
Temperature: -10 °C
Yield: 47.4 %

Procedure:
A solution of p-chlorobenzyl chloride (80.5 g, 0.5 mol) and ether (150 mL) is slowly added to a vigorously stirred slurry of magnesium turnings (12.15 g, 0.5 mol) and ether (50 mL) over a 45 minute period. After the addition is complete, the reaction mixture is refluxed for 1/2 hour then cooled in an ice bath. The Grignard reagent is then added to a solution of ethyl trifluoroacetate (71.04 g, 0.5 mol) and ether (150 mL) at -60° to -70° C. (acetone-dry ice bath) over a 45 minute period. The cooling bath is removed and the reaction mixture is allowed to warm to -10° C. The reaction mixture is then quenched with saturated ammonium chloride solution and then acidified with 10% hydrochloric acid solution. The organic layer is separated, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a liquid. Vacuum distillation of the liquid gives the title product as a clear liquid (52.8 g, bp 72°-74° C./34 mm, 47%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[N:11]=[C:12]([N:15]=[C:16]([NH2:18])[NH2:17])[S:13][CH:14]=2)[N:9]=1.[CH2:19]([S:25][CH2:26][C:27](O)=[O:28])[C:20]1[O:24][CH:23]=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O>[NH2:17][C:16](=[N:15][C:12]1[S:13][CH:14]=[C:10]([C:8]2[N:9]=[C:5]([CH2:4][NH:3][C:27](=[O:28])[CH2:26][S:25][CH2:19][C:20]3[O:24][CH:23]=[CH:22][CH:21]=3)[S:6][CH:7]=2)[N:11]=1)[NH2:18]
Reactant: O=C(O)CSCc1ccco1
Reactant: NCc1nc(-c2csc(N=C(N)N)n2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(N)=Nc1nc(-c2csc(CNC(=O)CSCc3ccco3)n2)cs1
Yield: 11 %

Procedure:
A suspension of 4-(2-aminomethylthiazol-4-yl)-2-(diaminomethyleneamino)thiazole dihydrochloride (1.6 g), (furfurylthio)acetic acid (0.98 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.2 g) and triethylamine (1.0 g) in N,N-dimethylformamide (20 ml) was stirred with cooling on an ice-water bath for 2.5 hours. The solvent was removed under the reduced pressure. The residue was washed with water and then chromatographed on a silica gel column eluting with a mixture of chloroform and methanol (10:1). The appropriate fractions was collected and the solvent was removed under the reduced pressure. The residue was suspended in water (20 ml) and the mixture was alkalized to pH 11 with a saturated aqueous potassium carbonate solution. The resulting precipitate was collected by filtration. Recrystallization from a mixture of methanol and water afforded 2-(diaminomethyleneamino)-4-[2-(furfurylthio)acetylaminomethylthiazol-4-yl]thiazole (0.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:18][CH2:17]1)[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[NH4+:40].[Cl-]>>[C:11]([C:10]1[CH:14]=[CH:15][C:7]([N:6]([CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2]([Cl:1])[CH:3]=2)[CH:16]2[CH2:17][CH2:18][N:19]([CH:22]([CH3:36])[CH2:23][CH2:24][NH:25][C:26](=[O:35])[C:27]3[C:28]([CH3:34])=[CH:29][CH:30]=[CH:31][C:32]=3[CH3:33])[CH2:20][CH2:21]2)=[CH:8][CH:9]=1)(=[O:13])[NH2:40]
Reactant: [NH4+]
Reactant: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(=O)O)cc2)CC1
Agent: [Cl-]
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(Cl)c2)c2ccc(C(N)=O)cc2)CC1
Yield: 75 %

