Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([N+:22]([O-])=O)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]>CO.[Ni]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc([N+](=O)[O-])cc4c3C2)nc1
Agent: [Ni]
Solvent: CO
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(N)cc4c3C2)nc1
Temperature: 25 °C
Yield: 43.9 %

Procedure:
To a solution of methyl-2-(8-nitro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate (0.5 g, 1.41 mmol) in methanol (50 mL) was added Raney Nickel (0.3 g). The reaction mixture was evacuated and stirred at rt under hydrogen atmosphere over night. The progress of the reaction was monitored by TLC and upon completion of the reaction, the mixture was filtered through celite under nitrogen atmosphere and washed with methanol (2×30 mL). The methanol was removed under reduced pressure to give crude residue which was purified by column chromatography to give the methyl-2-(8-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate (0.2 g, 43.9%); (Rt=12.46).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[CH:6][C:5]=1[OH:25].C([O-])([O-])=O.[K+].[K+].[CH2:33](I)[CH3:34].O>CN(C=O)C.CCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[CH:6][C:5]=1[O:25][CH2:33][CH3:34]
Reactant: COC(=O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOc1cc(OCCc2nc(-c3ccccc3)oc2C)ccc1C(=O)OC
Yield: 96.6 %

Procedure:
To a solution of the compound 25 (0.27 g) in DMF (5 mL) was added K2CO3 (0.16 g) and EtI (0.07 mL) and the mixture was allowed to stand over night. The reaction mixture was poured into water and the product was extracted with ethyl acetate (30 mL). The ethyl acetate phase was washed with water, satd. NaCl and dried over anhydrous Na2SO4 and filtrated. Evaporation of the filtered gave a residue, from which 0.28 g (96.6%) of the colorless objective compound was obtained by silicagel column chromatography (ethyl acetate:n-hexane=1:3).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[C:17]([Br:22])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.CCOCC>[Br:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Br:21])[CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)c(Br)c2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Brc1ccc(CN2CCNCC2)cc1Br
Reaction time: 16 h
Yield: 108.3 %

Procedure:
A suspension of 4-(3,4-dibromo-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (6.0 g) in MeOH (100 mL) was treated with 2 M HCl in Et2O (28 mL). After 16 h, the resulting suspension was diluted with Et2O (100 mL) and filtered. The solid was washed with Et2O (2×20 mL) and dried in vacuo, giving a white solid (5.0 g). This solid was partitioned between 10% aq. KOH (50 mL) and DCM (3×50 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a colorless glassy oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[CH3:23][S:24][CH2:25][CH2:26]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:23][S:24][CH2:25][CH2:26][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:22])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: CSCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSCCN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A mixture of the 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (100 mg, 0.333 mmol) produced in Example (8b), 2-chloroethyl methyl sulfide (38.7 mg, 0.349 mmol), potassium carbonate (78.2 mg, 0.566 mmol) and acetonitrile (2 mL) was stirred for 8 hours and 30 minutes at an external temperature of 80° C. The reaction mixture was concentrated and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 88 mg of 1-(2-methylsulfanylethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless solid.
Reaction SMILES: B(O)O.Br[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:6]1([C:11]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:5]=1
Reactant: Cc1ccccc1Br
Agent: [Pd]
Agent: OBO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
Cyclization substrate 5 is synthesized in FIG. 1. The Suzuki reaction is iterated, first by coupling 1,3-dimethoxyphen-2-yl boronic acid with 2-bromotoluene with tetrakis(triphenylphosphine) palladium catalysis to give biphenyl compound 1. Regioselective bromination of 1 gave 2, followed by Suzuki reaction with pyridine-3-boronic acid under palladium catalysis to yield 3. Demethylation of 3 with hydrobromic acid and acetic acid gave 4, followed by Friedel-Crafts acylation with 2,5-dichlorotrimellitic anhydride to yield 5.
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][N:5](C(OC(C)(C)C)=O)[CH2:6][C@H:7]\1[CH2:8][NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[ClH:27].O1CCOCC1>C(Cl)Cl>[ClH:27].[OH:1]/[N:2]=[C:3]1/[C@H:7]([CH2:8][NH:9][C:10](=[O:11])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][NH:5][CH2:4]/1
Reactant: CC(C)(C)OC(=O)N1C/C(=N\O)[C@H](CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(NC[C@@H]1CNC/C1=N\O)OCc1ccccc1

