Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12](CC#N)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:23]([OH:26])(=[O:25])[CH3:24]>O>[CH:9]1([C:7]([C:1]2[CH:2]=[CH:3][C:4]([CH2:24][C:23]([OH:26])=[O:25])=[CH:5][CH:6]=2)=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CC(=O)O
Reactant: N#CCc1ccc(C(=O)C2CCCCC2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(C(=O)C2CCCCC2)cc1

Procedure:
4-cyclohexylcarbonylphenylacetonitrile (1.5 g.), water (1.5 ml.), concentrated sulphuric acid (1.5 ml.) and acetic acid (1.5 ml.) were heated under reflux for 6 hours, cooled, poured into water and extracted with ether. Removal of the solvent and crystallisation from cyclohexane gave the acid, m.p. 94°-95.5°.
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:31]O>>[CH3:31][O:13][C:12](=[O:14])[C:11]1[CH:15]=[C:16]([S:17](=[O:20])(=[O:19])[NH2:18])[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:10]=1
Reactant: CO
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2)c1Oc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(N2CCCC2)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
36.2 g of 4-phenoxy-3-(1-pyrrolidinyl)-5-sulphamoylbenzoic acid are dissolved in 200 ml of methanol and 7 ml of concentrated H2SO4 and heated for 4 to 6 hours under reflux. Upon cooling, the ester crystallises. Recrystallisation from methanol; M.p. 191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[CH:12][C:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=3)[N:14]=2)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O.CC([O-])=O.[Na+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][C:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)[N:15]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH3:34])=[CH:30][CH:31]=3)[N:14]=2)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(-n2nc(C=C(C(=O)O)c3cccc(Cl)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-n2nc(CC(C(=O)O)c3cccc(Cl)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 100 °C
Yield: 23.1 %

Procedure:
To a solution of 2-(3-chloro-phenyl)-3-[5-(3,4-dichloro-phenyl)-1-(4-ethoxy-phenyl)-1H-pyrazol-3-yl]-acrylic acid (Example 108, Step B; 0.043 g, 0.084 mmol) in EtOH (5 mL) was added tosylhydrazine (0.22 g, 1.2 mmol). To the light yellow solution was added a mixture of NaOAc (0.098 g, 1.2 mmol) in H2O (1 mL). The resulting mixture was heated to 100° C. overnight, then cooled to rt, diluted with H2O (10 mL), and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (MgSO4) and then concentrated to provide a yellow oil. The oil was purified by preparative reversed-phase HPLC (acetonitrile/water) to afford the pure alkane as a colorless oil (10 mg, 23%). TLC (silica gel, 9:1 CH2Cl2/MeOH): Rf=0.43. HPLC: Rt=10.7 (Method A). MS (ESI): mass calculated for C26H21Cl3N2O3, 514.06; m/z found, 513 [M−H]−. 1H NMR (400 mHz, CDCl3): 7.32-7.23 (m, 6H), 7.14-7.10 (m, 2H), 6.92-6.89 (m, 1H), 6.88-6.85 (m, 2H), 6.23 (s, 1H), 4.03 (q, J=6.9 Hz, 2H), 4.04-4.00 (m, 1H), 3.50 (dd, J=6.7, 14.7 Hz, 1H), 3.09 (dd, J=8.7, 14.7 Hz, 1H), (1.42 (t, J=7.0 Hz, 3H),
Reaction SMILES: Cl.[OH:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7].C(N(CC)CC)C.[C:22]([C:24]1[CH:64]=[CH:63][C:27]([CH2:28][C@@:29]2([CH3:62])[N:33]3[C:34]([S:37](N4CCC[C@H]4C(N[C@H](C)C(O)=O)=O)(=[O:39])=[O:38])=[CH:35][N:36]=[C:32]3[N:31]([C:53]3[CH:58]=[C:57]([Cl:59])[CH:56]=[C:55]([Cl:60])[CH:54]=3)[C:30]2=[O:61])=[CH:26][CH:25]=1)#[N:23].CN(C=O)C>C(Cl)Cl>[OH:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[S:37]([C:34]1[N:33]2[C@@:29]([CH2:28][C:27]3[CH:63]=[CH:64][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)([CH3:62])[C:30](=[O:61])[N:31]([C:53]3[CH:54]=[C:55]([Cl:60])[CH:56]=[C:57]([Cl:59])[CH:58]=3)[C:32]2=[N:36][CH:35]=1)(=[O:38])=[O:39])=[O:7]
Reactant: CC(C)(O)CNC(=O)C1CCCN1
Reactant: C[C@@H](NC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1)C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)CNC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc2n1[C@](C)(Cc1ccc(C#N)cc1)C(=O)N2c1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
Pyrrolidine-2-carboxylic acid (2-hydroxy-2-methyl-propyl)-amide hydrochloride (0.241 g, 1.082 mmol) was dissolved in CH2Cl2 and triethylamine (0.206 mL, 1.513 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 10 min. (R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl chloride (see Example 5) (0.3 g, 0.605 mmol) in CH2Cl2 was added to the reaction mixture and stirred for 1 h. DMF (0.5 mL) was then added to the reaction mixture and stirred for another 30 min. The reaction solution was washed with 1N HCl and saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography using CH2Cl2-MeOH (10:1) as an eluent to afford 0.28 g of the title compound (M+1, 644.98).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1C(O)=O.CS(C)=O>O>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 27.5 h

