Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]1[C:14](=[O:15])[NH:13][C:12]([CH:16]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[C:33]([CH2:39][NH:40]C(OC(C)(C)C)=O)[CH:32]=2)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]=2[F:29])=[N:11]1)=[O:4].CO.C1COCC1.[OH-].[Na+]>C(O)(=O)C>[CH2:23]([C:21]1[CH:20]=[C:19]([O:25][CH2:26][CH2:27][OH:28])[C:18]([F:29])=[C:17]([CH:16]([NH:30][C:31]2[CH:32]=[C:33]3[C:34](=[CH:35][CH:36]=2)[C:37](=[NH:38])[NH:40][CH2:39]3)[C:12]2[NH:13][C:14](=[O:15])[N:10]([C:9]3[CH:8]=[CH:7][S:6][C:5]=3[C:3]([OH:2])=[O:4])[N:11]=2)[CH:22]=1)[CH3:24]
Reactant: CCc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ccsc3C(=O)OC)c(=O)[nH]2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cc(OCCO)c(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ccsc3C(=O)O)c(=O)[nH]2)c1
Yield: 35 %

Procedure:
A mixture of 3-(3-{[3-(t-butoxycarbonylaminomethyl)-4-cyanophenylamino]-[5-ethyl-2-fluoro-3-(2-hydroxyethoxy)phenyl]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)thiophene-2-carboxylic acid methyl ester (31 mg), a methanol:THF (2:1) mixed solvent (1.5 mL) and a 5N sodium hydroxide aqueous solution (0.1 mL) was heated for 14 hours at 65° C. under a nitrogen atmosphere. Acetic acid was added to the mixture, which was then purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (9.0 mg).
Reaction SMILES: [C:1]([N:6]1[C@@H:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][O:8][C:7]1=[O:17])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].CCN(C(C)C)C(C)C.CN1C(=O)CCC1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH:39]=[O:40]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[F:34][C:35]([F:48])([F:49])[C:36]1[CH:37]=[C:38]([C@@H:39]([OH:40])[C@H:2]([CH:3]=[CH2:4])[C:1]([N:6]2[C@@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][O:8][C:7]2=[O:17])=[O:5])[CH:41]=[C:42]([C:44]([F:47])([F:45])[F:46])[CH:43]=1
Reactant: C/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C=C[C@H](C(=O)N1C(=O)OC[C@@H]1c1ccccc1)[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: -40 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To (4S)-3-[(2E)-but-2-enoyl]-4-phenyl-1,3-oxazolidin-2-one (13.8 g, 59.7 mmol) in DCM (100 mL) was added TiCl4 (1M in DCM, 59.7 mL, 59.7 mmol) at −10° C. The resulting reaction solution was transferred by cannula to a flask containing DIPEA (11.26 mL, 64.5 mmol) and DCM (100 mL) at 10° C. NMP (11.49 mL, 119 mmol) was added via a syringe and the reaction mixture was aged for 1 hour before cooling to −40° C. 3,5-Bis(trifluoromethyl)benzaldehyde (17.3 g, 71.6 mmol) in DCM (25 mL) was added via a syringe and the reaction was allowed to warm to 0° C. over 1.5 hr. The reaction was quenched by addition of acetic acid (15 mL), saturated Rochelle's salt (50 mL) and HCl (1.0 M, 200 mL). The organic was separated and the aqueous was back extracted with DCM (50 mL). The organics were combined, washed with HCl (1.0 M, 100 mL), dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to give (4S)-3-{(2S)-2-[(S)-[3,5-bis(trifluoromethyl)phenyl](hydroxy)methyl]but-3-enoyl}-4-phenyl-1,3-oxazolidin-2-one (20 g, 42.3 mmol) as crystalline solid. 