Procedure:
Dissolve 1,1-dimethylethyl(3Z,4R)-3-(hydroxyimino)-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (0.90 g, 2.53 mmol) in methylene chloride (10 mL). Add HCl/dioxane (excess) and stir at ambient temperature for 3 hours. Concentrate solution under reduced pressure. (0.66 g, quant). LCMS: m/z 254.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([N:35]=[C:36]=[S:37])=[O:34].[ClH:38]>C1COCC1.CO>[ClH:38].[ClH:38].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[F:25])=[S:37])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1F)N=C=S
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4F)cc3F)c2s1
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of aniline 219 (100 mg, 0.29 mmol, scheme 47) and 2-(2-fluorophenyl)acetyl isothiocyanate (115 mg, 0.58 mmol) in THF (3 mL) was stirred for 1 hour, loaded directly onto a column containing silica gel and eluted sequentially with EtOAc and EtOAc/MeOH (100:1), to produce a white solid. This material was suspended in MeOH (5 mL) and HCl (1.0M in ether, 1 mL) was added to form a clear solution that was evaporated to dryness. The residue was washed with ether, suspended in H2O, and lyophilized to afford the title compound (80 mg, 45% yield) as a yellowish solid. 1H-NMR (DMSO-d6) δ (ppm): 12.42(s, 1H), 11.88(s, 1H), 8.65(d. 1H, J=5.5 Hz), 8.20(s, 1H), 8.05(d, 1H, J=1.7 Hz), 7.74(s, 1H), 7.58-7.55(m, 3H) 7.39-7.32(m, 2H), 7.21-7.16(m, 2H), 6.82(d, 1H, J=5.5 Hz), 4.02(s, 3H), 3.93(s, 2H), MS (m/z): 536.2(M+H) (found).
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([O:23][CH3:24])=[O:22]>>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([N:19]1[CH2:27][CH2:26][CH2:25][C@H:20]1[C:21]([O:23][CH3:24])=[O:22])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
Z-Val-OH (3.5 g, 13.9 mmol) and H-Pro-OMe*HCl (2.14 g, 13.9 mmol) were treated in the same manner as above for 1, to give 3 as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH:4]([NH:16][C:17](=[O:30])[CH:18]([NH:22]C(OC(C)(C)C)=O)[CH2:19][O:20][CH3:21])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[Cl:32]CCCl>Cl.O1CCOCC1>[ClH:32].[CH3:1][O:2][C:3](=[O:31])[CH:4]([NH:16][C:17](=[O:30])[CH:18]([NH2:22])[CH2:19][O:20][CH3:21])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: ClCCCl
Reactant: COCC(NC(=O)OC(C)(C)C)C(=O)NC(Cc1ccc2ccccc2c1)C(=O)OC
Agent: Cl
Solvent: C1COCCO1
Product: COCC(N)C(=O)NC(Cc1ccc2ccccc2c1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-tert-butoxycarbonylamino-3-methoxy-propionylamino)-3-naphthalen-2-yl-propionic acid methyl ester, 57, (5.2 g, 12.1 mmol) is dissolved in 4M hydrogen chloride in dioxane (40 mL) and stirred at room temperature for 1 hour. 1,2-Dichloroethane (40 mL) is added. The solution is concentrated in vacuo to afford 4.43 g (quantitative yield) of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[CH:12][C:11]=2[O:23][CH2:24][CH:25]([F:27])[F:26])=[CH:4][CH:3]=1.FC1C=C(F)C([N+]([O-])=O)=CC=1C(O)=O.C1(N)CC1.BrC1C=CC(N)=CC=1.FC(F)CO>[Ni].[H][H]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:19][CH:20]3[CH2:21][CH2:22]3)=[CH:12][C:11]=2[O:23][CH2:24][CH:25]([F:27])[F:26])=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1cc([N+](=O)[O-])c(NC2CC2)cc1OCC(F)F
Reactant: [H][H]
Agent: [Ni]
Agent: NC1CC1
Agent: Nc1ccc(Br)cc1
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)c(OCC(F)F)cc1NC1CC1