Procedure:
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of dimethyl sulfoxide. The reaction mixture was then heated with stirring for 27.5 hr. at a bath temperature of 149° C. The flask was then allowed to cool to room temperature and the contents were poured into 500 mL of water, and extracted with 4×200 mL of ethyl acetate. The combined organic extracts were washed with water (2×200 mL), dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator followed by drying at the pump overnight. The crude product was then dissolved in 25 mL of ethyl acetate and introduced at the top of a silica column (4.5 cm ID×56 cm, flushed with hexane). The product was then eluted with 90:10 hexane:ethyl acetate under a slight nitrogen pressure, and the fractions (500 mL each) were monitored by gas chromatography. The fractions containing the product were combined, the solvent removed on a rotary evaporator, and then dried at the pump overnight to give 2,4,5-trifluorobenzoic acid as a light yellow solid. Recrystallization of the product from toluene (50 mL, ca. 60° C.) gave a white product (66.9% overall yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11]COC)[C:3]=1[C:4]([OH:6])=[O:5].Cl>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COCOc1cccc(Cl)c1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1c(O)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-chloro-6-{[(methyloxy)methyl]oxy}benzoic acid (for a preparation see Intermediate 4)(2 g, 9.23 mmol) in THF (20 ml) was added 6 M aqueous HCl (20 ml, 120 mmol). The solution was stirred at ambient temperature for 3 h. The solution was partitioned between ethyl acetate (150 ml) and water (30 ml). The phases were separated and the organic extract washed with water (25 ml). The organic extract was dried (MgSO4), filtered and the solvent removed in vacuo to give the title compound as a white solid (1.54 g); LCMS: (System 1) (M-H)−=171, tRET=3.26 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[CH:12][C:11]([CH2:14]CBr)=[C:6]([C:7]([O:9]C)=O)[CH:5]=1.CCN(CC)CC.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][CH2:32][CH2:33][NH2:34]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:14][N:34]([CH2:33][CH2:32][NH:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)[C:7]2=[O:9])=[O:17]
Reactant: NCCNc1ccccn1
Reactant: COC(=O)c1ccc(CCBr)c(C(=O)OC)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2
Temperature: 25 °C

Procedure:
A solution of (5) (511 mg, 1.78 mmol) in toluene (10 ml) was treated with Et3N (744 μl 5.33 mmol) and N1-pyridin-2-yl-ethane-1,2-diamine (244 mg, 1.78 mmol) [prepared by treatment of 2-bromopyridine with excess ethylene diamine and pyridine] and the mixture refluxed for 6 hours. After cooling to room temperature and evaporation of the solvent, the residue was purified by flash chromatography: silica, CH2Cl2/acetone (3:2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13](F)=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1.Cl.[CH3:21][NH:22][CH3:23].CCN(CC)CC>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[CH:15]=[CH:14][C:13]([N:22]([CH3:23])[CH3:21])=[N:12][C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: Fc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)c1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Yield: 84 %

