Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)ccc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(F)cc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 2.4 %

Procedure:
A solution of 2-methyl-4-fluoro-benzonitrile (3.5 g, 25.9 mmol) in 40 mL of carbon tetrachloride was treated with N-Bromosuccinimide (4.6 g, 25.9 mmol) and benzoylperoxide (157 mg, 0.65 mmol). The mixture was heated to reflux for 3 hours, cooled to room temperature and allowed to stir overnight. The solids were filtered off and washed with carbon tetrachloride. The filtrate was condensed and purified by normal phase flash column chromatography on a 50 g silica gel column (5-50% ethyl acetate/hexanes gradient). Two peaks separated. It was determined that the second eluting peak is the desired product. Pure fractions of this peak were pooled and concentrated in vacuo to yield 2-(bromomethyl)-4-fluorobenzonitrile (1.35 g, 0.63 mmol, 25% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.79 (s, 2H), 7.44 (dt, J=8.59, 2.69 Hz, 1H), 7.68 (dd, J=9.53, 2.55 Hz, 1H), 8.01 (dd, J=8.59, 5.64 Hz, 1H).
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[NH:14][C:13](=O)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:18])=O>>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([Cl:18])[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC(=O)O[C@H](C)c1nccc(=O)[nH]1
Product: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reaction time: 3 h

Procedure:
(R)-2-(1-Butyryloxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Fourteen, 3.00 g, 16.5 mmol) was added to phosphorus oxychloride (10 mL) at ambient temperature and stirred for 3 h. Excess phosphorus oxychloride was removed under vacuum and the resulting oil was partitioned between dichloromethane and saturated aqueous sodium carbonate. The layers were separated and the organic layer was washed once with water, once with saturated aqueous sodium chloride and dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an orange oil, 3.19 g (85%). 1H NMR (CDCl3, 300 MHz) δ 0.98 (t, 3H), 1.54 (d, 3H), 1.67 (m, 2H), 2.48 (t, 2H), 5.68 (q, 1H), 6.36 (d, 1H), 8.21 (d, 1H); [α]D+27.6 (c, 1.0, MeOH).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[C:19]1([CH2:18][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][C:6]3=[O:11])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2c(OCc3ccccc3)cccc21

Procedure:
To a solution of 4.44 g (0.03 m) of 4-hydroxy-1-indanone in 50 ml of dimethylformamide is added 4.15 g (0.03 m) of potassium carbonate with stirring followed by the dropwise addition of 3.8 g (0.03 m) of benzyl chloride. The reaction mixture is heated at steam bath temperature for 3 hours, then cooled and diluted with water. The aqueous mixture is extracted with ethyl acetate and the extract is washed with water, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue is triturated with ether and concentrated to dryness to yield: 5.86 g (82%) of a brown solid, m.p. 70°-73° C., sufficiently pure to be used in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.CN(C=O)C.[NH2:17][C:18]1[CH:19]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][CH:23]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)[N:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CN(C)C=O
Solvent: CCCCO
Product: FC(F)(F)c1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1