Procedure:
The subtitle compound is prepared from N-(4-bromophenyl)-2-(2,2-difluoroethoxy)-4-cyclopropylamino-5-nitro-benzamide (prepared from 2,4-difluoro-5-nitrobenzoic acid, cyclopropylamine, 4-bromoaniline and 2,2-difluoroethanol in analogy to the examples 1c, 6a, 1e) and RaNi/H2 in analogy to example 5c.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:14].[Na+]>O.[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:8]([O-:10])=[O:9])[CH:2]2[C:11]([O-:13])=[O:12].[Na+:14].[Na+:14]
Reactant: O=C([O-])C1C2C=CC(C2)C1C(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: O=C([O-])C1C2CCC(C2)C1C(=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of disodium bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylate (10.0 g) in water (100 g) was added 0.5 g palladium on activated carbon (5 wt %). The mixture was transferred into a Parr reactor and was subjected to hydrogenation (50 psi, room temperature) for 8 hours. The activated carbon was filtered out, and the water was removed in vacuo at 75° C. The resulting product (m.p>300° C.) was dried and milled. NMR and IR analyses were consistent with that of the expected structure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)#[N:2]>CO.Cl>[CH3:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][NH2:2])[CH:8]=1
Reactant: Cc1ccnc(C#N)c1
Agent: Cl
Solvent: CO
Product: Cc1ccnc(CN)c1

Procedure:
2-Cyano 4-methylpyridine in MeOH (35 ml) and concentrated HCl (1 ml) was stirred under a H2 balloon for 14 hours. The reaction mixture was filtered and concentrated. The pH was adjusted to 12 by the addition of aq sodium hydroxide. The resulting reaction mixture was extracted with dichloromethane several times. Concentration of the solvent gave the crude title compound, which was used in the next step without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)=[O:27])=[CH:22][CH:21]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCOc1ccc(OCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOc1ccc(OCC(=O)n2n[n+]([O-])c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a suspension of 1-hydroxybenzotriazole (0.53 g) and 2-(4-octyloxyphenoxy)acetic acid (1 g) in dichlormethane (30 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.886 g), and stirred for 3 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-[2-(4-octyloxyphenoxy)actyl]benzotriazole 3-oxide (892 mg). To a solution of The Starting Compound (1.79 g) and 1-[2-(4-octyloxyphenoxy)acetyl]benzotriazole 3-oxide (892 mg) in N,N-dimethylformamide (18 ml) was added 4-(N,N-dimethylamino)pyridine (0.297 g), and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with ethyl acetate. The precipitate was collected by filtration, and dried under reduced pressure. The powder was added to water, and subjected to ion-exchange column chromatography on DOWEX-50WX4, and eluted with water. The fractions containing the object compound were combined, and subjected to column chromatograph on ODS (YMS-gel.ODS-AM.S-50), and eluted with 50% methanol aqueous solution. The fractions containing the object compound were combined, and evaporated under reduced pressure to remove methanol. The residue was lyophilized to give The Object Compound (24) (1.75 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.[C:36](Cl)(=[O:39])[CH2:37][CH3:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:36](=[O:39])[CH2:37][CH3:38])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f28) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:35]=[CH:34][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]([O:31]CC)=[O:30])=[N:20]2)=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O.Cl>O1CCCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]([CH2:28][C:29]([OH:31])=[O:30])=[N:20]2)=[CH:34][CH:35]=1)=[O:12]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc12
Yield: 57.9 %

Procedure:
Ethyl 2-[1-[4-(2-naphthamido)benzyl]-1H-indazol-3-yl]acetate (226 mg, 0.488 mmol) was dissolved in tetrahydrofuran (10 mL), and in an ice bath 10 mL aqueous solution of lithium hydroxide monohydrate (62 mg, 1.48 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated. It was filtered, and dried to obtain a white solid 123 mg, at a yield of 58%.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:19]>[Al+3].[Cl-].[Cl-].[Cl-]>[Br:19][CH:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: COc1ccc(C(=O)CCC2CCCCC2)cc1
Reactant: [Br-]
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C(Br)CC2CCCCC2)cc1
Yield: 96.6 %