1H NMR (500 MHz, CDCl3) δ7.86 (s, 2H), 7.83 (s, 1H), 7.4 (m, 5H), 5.7 (m, 1H), 5.4 (m, 1H), 5.31 (d, J=10.3 Hz, 1H), 5.28 (d, J=3.9 Hz, 1H), 5.10 (d, J=17.3 Hz, 1H), 4.8 (m, 1H), 4.7 (t, J=9.0 Hz, 1H), 4.3 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].OC1C=CC=CC=1C=O>>[CH2:25]([NH:27][C:28]([O:13][C:12]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][C:11]=1[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])[CH3:26]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: O=Cc1ccccc1O
Product: CCNC(=O)Oc1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
To a solution of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (5 g, 20 mmol) in DNF (100 mL) was added triethylamine (3.5 mL, 25 mmol) and the solution was stirred for 15 min at room temperature. Ethyl isocyanate (1.95 mL, 25 mmol) was added and the reaction mixture was stirred for 2 h at room temperature until no more hydroxybenzaldehyde was detected by TLC (Rf=0.78 for product and 0.89 for starting material using 1:1 hexanes/EtOAc). The reaction solution was concentrated by azeotropic removal of DMF with water. The resulting suspension was filtered, washed with water and dried in a vacuum oven to afford 96% of the title compound as a light buff solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH2:13][CH2:14][CH3:15])[CH:10]=[C:9](/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CO[CH2:24][N:25]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:26][Si](C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:31]([N:25]1[CH2:26][C@@H:16]([C:9]2[CH:10]=[C:11]([CH2:13][CH2:14][CH3:15])[CH:12]=[C:2]([Cl:1])[C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C@H:17]([C:18]([O:20][CH3:21])=[O:19])[CH2:24]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCCc1cc(Cl)c(C(=O)OCC)c(/C=C/C(=O)OC)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1cc(Cl)c(C(=O)OCC)c([C@@H]2CN(Cc3ccccc3)C[C@H]2C(=O)OC)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of (E)-ethyl 2-chloro-6-(3-methoxy-3-oxoprop-1-enyl)-4-propylbenzoate (0.92 g, 2.96 mmol) in 20 mL of CH2Cl2 was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.77 g, 3.25 mmol) and trifluoroacetic acid (0.045 mL, 0.6 mmol). The solution was allowed to stir at 40° C. for 2 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (0.1 g, 0.4 mmol) and trifluoroacetic acid (2 drops) were added and the reaction was stirred at 40° C. for an additional 30 min and then at ambient temperature for 18 h. The reaction was quenched with sat'd aq NaHCO3 and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (230-400 mesh silica gel, 6:1 hexane/EtOAc) to afford 1.17 g (90%) of the title compound as an oil. LRMS (ES)+: 444.25/446.24 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[C:20](Br)[CH:19]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([O:24][C:25]([F:26])([F:27])[F:28])[CH:23]=1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Reactant: FC(F)(F)Oc1cc(Br)cc(Br)c1
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(Br)cc(OC(F)(F)F)c3)cc21

