Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=O.C[N:23](C)C=C(C1C=CN=CC=1)C(C1C=CC(F)=CC=1)=O>>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=3)=[CH:3][NH:2][N:23]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccnc(F)c1
Reactant: CN(C)C=C(C(=O)c1ccc(F)cc1)c1ccncc1
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(F)c2)cc1
Yield: 88 %

Procedure:
The reaction was carried out in the same manner as in Example 1-2) except for using 4.17 g (14.5 mmol) of 3-dimethylamino-1-(4-fluorophenyl)-2-(2-fluoropyridin-4-yl)-2-propen-1-one obtained in Example 17-1) in place of 3-dimethylamino-1-(4-fluorophenyl)-2-(pyridin-4-yl)-2-propen-1-one to obtain 3.28 g of the title compound as a white powder. (Yield: 88%)
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6](Cl)=[O:7])=[O:4].[F-:10].[K+].C1OCCOCCOCCOCCOCCOC1>ClCCl>[Cl:1][CH2:2][C:3]([N:5]([CH3:9])[C:6]([F:10])=[O:7])=[O:4]
Reactant: CN(C(=O)Cl)C(=O)CCl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: ClCCl
Product: CN(C(=O)F)C(=O)CCl
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 10.0 g of N-Chloroacetyl-N-methylcarbamoyl chloride, 3.8 g of anhydrous potassium fluoride and 0.5 g of 18-crown-6 in 50 cc of dichloromethane was stirred at room temperature under nitrogen for about 16 hours. The liquid was decanted and the residue was extracted with 50 cc dichlormethane. The dichloromethane layers were combined and the solvent stripped off to afford 9.0 g. (Yield 100%) of N-chloroacetyl-N-methylcarbamoyl fluoride. The product was further purified by distillation under reduced pressure. B.p. 59° C./0.2 mm.
Reaction SMILES: BrBr.O=C1C2C=CC=CC=2N(C([C:17]2[CH:35]=[CH:34][C:20]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH:30]([CH3:32])[CH3:31])=[CH:19][CH:18]=2)=O)CCC1.O>C(Cl)(Cl)Cl>[CH:30]([O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:20]1[CH:19]=[CH:18][CH:17]=[CH:35][CH:34]=1)=[O:33])([CH3:32])[CH3:31]
Reactant: CC(C)Oc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1
Agent: BrBr
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccccc1C(=O)Nc1ccccc1
Reaction time: 20 h

Procedure:
A 1.32 g portion of bromine dissolved in 6.6 ml of chloroform was dropwise added gradually (spending about 60 minutes) to 36 ml of chloroform solution containing 3.55 g of 4'-[(5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-2-isopropoxybenzanilide at room temperature. When disappearance of the color of bromine was confirmed, the reaction solution was washed with a saturated sodium bicarbonate aqueous solution. The resulting organic layer was dried over anhydrous magnesium sulfate, concentrated under a reduced pressure and then evaporated to dryness using a vacuum pump. The thus obtained solid substance was dissolved in 40 ml of chloroform, and the resulting solution was mixed with 5.0 g of cyclopropylcarbamidine hydrochloride and 8.02 g of potassium carbonate and subjected to 20 hours of heating under reflux in a stream of argon. The resulting reaction solution was mixed with water to effect phase separation, and the separated organic layer was dried over anhydrous magnesium sulfate. After removing the solvent by distillation under a reduced pressure, the thus obtained residue was crystallized from toluene to obtain 2.96 g of 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazol4,5-d][1]benzazepin-6-yl)carbonyl]-2-isopropoxybenzanilide. A 1.08 g portion of this compound was dissolved in 20 ml of ethyl alcohol, mixed with 0.8 ml of 4N hydrochloric acid-ethyl acetate and recrystallized to obtain 916 mg of 4'-[(2-cyclopropyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)carbonyl]-2-isopropoxybenzanilide hydrochloride.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([O:9][CH3:10])=[O:8].[N:11]([O-])=[O:12].[Na+].C(O)(=O)C>O.C(OCC)(=O)C>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([N:11]=[O:12])[C@@H:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@@H]1[C@@H](O)CCN1N=O
Reaction time: 4 h

