Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][NH:17]2)[N:15]=1)([CH3:10])[CH3:9].C(N(CC)CC)C.[CH3:44][O:45][C:46](Cl)=[O:47]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:12]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:28]=3)=[CH:23][CH:22]=2)[CH:13]=[C:14]([CH:16]2[CH2:20][CH2:19][CH2:18][N:17]2[C:46]([O:45][CH3:44])=[O:47])[N:15]=1)([CH3:10])[CH3:9]
Reactant: COC(=O)Cl
Reactant: CC(C)(c1ccccc1Cl)c1nc(C2CCCN2)cn1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)N1CCCC1c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2)c(C(C)(C)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-4-pyrrolidin-2-yl-1H-imidazole in THF was added triethylamine, followed by methylchlorocarbonate. The mixture was stirred at room temperature for 20 min. After a routing aqueous work up, the crude product was purified by prep HPLC to give methyl 2-{2-[1-(2-chlorophenyl)-1-methylethyl]-1-[3′-(methylsulfonyl)biphenyl-4-yl]-1H-imidazol-4-yl}pyrrolidine-1-carboxylate: 1H NMR (CD3OD): δ 1.6 (m, 3H,), 1.8 (m, 1H), 1.9-2.3 (m, 5H), 3.2 (s, 3H), 3.4 (m, 1H), 3.7 (m, 4H), 4.6 (m, 1H), 5.1 (m, 1H), 6.9 (m, 1H), 7.2 (m, 6H), 7.7 (m, 3H), 7.95 (m, 2H), 8.2 (m, 1H); LC/MS M+H 578 (observed).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][NH:6][CH2:5][C:4]2[S:8][CH:9]=[CH:10][C:3]1=2.[C:11]1([N:17]=[C:18]=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC=CC=1.C(O)C>[OH:1][CH:2]1[CH2:7][N:6]([C:18](=[S:19])[NH:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][C:4]2[S:8][CH:9]=[CH:10][C:3]1=2
Reactant: S=C=Nc1ccccc1
Reactant: OC1CNCc2sccc21
Solvent: CCO
Solvent: c1ccccc1
Product: OC1CN(C(=S)Nc2ccccc2)Cc2sccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79 %

Procedure:
To a solution of 4-hydroxy-4,5,6,7-tetrahydro-thieno[2,3-c]-pyridine (5.8 g; 37.4 mmoles) in benzene (60 cc) and 95% ethanol (30 cc) is added dropwise a mixture of phenyl isothiocyanate (5.05 g; 37.4 mmoles) in benzene (20 cc). After stirring during 2.5 hours at room temperature, the resulting precipitate is filtered off, washed with ether and dried in vacuo (M.p. = 168° C; yield: 79%).
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[O:16]=[C:17]1[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][N:18]1[CH2:35][C:36](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCCl>[C:29]1([C:22]2([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:21][CH2:20][CH2:19][N:18]([CH2:35][C:36]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A solution of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.033 g, 0.162 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.050 g, 0.162 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.046 g, 0.242 mmol) were stirred together in 1,2-dichloroethane (0.5 mL) at room temperature. After stirring for 1 hour, the reaction was heated to 85° C. and stirred overnight. The reaction was cooled, loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% ethyl acetate/hexane to 100% ethyl acetate over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 8.22-8.26 (m, 2H), 7.76-7.80 (m, 2H), 7.21-7.35 (m, 10H), 4.93 (s, 2H), 3.64 (t, J=6.4 Hz, 2H), 2.69-2.74 (m, 2H), 1.88-1.97 (m, 2H); MS (ESI+) m/z 478 (M+H)+.
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][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[CH:30]1([CH2:29][O:28][C:22]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:33])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:34](=[O:37])[CH2:35][CH3:36])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:31][CH2:32]1
Reactant: CCC(=O)Cl
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f30) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([C:30]2[O:31][C:32]([C:38]([F:41])([F:40])[F:39])=[C:33]([C:35](O)=[O:36])[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35]([C:33]3[N:34]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:31][C:32]=3[C:38]([F:40])([F:41])[F:39])=[O:36])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1

Procedure:
To a solution of 4-fluoronitrobenzene (1.41 g, 10 mmol) in THF (50 mL) was added N-Boc-4-hydroxypiperidine (2.01 g, 10 mmol) and sodium hydride (60% in mineral oil, 583 mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs. After purification through flash column chromatography, 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.51 g, 78% yield) was obtained as a solid. This nitro compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid to give 4-{4-[(2-phenyl-5-trifluoromethyloxazole-4-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS showed a single peak with a retention time of 4.08 min. LRMS calcd for C27H28F3N3O5 (M+1) 532.20, obsd 532.1
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[Na].Br[CH:11]=[C:12]=[C:13]([CH3:15])[CH3:14].O>C(O)C>[C:1]([CH:3]([C:13]([CH3:15])([CH3:14])[C:12]#[CH:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CC(C)=C=CBr
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C#CC(C)(C)C(C#N)C(=O)OCC
Reaction time: 20 h