Procedure:
Prepared from (4,4-dimethyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-trifluoromethoxybenzene according to Procedure B. White solid: mp 214-216° C.; 1H-NMR (DMSO-d6) δ10.4 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.68-7.62 (m, 3H), 6.97 (d, 1H, J=8.0 Hz), 1.68 (s, 6H); MS (ESI) m/z 414 ([M−H]−, 100%); Anal. Calc. For C17H13BrF3NO3: C, 49.06; H, 3.15; N, 3.37. Found: C, 49.16; H, 3.05; N, 3.30.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[NH:18][C:17](=[O:20])[CH2:16][CH2:15]2.O>CN(C=O)C>[Br:8][C:12]1[CH:13]=[C:14]2[C:19](=[C:10]([F:9])[CH:11]=1)[NH:18][C:17](=[O:20])[CH2:16][CH2:15]2
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCc2cccc(F)c2N1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(Br)cc(F)c2N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.2 %

Procedure:
At 0° C., NBS (0.62 g, 3.5 mmol) was added dropwise to a solution of 8-fluoro-3,4-dihydro-1H-quinolin-2-one (0.52 g, 3.2 mmol) in DMF (5 mL). The resulting reaction mixture was stirred at room temperature for 12 hours before it was treated with water. The precipitated solid was collected through filtration, washed with ether, and dried in a vacuum to afford title compound (0.65 g, 85%) as a white solid. MS: 244.1 (M+H+)+.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O-:15])=O)[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]([NH2:19])=[S:18].[CH2:20](N(CCCC)CCCC)CCC.[OH-].[Na+].CI.Cl>C1CCCCC1.C(O)C>[C:1]1([CH:7]2[C:13](=[O:15])[NH:19][C:17]([S:18][CH3:20])=[N:16][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=S
Reactant: CCCCN(CCCC)CCCC
Reactant: CCOC(=O)C(C(=O)[O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Solvent: C1CCCCC1
Product: CSC1=NC(=O)C(c2ccccc2)C(=O)N1
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
60.0 g (208 mmol) of ethyl 2-phenylmalonate and 19.0 g (249 mmol) of thiourea were heated at 150° C. for 2.5 hours in 77 g (416 mmol) of tri-n-butylamine. The resultant ethanol was for the most part distilled off. After the reaction solution had cooled, 180 ml of an aqueous solution of 24.9 g (623 mmol) of NaOH were added to it. After adding 50 ml of cyclohexane and stirring for about 30 min the aqueous phase was separated off, treated with 35.4 g (142 mmol) of methyl iodide and stirred at approximately 20 to 25° C. for about 16 h. After acidification with dilute HCl solution and stirring for about 30 min the precipitate was filtered off. After washing with water and drying, 16.7 g of the compound in the title (28% of theoretical) were obtained in the form of white crystals.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:11]([F:14])([F:13])[F:12]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: C1CCNCC1
Product: Cn1ccc(=O)c(O)c1C(N1CCCCC1)C(F)(F)F
Yield: 54 %

Procedure:
In a similar manner, Apo7058 was prepared from 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) and piperidine (0.88 mL, 8.9 mmol). The title compound Apo7058 (700 mg) was obtained as a white solid after purification by flash chromatography (4% MeOH in CH2Cl2 as eluant). Yield=54%; 1H NMR (400 MHz, DMSO-D6, 75° C.) δ (ppm): 7.59 (d, J=6.8 Hz, 1H), 6.19 (d, J=6.8 Hz, 1H), 4.82 (q, J=9.0 Hz, 1H), 3.88 (s, 3H), 2.46-2.84 (m, 4H), 1.29-1.74 (m, 6H) MS m/z 291 [M+1]+, 206 (100%).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1)=[O:4].C([SiH2]OC(C)(C)C1C=CC(C(=O)C)=CC=1[F:29])(C)(C)C.[Br-].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>>[Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[C:7]([F:29])[CH:6]=1)=[O:4]
Reactant: CC(=O)c1ccc(C(C)(C)O[SiH2]C(C)(C)C)c(F)c1
Reactant: O=C(CBr)c1ccc(CO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: O=C(CBr)c1ccc(CO)c(F)c1

Procedure:
2-Bromo-1-(3-fluoro-4-hydroxymethyl-phenyl)-ethanone is prepared following preparation 15a from 280 mg (0.99 mmol) 1-[4-(tert-butyl-dimethyl-silanyloxymethyl)-3-fluoro-phenyl]-ethanone (preparation 16e) and 478 mg (0.99 mmol) tetrabutylammonium-tribromide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH3:22])[CH:15]=2)[OH:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([CH3:22])[CH:15]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(O)c2ccc(OC)c(C)c2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2ccc(OC)c(C)c2)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-methyl-phenyl) -methanol from above and activated MnO2 (3 g, 35 mmol) in methylene chloride (30 mL) was stirred at room temperature for 18 h. More MnO2 (1.3 g×2) was added and kept for overnight. The suspension was filtered thru a pad of Celite. Removal of solvent gave (3-ethoxy-4-methoxy-phenyl)-(4-methoxy-3-methyl-phenyl)-methanone as a white solid (1.23 g, 68% crude yield 2 steps). The sample was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:24]1=[CH:25][C:26]2[C:27]([CH:32]([O:35][Si:36]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[CH:37]([CH3:39])[CH3:38])[CH2:33][CH2:34]1)=[N:28][CH:29]=[CH:30][CH:31]=2)(=O)=O>C1(C)C=CC=CC=1.CO.C(OCC)(=O)C.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>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:24]1=[CH:25][C:26]2[C:27]([CH:32]([O:35][Si:36]([CH:40]([CH3:42])[CH3:41])([CH:43]([CH3:45])[CH3:44])[CH:37]([CH3:38])[CH3:39])[CH2:33][CH2:34]1)=[N:28][CH:29]=[CH:30][CH:31]=2
Reactant: OB(O)c1cccc(F)c1F
Reactant: CC(C)[Si](OC1CCC(OS(=O)(=O)C(F)(F)F)=Cc2cccnc21)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC1CCC(c2cccc(F)c2F)=Cc2cccnc21)(C(C)C)C(C)C
Temperature: 80 °C
Yield: 41.5 %