Procedure:
Reaction of 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (see a previous experimental) (0.12 g, 0.38 mmol) with dimethylamine. hydrochloride (92 mg, 1.13 mmol) and Et3N (0.18 mL, 1.32 mmol) in EtOH (15 mL) at 100° C. for 18 h in a pressure vessel, followed by evaporation of the solvent and workup, gives 4-(3-bromoanilino)-7-(dimethylamino)pyrido[2,3-d]pyrimidine (0.11 g, 84%). 1H NMR (DMSO) δ 9.58 (1H, brs), 8.56 (1H, d, J=9.3 Hz) 8.54 (1H, s), 8.18 (1H, t, J=1.9 Hz), 7.84 (dt, Jd=8.0, Hz, J=1.9 Hz), 7.33 (1H, dd, J=8.1, 8.0 Hz) 7.25 (1H, dt, Jd=9.3, Hz, Jt=1.9 Hz), 7.10 (1H, d, J=9.3 Hz), 3.18 (6H, s).
Reaction SMILES: [OH:1][NH:2][CH:3]([C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:10][CH:9]=1)[CH3:7])[C:4]#[N:5].Cl.[NH2:25]O.C([O-])(=O)C.[Na+]>CCO>[F:22][C:20]([F:23])([F:21])[C:18]1[N:19]=[C:15]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([C@H:6]([C:3]3[C:4]([NH2:25])=[N:5][O:1][N:2]=3)[CH3:7])=[CH:13][CH:12]=2)[S:16][CH:17]=1
Reactant: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)C(C#N)NO
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1nonc1N
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of intermediate 13a (0.738 gr, 2.16 mmol), hydroxylamine hydrochloride (83 mg, 2.50 mmol) and sodium acetate (410 mg, 5 mmol) in EtOH (15 ml) was refluxed for 4 h. After cooling, the precipitate was collected by filtration and dried. The precipitated α-oximido-acetamidoxime sodium acetate derivative was refluxed with excess PCl5 in dry Et2O (15 ml) for 6 h. After cooling at room temperature the reaction was quenched with a buffered solution at pH 8.2 (10 ml) and the two phases separated. The aqueous layer was extracted with Et2O (2×10 ml) and the collected organic phases were dried over anhydrous Na2SO4 and evaporated under vacuum to give 4-[(1R)-1-{4-[(4-(trifluoromethyl)-1,3-thiazol-2-yl)amino]phenyl}ethyl]-1,2,5-oxadiazol-3-amine (0.57 g, 1.62 mmol) as a white solid (75%). 1H-NMR (DMSO-d6): δ 8.25 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.05 (s, 1H), 5.15 (bs, 2H, NH2), 3.90 (q, 1H, J=7 Hz), 1.75 (d, 3H, J=7 Hz).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1CCCCC1.S(=O)(=O)(O)O>O>[CH:13](=[C:11]([C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10])[OH:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Solvent: C1CCCCC1
Solvent: O
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=Cc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of 40.0 g of 70% sorbitol, 29.4 g of benzaldehyde and 520 ml of cyclohexane under nitrogen gas was added 0.3 ml of 96% sulfuric acid dropwise with stirring, then the mixture was heated to allow to condense while eliminating the generated water by azeotropic distillation. After about 7 hours' continuation of the reaction, the reaction mixture was cooled to room temperature and then neutralized. The precipitate was settled and washed with water by decantation, then filtered and rinsed several times with hot water, further finally dried to obtain the reaction product as white powder.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[H-].[Na+].B(OCC)(OCC)OCC.B([O-])([O-])O[CH2:24][CH:25]=[CH2:26]>CN(C)C=O>[CH2:26]([O:2][C:1]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[CH:25]=[CH2:24]
Reactant: Oc1cccc(O)c1O
Reactant: C=CCOB([O-])[O-]
Agent: CCOB(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(O)c1O
Reaction time: 3 h

Procedure:
A mixture of 3.8 g of pyrogallol, 76 ml of anhydrous dimethylformamide and 2.72 g of sodium hydride in suspension at 53% in oil was stirred for 3 hours under an inert gas atmosphere and then 5.27 ml of triethyl borate were added, followed by stirring for 30 minutes. Then, 2.6 ml of allyl borate in solution in 26 ml of dimethylformamide were added over 45 minutes and the mixture was stirred for 16 hours and poured into water-ice-N hydroohloric acid mixture. Extraction took place with ethyl acetate and the crude product was chromatographed on silica, eluting with a cyclohexane-ethyl acetate mixture (7-3) to obtain 3.8 g of the expected product in the form of white crystals (Yield: 76.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)cc1
Yield: 53 %