Procedure:
Ethyl cyanoacetate (77.0 g.) was slowly added at 40° C. to a stirred solution of sodium (15.7 g.) in ethanol (400 ml.) and 15 minutes after the addition was completed 1-bromo-3,3-dimethylallene (100 g.) was carefully added over about 30 minutes. The mixture was then heated at the reflux temperature for a period of 2.5 hours and then kept at the ambient temperature for a further 20 hours. The mixture was then poured into an excess of water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent. The residual oil was distilled and ethyl 2-cyano-3,3-dimethylpent-4-ynoate was obtained as a colourless oil (boiling point 75°-76° C./0.1 mm Hg.).
Reaction SMILES: ClC1C=C[C:5]([CH:8]2[NH:12][C:11]([C:13]3C=CC(OC)=[CH:15][C:14]=3OCC)=N[CH:9]2[CH:24]2CCCCC2)=CC=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:41]([C:42]([N:44]3CCN(C)C[CH2:45]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH2:62][CH:63]2[CH2:67][CH2:66][CH2:65][CH2:64]2)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]2[N:41]([C:42]([N:44]3[CH2:24][CH2:9][CH:8]([N:12]4[CH2:15][CH2:14][CH2:13][CH2:11]4)[CH2:5][CH2:45]3)=[O:43])[C:40]([C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH2:60][CH3:61])=[N:39][CH:38]2[CH:62]2[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]2)=[CH:33][CH:32]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCOc1cc(OC)ccc1C1=NC(C2CCCCC2)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(C2CCCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-4-cyclohexyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-4-cyclohexyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 11) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 593.3260, calculated for C36H46N4O3Cl [(M+H)+]593.3253.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[N:12]=[C:13]([C:21]#[N:22])[CH:14]=[C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][C:16]=12.[CH2:23](Br)[CH:24]=[CH2:25]>>[CH2:25]([N:17]1[C:16]2=[C:11]([N:2]3[CH2:3][CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH2:1]3)[N:12]=[C:13]([C:21]#[N:22])[CH:14]=[C:15]2[CH:19]=[C:18]1[CH3:20])[CH:24]=[CH2:23]
Reactant: Cc1cc2cc(C#N)nc(N3CCc4ccccc4C3)c2[nH]1
Reactant: C=CCBr
Product: C=CCn1c(C)cc2cc(C#N)nc(N3CCc4ccccc4C3)c21
Yield: 79 %

Procedure:
In accordance with the same procedures as in Example 657, except for using 7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carbonitrile prepared in Step 2 and allyl bromide, the titled compound was obtained as a white solid. (Yield: 79%)
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([F:35])[CH:34]=1)[CH2:31][C:30](=O)[CH2:29][CH2:28]2>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][CH:30]2[CH2:29][CH2:28][C:27]3[C:32](=[C:33]([F:35])[CH:34]=[C:25]([F:24])[CH:26]=3)[CH2:31]2)[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: Diast #1 (RT 12 min) 14.2, 19.5, 2.9, 26.0, 28.2, 28.9, 29.7, 36.5, 52.9, 55.5, 58.9, 60.9, 67.5, 68.9, 101.1, 104.5, 110.7, 131.2, 137.4, 172.4; MS m/z 490.3 (M+1). Diast #2 (RT 18 min) 14.2, 19.6, 25.9, 26.0, 28.3, 28.9, 29.6, 36.5, 52.5, 55.5, 58.8, 60.4, 67.5, 68.9, 101.1, 104.5, 110.6, 131.2, 137.3, 172.2; MS m/z 490.3 (M+1). Chiral sep using a Kromasil TBB column, elute 95/5, heptane/IPA, flow rate 85 ml/min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13]([OH:15])=O)=[CH:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:57][CH2:58][C:59]1[CH:60]=[C:61]([OH:65])[CH:62]=[CH:63][CH:64]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:13](=[O:15])[NH:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([OH:65])[CH:60]=2)=[CH:8][C:9]=1[CH:10]([CH3:11])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C(C)C
Reactant: NCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.7 %