Procedure:
Using general procedure E (Wang, W.; McMurray, J. S. Tetrahedron Lett., 1999, 40, 2501-2504) 4-((3-chloro-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid (see EXAMPLE 86) (90 mg, 0.16 mmol) and NH4Cl (22 mg, 0.41 mmol) gave COMPOUND 90 as a white solid (64.1 mg, 0.12 mmol, 71%). 1H NMR (CDCl3) δ 0.95-1.09 (m, 1H), 1.01 (d, 3H, J=6.6 Hz), 1.10-1.25 (m, 1H), 1.48-1.58 (m, 1H), 1.68-1.83 (m, 3H), 2.13-2.24 (m, 1H), 2.31 (s, 6H), 2.52-2.63 (m, 1H), 2.73-2.94 (m, 3H), 3.23-3.34 (m, 1H), 3.64-3.76 (m, 1H), 3.83-3.93 (m, 1H), 3.85 (s, 2H), 5.67 (br s, 2H), 6.55 (d, 2H, J=8.4 Hz), 6.94-7.04 (m, 3H), 7.06-7.13 (m, 2H), 7.20-7.27 (m, 2H), 7.61 (d, 2H, J=8.4 Hz), 8.34 (br d, 1H, J=5.1 Hz). 13C NMR (CDCl3) δ 13.37, 19.05, 28.90, 30.19, 30.84, 39.72, 43.48, 48.09, 51.94, 55.68, 60.37, 111.78, 120.97, 124.13, 126.10, 126.93, 127.29, 128.40, 129.07, 129.77, 133.95, 134.40, 138.46, 141.59, 151.10, 169.07, 169.83. ESI-MS m/z 547 (MH)+, 549 (MH+2)+. Anal. Calcd. for C32H39ClN4O2.0.7CH2Cl2.0.3H2O: C, 64.18; H, 6.75; N, 9.15; Cl, 13.90. Found. C, 64.11; H, 6.58; N, 9.11; Cl, 13.99.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>CO>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(CNCc2ccc(Oc3ccccc3)cc2)cc1
Reaction time: 48 h
Yield: 97.6 %

Procedure:
4-Phenoxybenzaldehyde (1.0 g, 5.0 mmol) and 4-fluorobenzylamine (631 mg, 5.0 mmol) were dissolved in methanol (17 mL) under a nitrogen at room temperature. Sodium cyanoborohydride (317 mg, 5.0 mmol) was added, and stirring was continued for 48 hours. The solvent was evaporated, and the residue was suspended in ether, washed with brine, and dried over Na2SO4. The ether was evaporated, and the crude product was chromatographed on silica gel eluting with 3% methanol in methylene chloride to provide 1.5 g (97%) of the title compound as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 1.55 (s, 1H), 3.76 (s, 2H), 3.78 (s, 2H), 6.95-7.15 (m, 7H), 7.25-7.40 (m, 6H). MS (DCl/N H3) m/e 308 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1ccncc1
Yield: 55.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (100 mg, 0.43 mmol) was coupled to 4-fluoro-3-(pyridin-4-yl)benzeneboronic acid (121 mg, 0.56 mmol) as described in Example 3 part g), affording 5-(4-fluoro-3-pyridin-4-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (88 mg, 55%). δH (360 MHz, CDCl3) 7.41-7.47 (1H, m), 7.52-7.63 (5H, m), 7.85 (1H, d, J 8.8), 8.52 (1H, d, J 8.4), 8.73-8.74 (2H, m), 9.30 (1H, d, J 4.2). m/z (ES+) 370 [MH]+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([Br:18])[S:17][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19].O1CCOCC1>CCOCC>[Br:18][C:16]1[S:17][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[CH:15]=1.[ClH:19]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)sc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Brc1cc2c(s1)CCNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of step g) (0.39 mmol) dissolved in ether (1 ml) was treated with 4 M HCl/dioxane (1 ml). The reaction mixture was stirred for 18 hours at ambient temperature. The resulting precipitate was filtered and washed with anhydrous diethyl ether to give the title compound as its HCl salt. 1H NMR (300 MHz, DMSO) δ 9.40 (s, 2H), 7.05 (s, 1H), 3.14-3.33 (m, 4H), 2.94-3.23 (m, 2H), 2.76-3.06 (m, 2H). MS: ESI (positive): 232, 234 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][C:19]=3[S:20][C:21]=2N(C)C)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[N:38]1([CH2:43][CH2:44][O:45][C:46]2[CH:51]=[CH:50][C:49]([Mg]Br)=[CH:48][CH:47]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:1][N:2]([CH3:37])[C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][C:19]=3[S:20][C:21]=2[C:49]2[CH:48]=[CH:47][C:46]([O:45][CH2:44][CH2:43][N:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[CH:51][CH:50]=2)=[O:16])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: CN(C)c1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Reactant: Br[Mg]c1ccc(OCCN2CCCC2)cc1
Product: CN(C)c1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Yield: 79 %