Procedure:
As described for Example 44, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.32 mmol), using 4-fluorobenzonitrile instead of 4-fluoroacetophenone, was converted to the title compound (70 mg, 53%) which was obtained as a white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7](=[O:8])[NH:6][CH2:5][CH2:4][N:3]1[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>>[C:33]([O:32][C:30]([CH2:29][N:6]1[CH2:5][CH2:4][N:3]([CH2:9][CH2:10][CH2:11][C:12]([O:14][CH:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[C:2](=[O:1])[C:7]1=[O:8])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C(CCCN1CCNC(=O)C1=O)OC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CN1CCN(CCCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)C1=O

Procedure:
With 1.30 g of diphenylmethyl 4-(2,3-dioxopiperazin-1-yl)butyrate was reacted 0.63 ml of tert-butyl bromoacetate by the same method as in Reference Example 12 to obtain 1.48 g of diphenylmethyl 4-(4-tert-butoxycarbonylmethyl-2,3-dioxopiperazin-1-yl)butyrate as a yellow oil.
Reaction SMILES: N1C=CC=CC=1.Cl.Cl.[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][N:18]=[CH:19][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH2:11][CH2:10]1.Cl.[C:31]([C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[C:40]([CH2:44][C:45](=[O:47])[NH2:46])=[C:39](O)[CH:38]=[CH:37]2)(=[NH:33])[NH2:32].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(C(C)=O)C.O.C(O)=O>[O:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][N:18]=[CH:19][NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([O:27][C:39]3[CH:38]=[CH:37][C:36]4[C:41](=[CH:42][CH:43]=[C:34]([C:31](=[NH:32])[NH2:33])[CH:35]=4)[C:40]=3[CH2:44][C:45](=[O:47])[NH2:46])=[O:26])=[CH:23][CH:22]=2)[CH2:11][CH2:10]1
Reactant: N=C(N)c1ccc2c(CC(N)=O)c(O)ccc2c1
Reactant: O=C(O)c1ccc(NC=NNCCN2CCOCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCC(C)=O
Solvent: c1ccncc1
Solvent: O=CO
Product: N=C(N)c1ccc2c(CC(N)=O)c(OC(=O)c3ccc(NC=NNCCN4CCOCC4)cc3)ccc2c1
Reaction time: 2 h
Yield: 49.4 %

Procedure:
30 Milliliters of 20% hydrous pyridine was added to 1.2 g of 4-[(2-morpholinoethyl)aminoiminomethylamino]benzoic acid.dihydrochloride, 1.72 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.06 g of DCC and 52.4 mg of DMAP, followed by stirring for 2 hours under cooling with ice and then 48 hours at room temperature. The precipitate was filtered and the filtrate was concentrated under reduced pressure. To the residue was added 15 ml of DMF, and the solution was added dropwise to 400 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain a crude product. Then, the product was subjected to silica gel column chromatography using methyl ethyl ketone-water-formic acid (80:15:5) as an eluent, and the desired fractions were collected and the solvent was distilled off under reduced pressure. To the residue were added 15 ml of methanol and 2.2 ml of concentrated hydrochloric acid, and the solution was added dropwise to 450 ml of acetone, followed by stirring for 15 minutes under cooling with ice. Then, the precipitate was collected by filtration to obtain 840 mg of the desired product.
Reaction SMILES: [NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18](O)=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].C1C=CC2N(O)N=NC=2C=1.[NH2:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.O>[NH:1]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:2]([C:6]([NH:8][C@H:9]([C:18]([NH:41][C@H:42]([C:55]([O:57][CH3:58])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
13.8 g of Z-Val-Tyr-OH [R. Schwyzer et al., Helv. Chim. acta. 41, 1273 (1958)] and 5.1 g of HOBt×H2O are dissolved in 100 ml of DMF and there is added thereto the above solution of H-Lys(Boc)-OMe in a small amount of DMF. The whole is cooled to 0°, 7.6 g of DCCI are added and the whole is stirred for 6 hours at 0° and for 10 hours at room temperature. The DCH which has separated out is filtered off and the filtrate is concentrated to dryness. Purification is carried out by triturating with diisopropyl ether and by dissolving and reprecipitating from trifluoroethanol/ethyl acetate/petroleum ether, yielding Z-Val-Tyr-Lys(Boc)-OMe; Rf (F)=0.39.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([OH:3])=[O:2].[NH2:14][C:15]1[C:16](=[O:29])[N:17]([CH2:26][CH2:27][CH3:28])[C:18](=[O:25])[N:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[NH2:21]>CO.C(O)(=O)C>[NH2:21][C:20]1[N:19]([CH2:22][CH2:23][CH3:24])[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH3:28])[C:16](=[O:29])[C:15]=1[N:14]=[CH:10][C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C:1]([OH:3])=[O:2])=[CH:7][CH:8]=1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Reactant: O=Cc1ccc(OCC(=O)O)cc1
Solvent: CO
Solvent: CC(=O)O
Product: CCCn1c(N)c(N=Cc2ccc(OCC(=O)O)cc2)c(=O)n(CCC)c1=O