Procedure:
The mixture of 2,3-difluorophenylboronic acid (0.936 g, 5.93 mmol), sodium carbonate (4.57 mL, 9.14 mmol), (E)-9-(triisopropylsilyloxy)-8,9-dihydro-7H-cyclohepta[b]pyridin-6-yl trifluoromethanesulfonate (2.3 g, 4.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.285 g, 0.247 mmol) in toluene (30 mL) and MeOH (6 mL) was heat to 80° C. under N2 for 3 hours. LCMS showed no more starting material. The reaction was diluted with ethyl acetate and washed with water one time. The ethyl acetate layer was separated, dried (Na2SO4), filtered and concentrated. Flash column by ethyl acetate in hexane from 0 to 25% afforded the desired product (0.8797 g, 54%). MS(ESI)[M+H+]=430.43.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1.C(OCC)(=O)C.C(N(CC)CC)C.Cl>CS(C)=O>[CH:2]([C@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][S:11][C:12]1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1)=[O:1]
Reactant: CCOC(=O)c1csc(SCCN2C(=O)OC[C@@H]2CO)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1csc(SCCN2C(=O)OC[C@@H]2C=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of the compound 4 (338 mg) in dimethylsulfoxide (3.40 mL)/ethyl acetate (6.80 mL) were added triethylamine (1.00 mL) and sulfur trioxide-pyridine complex (650 mg) at 10° C. and the solution was stirred at room temperature for 1 hour. To the reaction solution was added 1N hydrochloric acid and the solution was extracted with ethyl acetate. The organic layer was washed water and brine, dried over anhydrous sodium sulfate and concentrated to give the title compound (336 mg) having the following physical data. The compound was used in the next reaction without purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6](Br)[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]=3[C:3]1=2.[C:18]([Cu])#[N:19].[C-]#N.[K+].CO>O>[CH3:1][CH:2]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[N:7]=[C:6]([C:18]#[N:19])[C:5]3[N:14]=[CH:15][CH:16]=[CH:17][C:4]=3[C:3]1=2
Reactant: N#C[Cu]
Reactant: CC1CC(=O)Nc2nc(Br)c3ncccc3c21
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1CC(=O)Nc2nc(C#N)c3ncccc3c21
Yield: 70 %

Procedure:
2 g (0.007 mol) of 1-methyl-6-bromo-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one, 0.3 g (0.003 mol) of CuCN and 0.3 g (0.005 mol) of KCN are heated for 7 hours at 160° C. in an autoclave with 20 ml of methanol and 10 ml of water. After cooling, the mixture is filtered under suction, and the residue digested in chloroform/methanol, 1:1, under reflux for 4 hours. The organic phase is filtered, dried and concentrated. The residue is purified by recrystallization from ethanol/petroleum ether, and 0.5 g (60.1% of theory) of 1-methyl-6-cyano-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17](OS(C)(=O)=O)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([O-:27])=[O:26]>CN(C=O)C>[C:7]([O:11][C:12]([N:14]1[CH2:15][CH2:16][CH:17]([S:34][C:31]2[CH:32]=[CH:33][C:28]([N+:25]([O-:27])=[O:26])=[CH:29][CH:30]=2)[CH2:18][CH2:19]1)=[O:13])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Yield: 87.5 %