Procedure:
A procedure similar to step 3 of Example 1 was used. 3-cyclohexyl-1-(4-methoxy-phenyl)-propan-1-one prepared in the step 2 and bromide were used as starting materials, and anhydrous AlCl3 was used as catalyst, a colorless oily product was obtained in a yield of 96.6%. 1H-NMR (CDCl3, 400 MHz) δ: 0.85˜1.30 (5H, m), 1.45˜1.85 (6H, m), 2.04 (2H, t, J=8.08 Hz, CH2CHBr), 3.89 (3H, s, OCH3), 5.24 (1H, t, J=7.48 Hz, CHBr), 6.96 (2H, d, J=9.16 Hz, ArH), 8.02 (2H, d, J=8.68 Hz, ArH); ESI-MS m/e (%): 346.9 (M+Na, 100), 327.3 (M+1, 71).
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30])=O)C1C=CC=CC=1.[N:33]1[C:42]2[C:37](=[N:38][C:39]([CH:43]=O)=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.N1CCCCC1>CC(O)C>[F:32][C:29]([F:30])([F:31])[C:20]1[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:43][C:39]2[CH:40]=[CH:41][C:42]3[C:37](=[CH:36][CH:35]=[CH:34][N:33]=3)[N:38]=2)[C:14](=[O:16])[N:13]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)=N1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1N=C(NCc2ccc(C(F)(F)F)cc2C(F)(F)F)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C
Yield: 23.2 %

Procedure:
To a mixture of 2-(2,4-bis-trifluoromethyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (94.5 mg, 0.20 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.7 mg, 0.20 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4.5 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, ether and dried in vacuum at 100° C. for 3 h to give 2-(2,4-bis-trifluoromethyl-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-1,5-dihydro-imidazol-4-one as a light yellow solid (21.6 mg, 23.2%). HR-ES (+) m/e calcd. for C21H13F6N5O: (M+H)+ 466.1097. Found: 466.1098.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.C([Li])CCC.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[OH:25][C:22]1([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)[CH2:21][CH2:20][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:24][CH2:23]1
Reactant: Cn1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccnc1C1(O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
1-Methylimidazole (4.1 mL, 50 mmol) in dry tetrahydrofuran was treated with n-butyllithium (25 mL, 50 mmol) at room temperature and heated at 40° C. for 3 hours. The reaction was cooled to −78° C. and 4-oxo-piperidine-1-carboxylic acid tert-butylester (9.96 g, 50 mmol) added. The mixture was allowed to warm to room temperature, stirred for 6 hours the heated to 40° C. for an additional 3 hours. The reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was recrystallized from methanol to provide the title compound (8.2 g, 84%) as white solid. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.8 (d, 2H, J=15 Hz), 2.1 (m, 2H), 3.3 (t, 3H, J=15 Hz), 3.8 (s, 4H), 6.8 (dd, 2H, J=9, 3 Hz); MS (DCI/NH3) m/e 282 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([NH:35]O)=[NH:34])=[CH:31][N:30]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[N:15]3[N:22]=[CH:23][C:24]([C:25]4[O:26][N:35]=[C:33]([C:32]5[CH:37]=[CH:38][C:29]([NH2:28])=[N:30][CH:31]=5)[N:34]=4)=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:11])[F:10]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: N=C(NO)c1ccc(N)nc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5ccc(N)nc5)no4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) (195 mg, 0.5 mmol) and 6-amino-N-hydroxy-nicotinamidine (example B.4) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane/hexane) as a yellow solid (98 mg, 39%). MS (ISP) 506.2 [(M+H)+]; mp 220° C.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11](N)[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].[C:30]([N:33]1C2C(=CC(C3C=CC(S(C)(=O)=O)=CC=3)=C(Br)C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>[Cu]Br>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11]([C:30]#[N:33])[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(Br)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Agent: [Cu]Br
Product: CC(=O)N1c2cc(C#N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-6-cyano-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-bromo-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 238), substituting copper (I) cyanide for copper (I) bromide. MS (ESI, pos. ion) m/z 408 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.CC1C2[O:20]C=CC=2C=CC=1>>[CH3:11][C:10]1[C:4]2[O:3][C:2]([CH:1]=[O:20])=[CH:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cc2cccc(C)c2o1
Reactant: Cc1cccc2ccoc12
Product: Cc1cccc2cc(C=O)oc12

Procedure:
i. 2,7-Dimethyl-benzofuran. 7-Methyl-benzofuran (of. compound (2) g.) is subjected to a WILSMEYER reaction to form 7-methyl-benzofuran-2-aldehyde which is converted into 2,7-dimethyl-benzofuran by a WOLFF-KISHNER reaction by the method described in Bull.Soo.Chim.France 29, 1875 (1952). The product thus obtained has the following peaks in its MS: 146 (100%), 145 (92%) and 131 (32%).