Procedure:
To a solution of (2S,3S)-methyl 3-hydroxypyrrolidine-2-carboxylate (16 g, 0.110 moles) in water (60 mL) was added NaNO2 (16 g, 0.220 moles) in water (30 mL) followed by the addition of glacial acetic acid (9.43 mL, 0.165 moles) at 0° C. and the reaction mixture was stirred for 4 h. Once the starting material had disappeared (monitored by TLC), the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4 and concentrated to get the title compound which was used in the next step without purification.
Reaction SMILES: [Li+].[Br-].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Cl)[CH:17]=2)[C:12]2([CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br-].[CH2:27]([Zn+])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN1C(=O)CCC1.C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:17]=2)[C:12]2([CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [Zn+]Cc1ccccc1
Reactant: CC(=O)N1CC2(C1)CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CC2(C1)CN(C(=O)OC(C)(C)C)c1cc(Cc3ccccc3)ccc12
Reaction time: 4 h
Yield: 175.7 %

Procedure:
(1,3-Diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (2 mg, 10 mol %) and LiBr (41 mg, 0.47 mmol) were dissolved in dry NMP and the solution was degassed with N2 for 5 minutes. Then 1-acetyl-6′-chloro-1′,2′-dihydrospiro[azetidine-3,3′-indole]-1′-yl-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol) and benzylzinc bromide (0.5M solution in toluene, 950 μL, 0.475 mmol) were added. The reaction mixture was stirred under N2 for 4 h. A second aliquot of catalyst (2 mg) and benzylzinc bromide (950 μL) were added and stirring maintained for 4 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The crude material was purified by column chromatography (EtOAc:petrol 1:1 to EtOAc 100%) to give the title compound (200 mg) as a pale yellow oil (ca. 50% pure by NMR, contaminated with NMP), used without further purification. MS: [M+H]+=393.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([O:17][C:18]1[CH:28]=[CH:27][C:21]([CH:22]=[CH:23][C:24](O)=O)=[CH:20][CH:19]=1)[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:28]=[CH:27][C:21](/[CH:22]=[CH:23]/[C:24]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=3[N:8]=2)=[CH:20][CH:19]=1)[CH3:16]
Reactant: CCOc1ccc(C=CC(=O)O)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CC)c(=O)n3CC)cc1
Yield: 55.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.20 g (16.7 mmol) of 4-ethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.97 g (yield 55%) of Compound 98 as pale yellow needles.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C:21]4[C:16](=[C:17]([N+:22]([O-])=O)[CH:18]=[CH:19][CH:20]=4)[C:15]([CH3:25])=[N:14]3)[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C:21]4[CH:20]=[CH:19][CH:18]=[C:17]([NH2:22])[C:16]=4[C:15]([CH3:25])=[N:14]3)[CH:9]=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nn(Cc2cccc(C3CCCC3)n2)c2cccc([N+](=O)[O-])c12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(Cc2cccc(C3CCCC3)n2)c2cccc(N)c12
Reaction time: 2 h