Procedure:
To a solution of 3-Isopropyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (110 mg, 0.48 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.20 mL, 1.45 mmol), HBTU (0.27 g, 0.72 mmol), HOBT (78 mg, 0.58 mmol), and 3-Aminomethyl phenol (65 mg, 0.53 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-60% EtOAc in hexane to afford the desired product (0.070 g, 44% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)=O)=[CH:4][CH:3]=1.[CH:21]1([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:31]([C:30]3[CH:32]=[CH:33][C:27]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:28][CH:29]=3)[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=C(CCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Product: Brc1ccc(-c2ccc(-c3ccc(Br)cc3)n2-c2ccc(C3CCCCC3)cc2)cc1
Yield: 91 %

Procedure:
The product from Example 26E and 4-cyclohexylaniline (Alfa) were processed using the method described in Example 26F to provide 1.23 g (91%) of the title compound. 1H NMR (400 MHz, benzene-D6) δ1.09 (s, 5 H) 1.60 (s, 5 H) 2.14 (s, 1 H) 6.52 (s, 2 H) 6.67 (s, 4 H) 6.84 (s, 4 H) 7.11 (s, 4 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](Cl)=[N:12][OH:13])=[N:2]1.[NH3:15]>C(Cl)(Cl)Cl.C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][C:11](=[N:12][OH:13])[NH2:15])=[N:2]1
Reactant: N
Reactant: ON=C(Cl)Cc1noc2ccccc12
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: NC(Cc1noc2ccccc12)=NO
Reaction time: 0.5 h

Procedure:
In a mixture of chloroform (250 ml) and ethanol (250 ml) was dissolved 1,2-benzisoxazole-3-acetohydroximic chloride (0.5 g) and the mixture was saturated with ammonia by passing through thereto ammonia gas under ice-cooling. The mixture was allowed to stand for 0.5 hour and then the solvent was distilled off under a reduced pressure. To the residue was added chloroform and the insoluble substance was filtered off. The filtrate was distilled to remove the solvent and the residue was recrystallized from ethanol to give the desired compound (0.38 g). m.p. 161° to 163°C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]2[C:6]3[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=3[CH2:8][CH2:9][C:10]=2[CH:11]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.[NH4+]>>[N:16]1[CH:21]=[CH:20][CH:19]=[N:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[N:4][C:5]3[C:6]4[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=4[CH2:8][CH2:9][C:10]=3[CH:11]=2)[CH2:24][CH2:23]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Clc1cc2c(nn1)-c1ccccc1CC2
Agent: Cl
Agent: [NH4+]
Product: c1cnc(N2CCN(c3cc4c(nn3)-c3ccccc3CC4)CC2)nc1
Temperature: 130 °C
Reaction time: 48 h
Yield: 87 %

Procedure:
A mixture of comprising about 0.01 mol of 3-chloro-5,6-dihydrobenzo[h]cinnoline, about 0.05 mol of 1-(2-pyrimidyl)piperazine and about 0.01 mol of ammonium hydrochloride was prepared in about 15 ml of 1-BuOH. The mixture was stirred at 130° C. for 48 h, and then the solvent was removed under reduced pressure. The remaining residue was then extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4. Removal of solvent followed by recrystallization from 95% ethanol yielded golden yellow crystals, yield 87.0%; HPLC: 96.6% purity; HRMS calculated 344.1744, found 344.1738; 1H NMR (CDCl3): d 8.452 (d, J=7.5, 1H), 8.346 (d, J=4.5, 2H), 7.200-7.364 (m, 3H), 6.794 (S, 1H), 6.542 (t, J=4.5, 1H), 3.999 (t, J=5.0, 4H), 3.808 (t, J=5.0, 4H), 2.909 (s, 4H).
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-:13].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:13][C:10]1[CH:9]=[CH:8][C:7]([OH:12])=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:11]=1
Reactant: Oc1ccccc1C1CCCC1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1C1CCCC1
Temperature: 25 °C

Procedure:
2-cyclopentyl phenol (3.0 g, 0.0185 mol) was dissolved in CHCl3 (100 mL) and magnetically stirred at room temperature. To this solution was added a solution of Tetrabutyl ammonium tribromide (8.92 g, 0.0185 mol) in CHCl3 (100 mL). The resulting yellow solution was allowed to stir at room temperature for 1 hour. The reaction was quenched with a 5% solution of sodium thiosulfate (200 mL). The biphasic mixture was stirred for 15 min. The organics were separated and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 3% EtOAc in Hexanes. The result was a yellow oil (3.70 g). 1H NMR (CDCl3): δ 1.39-1.73 (brm, 8H), 2.83 (m, 1H), 4.81 (s, 1H), 6.68 (d, J=7.10 Hz 1H), 7.19 (d, J=7.10 Hz, 1H), 7.26 (s, 1H).
Reaction SMILES: [N:1]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][C@H:2]1[C:3]([N:5]([CH3:20])[C@@H:6]([C:17](O)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[NH2:31][C@H:32]([C:41]([O:43][C:44]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:45])=[O:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37]C=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O>>[N:1]1([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23][CH2:22][CH2:21][C@H:2]1[C:3]([N:5]([CH3:20])[C@@H:6]([C:17]([NH:31][C@H:32]([C:41]([O:43][C:44]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:45])=[O:42])[CH2:33][C:34]1[CH:35]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@@H](CCc1ccccc1)C(=O)OC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Product: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)c1ccccc1
Yield: 83 %