Procedure:
1.9 g (10 mmol) of 2,6-dichloro-purine are stirred in 60 ml of butanol and 3 ml of DMF with 8.05 g (50 mmol) of 3-amino-benzotrifluoride at 60° C. for 3 h. On cooling, 2-chloro-6-(3-trifluoromethyl-phenyl-amino)-purine is obtained as a crystalline mass. This is filtered off and dried in vacuo; m.p. 248° C.; FAB-MS: (M+H)+=314; Rf=0.45 (CH2Cl2:methanol=95:5).
Reaction SMILES: O.[NH:2]1[C:10](=[O:11])[C:8](=[O:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.Cl>C(O)C>[OH:9][C:8]1([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[C:13]([Br:12])[CH:14]=3)[NH:18][CH:17]=2)[C:6](=[O:7])[NH:5][C:3](=[O:4])[NH:2][C:10]1=[O:11]
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1NC(=O)C(O)(c2c[nH]c3ccc(Br)cc23)C(=O)N1
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
Alloxan hydrate (1.6 g., 0.01 mole) was dissolved in 40 ml. of ethanol by heating. 5-Bromoindole (1.96 g., 0.01 mole) was added and heating near reflux continued for 15 minutes. Tlc did not indicate that reaction had occured. 1N Hydrochloric acid (10 ml.) was then added while maintaining the reaction near reflux. After 10 minutes, the reaction was concentrated to wet solids. Trituration of these wet solids with water gave the title product [3.17 g., m.p. >250° C.; Rf 0.45 (1:1 ethyl acetate:hexane/5% acetic acid); Rf 0.3 (1:5 ethyl acetate:hexane/5% acetic acid)].
Reaction SMILES: [C:1]([O:4][C:5]([CH3:25])([CH2:7][CH2:8][CH2:9][N:10]1[CH2:19][C@@H:18]2[CH2:20][O:21][CH2:22][CH2:23][N:17]2[C:16]2[N:15]=[C:14](Cl)[N:13]=[CH:12][C:11]1=2)[CH3:6])(=[O:3])[CH3:2].[NH:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[C:29]=2[CH:28]=[CH:27]1>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:4][C:5]([CH3:25])([CH2:7][CH2:8][CH2:9][N:10]1[CH2:19][C@@H:18]2[CH2:20][O:21][CH2:22][CH2:23][N:17]2[C:16]2[N:15]=[C:14]([C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:29]=3[CH:28]=[CH:27][NH:26]4)[N:13]=[CH:12][C:11]1=2)[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CC(=O)OC(C)(C)CCCN1C[C@@H]2COCCN2c2nc(-c3cccc4[nH]ccc34)ncc21
Temperature: 120 °C
Yield: 26.6 %

Procedure:
To a 2 mL microwave vial were added (R)-5-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpentan-2-yl acetate (PREPARATION x81, 148 mg, 0.401 mmol), indole-4-boronic acid (64.6 mg, 0.401 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (16.50 mg, 0.020 mmol). The vial was evacuated and filled with nitrogen. After sealing the vial, dioxane (1600 μL) and saturated NaHCO3 (400 μL) were added. The mixture was then heated in a microwave to 120° C. for 45 minutes. After the mixture was cooled to room temperature, ACN (4 mL) was added and the mixture was filtered by syringe filter. The crude product was purified by preparatory HPLC using a gradient of 20-40% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The collected fractions were pooled, neutralized with NaHCO3, concentrated, and extracted with EtOAc. The combined organics were dried over MgSO4, filtered, and concentrated to give the title compound (48 mg, 27%). ESI-MS m/z [M+H]+ calc'd for C25H31N5O3, 450.25; found 450.3.
Reaction SMILES: [CH2:1]=[C:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH2:10]([NH:17][CH2:1][CH:2]([CH2:8][CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: C=C(CC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(CC)CNCc1ccccc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
The compound obtained in Step 1 was dissolved in ethanol (7 mL). To the solution, benzylamine (2.7 mL) was added at room temperature, and the mixture was stirred at 70° C. for 17 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluting solvent: hexane-hexane/ethyl acetate=7/3) to obtain the title compound (2.34 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C@H:7]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH:8]C(OCC1C=CC=CC=1)=O.C1COCC1.[C:40]1([S:50](Cl)(=[O:52])=[O:51])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1>CN(C)C=O.CN(C1C=CN=CC=1)C.[C].[Pd]>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[NH:5][C:6](=[O:23])[C@H:7]([C@H:19]([CH2:21][CH3:22])[CH3:20])[NH:8][S:50]([C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)(=[O:52])=[O:51]
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: [Pd]
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-isoleucyl-(L)-tryptophan methyl ester (11.3 g), palladium-carbon (5%, 50% wet, 3.0 g) and THF (50 ml) was subjected to catalytic hydrogenation at room temperature and atmospheric pressure. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to yield an oily substance. The oil was dissolved in N,N-dimethylformamide (50 ml), and 1-naphthalenesulfonyl chloride (5.8 g) and 4-(N,N-dimethylamino)pyridine (DMAP) (3.2 g) were added to the ice-cooling mixture. After stirring at 0° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was suspended in ethyl acetate and the mixture was successively washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate and brine, and dried (MgSO4). The organic solvent was evaporated off to yield N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophan methyl ester (9.8 g, 77%) as crystals. Melting point: 172°-174° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.S(N1CC(C)(C)N(C)C1)([C:16]1C=CC(C)=CC=1)(=O)=O>>[CH2:16]1[C:5]2[NH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]=2[CH2:3][CH2:2][NH:1]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)N2CN(C)C(C)(C)C2)cc1
Product: c1ccc2c3c([nH]c2c1)CNCC3