Procedure:
The title compound was prepared in 79% yield by essentially following the procedures outlined in Example 81, Part E, from 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-(dimethylamino)-4-(1-pyrrolidinylmethyl)phenyl ketone (Part F) and 4-[2-(1-pyrrolidinyl)ethoxy]phenyl magnesium bromide (Example 81, Part D).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:16][CH2:17]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N1CCC(Nc2ccccc2[N+](=O)[O-])CC1
Temperature: 100 °C

Procedure:
A suspension of 2-fluoronitrobenzene (3.52 g, 25 mmol), 4-amino-1-(phenylmethyloxycarbonyl)piperidine† (4.0 g, 17 mmol) and potassium carbonate (64 g, 19 mmol) in DMSO (25 ml) was heated to 100° C. After 5 h the mixture was poured into ice/water and the resulting yellow solid was collected by filtration and washed with water. The solid was dried to give the title compound as a yellow solid (5.69 g, 16 mmol); NMR: 1.6 (m, 2H), 2.1 (d, 2H), 3.1 (t, 2H), 3.7 (m, 1H), 4.1 (d, 2H), 5.2 (s, 2H), 6.7 (t, 1H), 6.9 (d, 1H), 7.3-7.5 (m, 6H), 8.1 (d, 1H) and 8.2 (dd, 1H); MS: 356.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:7]1[C:8]2[N:9]([CH:12]=[CH:13][N:14]=2)[C:10]2[C:5]([N:6]=1)=[CH:4][CH:3]=[C:2]([Cl:1])[CH:11]=2
Reactant: O=c1[nH]c2ccc(Cl)cc2n2ccnc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2nc(Cl)c3nccn3c2c1

Procedure:
By reaction of 8-chloroimidazo[1,2-a]quinoxaline-4(5H)-one (example 17) with POCl3, following a procedure that is similar to that described in example 1, there is obtained 4,8-dichloroimidazo[1,2-a]quinoxaline that is subsequently reacted with cyclopentylamine according to the method described in example 3, thereby obtaining 4-cyclopentylamino-8-chloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=140.1° C.(onset); IR (KBr): 3401, 2955, 1554 cm-1 ; 1H-NMR (CDCl3): δ7.8 (1H,d, J=2 Hz), 7.7÷7.2 (4H,m), 6.15 (1H,d), 4.6 (1H,m), 2.3÷2.05 (4H,m), 2.05÷1.3 (4H,m); UV (EtOH): λmax =229, 245, 289, 301, 326, 340 nm. Elementary analysis for C15H15ClN4 (m.w. 286.76): calcd. C 62.83, H 5.27, N 19.54%; found C 63.04, H 5.36, N 19.64%.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:25][C:26]3[CH:35]=[CH:34][CH:33]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:27]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.50 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 24 mg (0.60 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 160 mg (0.70 mmol) of methyl 3-(bromomethyl)benzoate was added to the reaction mixture, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH2:30])[CH2:4]1)[CH3:2].[CH3:31][O:32][C:33]1[C:34](=O)[C:35](=[O:39])[C:36]=1[O:37]C.CCN(C(C)C)C(C)C>CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([S:20]([C:23]5[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=5)(=[O:22])=[O:21])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([NH:30][C:34]2[C:35](=[O:39])[C:36](=[O:37])[C:33]=2[O:32][CH3:31])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](N)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Reactant: COc1c(OC)c(=O)c1=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C[C@H](Nc2c(OC)c(=O)c2=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 71.5 %

Procedure:
To a solution of (1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanamine (0.40 g, 0.942 mmol, Example #8 Step M) in MeOH (3 mL) was added 3,4-dimethoxycyclobut-3-ene-1,2-dione (0.14 g, 0.98 mmol) and DIEA (0.18 mL, 1.0 mmol). The reaction was stirred at rt for about 16.5 h. Then the solid from the reaction mixture was collected via vacuum filtration, while washing with cold MeOH (about 4° C., 10 mL), and dried in a vacuum oven at about 60° C. to give crude 3-((1S,3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylamino)-4-methoxycyclobut-3-ene-1,2-dione (0.36 g, 73%, 90% purity): LC/MS (Table 1, Method a) Rt=2.13 min; MS m/z: 535 (M+H)+.