Procedure:
Condensation of BocProOH (4.63 g.) and MeDTrpOMe (5.00 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-MeDTrpOMe in 69% yield. Demethylation of BocPro-MeDTrpOMe (6.33 g.) using aqueous sodium hydroxide gave BocPro-MeDTrpOH in 77% yield. Condensation of BocPro-MeDTrpOH (3.60 g.) and HPheOBz (3.70 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocPro-MeDTrp-PheOBz in 83% yield. Debenzylation of BocPro-MeDTrp-PheOBz (4.60 g.) by hydrogenation with palladium catalyst gave BocPro-MeDTrp-PheOH in 100% yield.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[I:22][C:23]1[CH:24]=[C:25]([CH2:29][NH2:30])[CH:26]=[CH:27][CH:28]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:4]([NH:30][CH2:29][C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([I:22])[CH:24]=2)[N:3]=1
Reactant: CCC(CC)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1cccc(I)c1
Solvent: CCCCO
Solvent: CC(C)O
Product: CCC(CC)n1cnc2c(NCc3cccc(I)c3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 3 starting from 200 mg of the product obtained in Stage 1 of Example 3 and 4 ml of butanol and using 0.123 ml of 3-iodo-benzenemethanamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol, left for three hours at a temperature of approximately 0° C., followed by separating, washing with 10 ml of isopropanol and drying at a temperature of approximately 50° C. After purification on silica eluting with cyclohexane/ethyl acetate/ methylene chloride in a proportion of 70/15/15, 235 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.I[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[O:35][C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[N:33][N:32]=3)[CH:29]=2)[N:24]([S:46]([C:49]2[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:23]=1.CN(C=O)C>C(Cl)Cl.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]4[O:35][C:34]([NH:36][CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)=[N:33][N:32]=4)[CH:29]=3)[N:24]([S:46]([C:49]3[CH:50]=[CH:51][C:52]([CH3:53])=[CH:54][CH:55]=3)(=[O:48])=[O:47])[CH:23]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
In a 20 mL glass microwave tube, 2-chloro-6-(tributylstannyl)pyrazine (0.807 g, 1.999 mmol), 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.00 g, 1.665 mmol), CuI (0.381 g, 1.999 mmol), Pd(PPh3)4 (0.096 g, 0.083 mmol) was purged with argon and treated with DMF (15 mL). The tube was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h. The crude mixture was then diluted with DCM and washed with water. The organic layer was dried, filtered and concentrated and the residue was purified with flash chromatography to give 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.48 g, 0.818 mmol, 49%) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 586.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.44 (1H, s), 9.02 (1H, s), 8.85 (1H, s), 8.71 (1H, s), 8.28-8.36 (1H, m), 8.18 (1H, d, J=8.8 Hz), 8.03 (1H, m, J=8.4 Hz), 7.95 (1H, s), 7.88-7.95 (1H, m), 7.45 (1H, m, J=8.2 Hz), 7.33 (2H, m, J=8.6 Hz), 6.90 (2H, m, J=8.6 Hz), 4.37 (2H, d, J=6.1 Hz), 3.72 (3H, s), 2.33 (3H, s).
Reaction SMILES: CC(OC([NH:8][CH:9]1[C@@H:14]2[C@H:10]1[CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:13]2)=O)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[NH2:8][CH:9]1[C@@H:14]2[C@H:10]1[CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:13]2
Reactant: CC(C)(C)OC(=O)NC1[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1[C@H]2CN(C(=O)OCc3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl(1R,5S)-6-[(2-methylpropan-2-yl)oxycarbonylamino]-3-azabicyclo[3.1.0]hexane-3-carboxylate (Bioorganic & Medicinal Chemistry Letters (2004), 14(11), 2773-2776, Compound 9; 6.74 g, 20.3 mmol) was stirred and dissolved in DCM (90 mL) at ambient temperature and TFA (10 ml) was added. The solution was stirred at room temperature for 2 hours. Sat. bicarbonate (100 ml) was added followed by potassium carbonate solid until neutral. The DCM layer was separated and washed once more with water. The DCM solution was dried (MgSO4), filtered and evaporated to a gum.