Procedure:
treating the 3-(2-amino)ethyl indole with 1-tosyl-3,4,4-trimethylimidazolidine to produce a tetrahydro-β-carboline derivative; and
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCOCC2)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 68.1 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (119 mg, 0.282 mmol) obtained in Example 12 in methylene chloride (3 ml), morpholine (30 μl, 0.339 mmol), 1-hydroxybenzotriazole (38 mg, 0.282 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.339 mmol) and 4-methylmorpholine (37 μl, 0.339 mmol) were added. The reaction solution was stirred for 5 days at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with 65% ethyl acetate/hexane was concentrated under reduced pressure. Ethyl acetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (94 mg, 0.192 mmol, 68%) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]=1[C:17]([OH:19])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1.CCN(CC)CC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[O:11][C:10]=1[C:17]([NH:37][CH:33]1[CH2:36][CH2:35][CH2:34]1)=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCC1
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)O)o1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCC2)o1
Temperature: 50 °C
Reaction time: 5 h
Yield: 91.8 %

Procedure:
A mixture of 3-(benzyloxy)-6-methyl-4-oxo-4H-pyran-2-carboxylic acid (2.5 g, 9.6 mmol, 1.0 equiv), 1,1′-carbonyldiimidazole (2.49 g, 15.37 mmol, 1.6 equiv) in DMF (20 mL) was stirred at 50° C. for 5 h. The mixture was cooled to room temperature. Cyclobutylamine hydrochloride (1.24 g, 11.52 mmol, 1.2 equiv) and Et3N (1.74 mL, 12.48 mmol, 1.3 equiv) was added, and the mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. Purification by chromatography (1:1 hexanes/EtOAc, then EtOAc) provided the titled compound (2.76 g, 91.56%) as a yellow solid. M.p. 69.3-71.0° C.; 1H-NMR (CDCl3, 400 MHz) δ 1.51-1.72 (m, 4H, cyclobutyl H), 2.19-2.28 (m, 2H, cyclobutyl H), 2.37 (s, 3H, CH3), 4.39-4.41 (m, 1H, CH), 5.41 (s, 2H, OCH2Ph), 6.30 (s, 1H, CH), 7.39-7.49 (m, 5H, ArH), 7.86 (br, 1H, NH), and MS (m/z) 314 (M++1), 217, 91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)[C:17]([O:19]C(C)(C)C)=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:34]#[N:35])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:24][CH:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)[C:17]([OH:19])=[O:18])[C:10](=[O:33])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCS(=O)(=O)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cn(C(CC2CCS(=O)(=O)CC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
860 mg (1.65 mmol) of tert-butyl 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)propanoate (racemate) in 16.6 ml of dichloromethane and 4.77 ml (61.9 mmol) of TFA were reacted according to General Method 6A. Yield: 1.18 g (purity 72%, quant.)
Reaction SMILES: Cl.[CH2:2](NC(N1CCN(C(C2CCCC2)=O)CC1)=O)C.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[CH:28][C:25]([C:26]#[N:27])=[C:24]([NH2:32])[CH:23]=1.[H-].[Na+]>O>[CH3:31][O:30][C:29]1[CH:28]=[C:25]2[C:24](=[CH:23][C:22]=1[O:21][CH3:20])[N:32]=[CH:2][N:27]=[CH:26]2
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CCNC(=O)N1CCN(C(=O)C2CCCC2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc2cncnc2cc1OC
Reaction time: 0.5 h