Procedure:
A representative synthesis of benzylidene adduct is given. Compound A (1.51 g, 8.37 mmol) was dissolved in a mixture of methanol (35 ml) and acetic acid (5 ml) in a 50 ml boiling flask on a steam bath. To this was added a methanolic solution (60 ml) of freshly synthesized 5,6-diamino-1,3-dipropyluracil. After heating 15 minutes, the volume was reduced by evaporation until crystallization occurred. Ether (40 ml) was added and the nearly white solid was collected. Yield 2.80 g (86%), mp 179°-180° C. Analysis (C19H24N4O5): calc. 58.60% C, 6.21% H, 14.39% N; found 58.72% C, 6.16% H, 14.43% N.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]3[C:21](=[CH:22][C:23](B4OC(C)(C)C(C)(C)O4)=[CH:24][CH:25]=3)[C:20]([CH3:37])([CH3:36])[NH:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[C:26]3[C:21](=[CH:22][C:23]([C:5]4[N:4]=[N:3][C:2]([NH2:1])=[CH:7][CH:6]=4)=[CH:24][CH:25]=3)[C:20]([CH3:37])([CH3:36])[NH:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: CC1(C)NCC(c2ccc(Cl)c(Cl)c2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: Nc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC1(C)NCC(c2ccc(Cl)c(Cl)c2)c2ccc(-c3ccc(N)nn3)cc21
Temperature: 90 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
3-amino-6-chloropyridazine (420 mg, 3.23 mmol) was added to a mixture of 4-(3,4-dichlorophenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (700 mg, 1.68 mmol) which was prepared in Step D of Example 10, cesium carbonate (1.58 g, 4.85 mmol) in DMF (50 mL) and water (10 mL). The reaction mixture was deoxygenated with argon. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (66 mg, 0.081 mmol) was added and the reaction mixture was stirred at 90° C. for 1 hour, cooled, diluted with water, and extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash column chromatography (0 to 100% 90:9:1 dichloromethane/methanol/concentrated ammonium hydroxide solution in dichloromethane) gave 4-(3,4-dichlorophenyl)-7-(6-aminopyridazin-3-yl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline (387 mg, 60% over 2 steps): 1H NMR (CDCl3, 500 MHz) 1H NMR (CDCl3, 500 MHz) δ 8.01 (d, J=2.0 Hz, 1H), 7.64-7.54 (m, 2H), 7.37 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.98-6.90 (m, 2H), 6.82 (d, J=9.0 Hz, 1H), 4.74 (s, 2H), 4.07 (t, J=5.5 Hz, 1H), 3.45 (dd, J=13.0, 5.5 Hz, 1H), 3.10 (dd, J=13.0, 5.5 Hz, 1H), 1.64 (s, 3H), 1.60 (s, 3H); ESI MS m/z 399 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:16]4([CH3:23])[NH:21][C:20](=O)[CH2:19][O:18][CH2:17]4)[CH:13]=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:24]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:16]4([CH3:23])[NH:21][C:20](=[S:34])[CH2:19][O:18][CH2:17]4)[CH:13]=[CH:14][CH:15]=3)[NH:7][C:6]=2[CH:24]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cccc(-c3nc4ccc(Cl)cc4[nH]3)c2)COCC(=O)N1
Product: CC1(c2cccc(-c3nc4ccc(Cl)cc4[nH]3)c2)COCC(=S)N1
Yield: 98 %

Procedure:
In close analogy to the procedure described for the preparation of Intermediate XVIII-1, the reaction of 5-[3-(6-chloro-1H-benzoimidazol-2-yl)-phenyl]-5-methyl-morpholin-3-one (202 mg, 0.6 mmol) with Lawesson's reagent yielded the title compound (210 mg, 98% of theory).