Procedure:
Potassium carbonate (0.45 g, 3.5 mmol) was added in one portion to a stirred solution of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (0.75 g, 2.5 mmol) and 4-nitrothiophenol (0.5 g, 3.2 mmol) in DMF (25 ml) and the mixture heated to 70° C. for 7 hours. After this time, the reaction mixture was concentrated under vacuum and re-dissolved in ethyl acetate (25 ml) and washed with NaOH (1M solution, 20 ml) and brine (20 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum. The resulting residue was purified by column chromatography (elution: 60% heptane, 40% ethyl acetate) to afford the title compound (0.74 g, 68% yield) as an off-white solid. δH (250 MHz, DMSO) 8.14 (2H, d), 7.55 (2H, d), 3.89-3.69 (3H, m), 3.07-2.90 (2H, m), 2.04-1.89 (2H, m), 1.51-1.33 (10H, m).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[CH2:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:12]>C1(C)C=CC=CC=1.O>[CH2:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[N:28]=[N:29][C:30]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CC[C@H]1CC[C@H](CCc2ccc(-c3ccc(Cl)nn3)cc2)CC1
Reactant: CCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCOc1ccc(-c2ccc(CC[C@H]3CC[C@H](CC)CC3)cc2)nn1
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
A solution of n-heptanol (3.5 g) in toluene (50 ml) was dropwise added to a suspension of sodium hydride (about 55%) (1.5 g) in toluene (50 ml). The mixture was agitated for 30 minutes, dropwise adding a solution of 3-(4-(2-(trans-4-ethylcyclohexyl)ethyl)phenyl)-6-chloropyridazine (5 g) obtained above, in toluene (100 ml), heating the mixture under reflux for 3 hours. The reaction solution was poured in water. The resulting organic layer was washed with water until the organic layer became neutral. After drying it over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure and recrystallizing the residue from ethanol, the captioned 3-(4-(2-(trans-4-ethylcyclohexyl)ethyl)phenyl)-6-heptyloxypyridazine (3.7 g) was obtained. ##STR12##
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:21]([C:32](O)=[O:33])[C@H:22]([CH3:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[NH:20]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[C@@H:21]([C:32]([N:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:33])[C@H:22]([CH3:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 18 h
Yield: 72.7 %

Procedure:
0.959 g (2.0 mmole) of the 2HCl.H-Pro-Arg-CHA was dissolved in 8 ml of 0.75N NEM/DMF, to which was added 0.863 g (2.0 mmole) of BOC-D-Thr(OBzl)-SDP at0°-5° C., and the reaction was effected at room temperature for 18 hours, after which the reaction mixture was poured into 2000 ml of cold 1/1 solution of 10% citric acid/sat. aqueous Nacl. The precipitate was filtered out and dried, to obtain 1.07 g (72.7%) of BOC-D-Thr(OBzl)-Pro-Arg-CHA.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+].[CH3:22]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:22])[C:7](=[O:12])[N:6]([CH3:13])[CH:5]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CI
Reactant: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)N(C)C(c2ccccc2)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-Bromo-3-methyl-4-phenyl-3,4-dihydro-1H-quinazolin-2-one (0.2 g, 0.6 mmol) in DMF (10 mL) is cooled to 0° C., then NaH (16.7 mg, 0.7 mmol) is added. After the addition the mixture is stirred at 0° C. for 0.5 h. Then CH3I (107 mg, 0.76 mmol) is added and the mixture is stirred at r.t. for 2 h. Then H2O is added and is extracted with EtOAc, dried over Na2SO4 and concentrated to give product. This is used in the next step without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17]/[CH:18]=[CH:19]/[CH2:20][NH:21][CH2:22][CH2:23][CH2:24][NH2:25].[OH-:26].[Na+]>C(Cl)Cl>[S:7]([NH:25][CH2:24][CH2:23][CH2:22][N:21]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:20]/[CH:19]=[CH:18]/[CH2:17][N:16]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:15][CH2:14][CH2:13][NH:12][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:8])=[O:26])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [OH-]
Reactant: NCCCNC/C=C/CNCCCN
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NCCCN(C/C=C/CN(CCCNS(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 38.13 g (0.2 mol) of p-toluenesulfonic acid chloride in 300 ml of methylene chloride is added dropwise at room temperature, with stirring and under a nitrogen atmosphere, to a solution of 10.02 g (0.05 mol) of (E)-1,5,10,14-tetraazatetradec-7-ene in 100 ml (0.2 mol) of 2N sodium hydroxide solution. The reaction mixture is stirred for a further 2 h at room temperature, and then the organic phase is separated off and the aqueous phase is extracted with methylene chloride. The organic phases are combined, washed with water, dried over sodium sulfate and concentrated by evaporation. The residue is purified by means of flash chromatography over silica gel having a particle size of 0.04-0.063 mm, using ethyl acetate-hexane (1:1). Concentration of the product-containing fractions by evaporation yields the title compound in the form of an amorphous residue, Rf value=0.51 (silica gel/methylene chloride:methanol (50:1)).