Procedure:
Ethyl-4-(cyclopentylcarbonyl)piperazin-1-yl-formamidate hydrochloride (0.01 mole) is added to a solution of 4,5-dimethoxy-2-aminobenzonitrile (0.01 mole) in 30 ml. of N1N-dimethylformamide. Sodium hydride (0.02 mole of a 56% suspension in mineral oil) is added and the mixture stirred 0.5 hr. at room temperature and then at 100° C. for a period of 12 hr. When the reaction period is complete, water is added providing 4-amino-2-[4-cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazoline.
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[S:11](Cl)(=[O:13])=[O:12].[CH3:15][CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)[NH:17]1>N1C=CC=CC=1>[CH3:15][CH:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[N:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:30][CH2:31]2)[N:17]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CC1CCc2c(cccc2N2CCN(C(=O)OC(C)(C)C)CC2)N1
Solvent: c1ccncc1
Product: CC1C=Cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2N1S(=O)(=O)c1ccc2ccccc2c1

Procedure:
2-Naphthalenesulfonyl chloride (0.33 g, 1.45 mmol) was added to a solution of the tert-butyl 4-(1,2,3,4-tetrahydro-2-methylquinolin-5-yl)piperazine-1-carboxylate prepared in example 7 (0.4 g, 1.2 mmol), in pyridine (3 mL). The resulting mixture was heated under reflux for 3 h. The solvent was evaporated in vacuo and the residue was purified by column chromatography (using CH2Cl2 eluent). Yield: 0.26 g (41.2%). Rf=0.7 (CH2Cl2-acetone 98:2).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(Cl)cc1
Product: N#Cc1ccc(N2CCCCC2)cc1
Temperature: 100 °C
Yield: 89 %

Procedure:
To commercially available 4-chlorobenzonitrile 17 (1 g, 7.26 mmol) 3 ml of piperidine were added and the reaction was heated at 100° C. for 72 hours in closed vessel. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The purification of the crude residue by chromatographic column using AcOEt 1/Petroleum ether 9 as eluant gave 1.2 g of a pale yellow oil. Yield=89% 1HNMR (DMSO, 200 MHz) δ 1.57 (6H, m), 3.34 (4H, m), 6.98 (2H, d, J=9 Hz), 7.53 (2H, d, J=9 Hz)
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH:4]([NH2:19])[C:3]1=[O:20].[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:19][CH:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:20])=[O:27])=[CH:24][CH:23]=1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CN1C(=O)C(NC(=O)c2ccc(Br)cc2)N=C(c2ccccc2)c2ccccc21

Procedure:
The procedure of Example 134 was carried out employing equivalent amounts of 1,3-dihydro-1-methyl-3(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-bromobenzoyl chloride. The product was purified by chromatography on silica gel (5% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized to give the title compound which was dried at 65° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:39])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:39][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:36])[F:37])[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2C(F)(F)F)n1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2ccccc2C(F)(F)F)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2-trifluoromethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 519.05 [M+H]+; tR=3.08 min (System 3).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH2:17]([CH:21]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39](O)=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20]>>[CH2:17]([CH:21]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCCC(c1ccccc1)n1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
0.61 g of compound 42 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.28 g of ethyl 4-(2-aminophenoxy)butyrate and 1.0 g of 3-[1-(α-butylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([N:14]=[C:15]=[O:16])[CH2:11][CH2:12][CH3:13].Cl.[F:18][B-:19]([F:22])([F:21])[F:20].[Na+]>C(OCC)(=O)C.CO>[F:18][B-:19]([F:22])([F:21])[F:20].[CH2:10]([NH:14][C:15]([NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:16])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCN=C=O
Reactant: CCCCCCCCN
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCNC(=O)NCCCC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
A four necked flask equipped with a thermometer, stirrer and drip funnel was charged with 2.58 g of octylamine and 200 g of ethyl acetate. To this was added dropwise a solution of 1.98 g of n-butylisocyanate in 30 g of ethyl acetate with stirring over 30 minutes while maintaining the inner temperature at 10° C. and allowed to react until the absorption of isocyanato group (2240 cm-1) disappeared IR spectrometrically. After dissolving the solidified reaction product in 50 g of methanol, a mixture of 2.086 g of 35% hydrochloric acid and 50 g of methanol was added dropwise to the solution over 30 minutes and allowed to react at room temperature for 20 hours. Then a solution of 2.2 g of sodium tetrafluoroborate in 50 g of methanol was added dropwise over 30 minutes and allowed to react at room temperature for 20 hours. The reaction mixture was then filtered to remove NaCl by-product and evaporated to remove the solvent. 6.1 g of the title compound was obtained as a pale yellow liquid.