Procedure:
1-((6-cyclopentylpyridin-2-yl)methyl)-3-methyl-4-nitro-1H-indazole (0.470 g, 1.40 mmol) was dissolved in 14 mL of methanol. To this solution was added 20% Pd(OH)2 (0.470 g, 50% water content) and the reaction mixture was stirred under a hydrogen balloon for 2 hours. This mixture was filtered through GF/F filter paper and the filtrate was concentrated to 0.340 g (79%) of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][C:6]1[N:7]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[S:35](=[O:38])(=[O:37])[NH2:36])=[CH:25][CH:24]=2)[C:8](=[O:21])[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:10]=1.[C:39](O)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[C:39]([NH:36][S:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:7]2[C:6]([CH2:5][CH:3]3[CH2:4][CH:2]3[CH3:1])=[N:10][N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:17]([F:18])([F:20])[F:19])[C:8]2=[O:21])=[CH:28][CH:27]=1)(=[O:38])=[O:37])(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: O=C(O)c1ccccc1
Reactant: CC1CC1Cc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Product: CC1CC1Cc1nn(-c2ccccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from 2,4-dihydro-5-[(2-methylcyclopropyl)methyl]-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-2-[2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step G) and benzoic acid according to the procedure of Example 43. The crude material was purified by flash chromatography over silica gel (gradient elution using 0.5-5.0% MeOH/CH2Cl2) to give a 64% of the desired material as a white solid, homogeneous by TLC (5% MeOH/CH2Cl2); mass spectrum (FAB) m/e 647 (M+1)+ ; mp 123°-125° C.
Reaction SMILES: [NH2:1][C@@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:3]1=[O:24].[C:25]([C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][C:33]1([C:41](=[O:42])[NH:40][C:39](=[O:43])[NH:38]1)[CH2:32][CH2:31]2)(O)=[O:26].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:43]=[C:39]1[NH:38][C:33]2([CH2:32][CH2:31][C:30]3[C:35](=[CH:36][CH:37]=[C:28]([C:25]([NH:1][C@@H:2]4[N:8]=[C:7]([C:9]5[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=5)[C:6]5[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=5[N:4]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:3]4=[O:24])=[O:26])[CH:29]=3)[CH2:34]2)[C:41](=[O:42])[NH:40]1
Reactant: N[C@@H]1N=C(c2ccccc2)c2ccccc2N(CC(F)(F)F)C1=O
Reactant: O=C1NC(=O)C2(CCc3cc(C(=O)O)ccc3C2)N1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NC(=O)C2(CCc3cc(C(=O)N[C@@H]4N=C(c5ccccc5)c5ccccc5N(CC(F)(F)F)C4=O)ccc3C2)N1

Procedure:
A mixture of (3R)-3-amino-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-1,4-benzodiazepine (Shi et al. Tetrahedron 1999, 55, 909) (507 mg, 1.52 mmol), (±)-6′-carboxy-3′,4′-dihydro-1′H-spiro[imidazolidine-4,2′-naphthalene]-2,5-dione (described in Intermediate 1) (396 mg, 1.52 mmol), EDC (438 mg, 2.28 mmol), HOBT (308 mg, 2.01 mmol), and N,N-diisopropylethylamine (0.795 mL, 4.56 mmol) was stirred in DMF (5 mL) at ambient temperature for 18 h. The crude mixture was partitioned between saturated aqueous NaHCO3 (25 mL) and CH2Cl2 (25 mL), and the aqueous phase was extracted further with CH2Cl2 (2×25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:MeOH—100:0 to 95:5 to provide the title compound as an off-white solid. MS: m/z=576 (M+1). HRMS: m/z=576.1840; calculated m/z=576.1853 for C30H24F3N5 O4.
Reaction SMILES: [C:1]([C:5]1([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1>CN(C)C=O>[C:1]([C:5]([OH:6])([CH2:7][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1nc[nH]n1
Reactant: CC(C)(C)C1(COC2CCCCO2)CO1
Solvent: CN(C)C=O
Product: CC(C)(C)C(O)(COC1CCCCO1)Cn1cncn1
Temperature: 80 °C
Reaction time: 6 h
Yield: 50.5 %

Procedure:
A solution of 160 g (0.75 mol) of 2-tert.-butyl-2-(tetrahydro-2H-pyran-2-yloxymethyl)-oxirane in 180 ml of absolute dimethylformamide is added dropwise to a mixture of 168 g (2.45 mols) of 1,2,4-triazole, 18.2 g (0.16 mol) of potassium tert.-butylate and 350 ml of absolute dimethylformamide at 80° C. under a nitrogen atmosphere. The reaction mixture is stirred at 80° C. for 6 hours and is then concentrated by stripping off the diluent under reduced pressure. The residue which remains is taken up in ethyl acetate and the organic solution formed is washed with water and then dried over sodium sulphate, and concentrated by stripping off the solvent under reduced pressure. The product thus obtained is purified chromatographically over silica gel with chloroform as the mobile phase. 107.3 g (51% of theory) of 2-tert.-butyl-1-(tetrahydro-2H-pyran-2-yl-oxy)-3-(1,2,4-triazol-1-yl)-propan-2-ol (mixture of diastereomers) are obtained in this manner.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]2[CH2:16][NH:17][C@@H:10]1[C@H:11]([O:14]2)[O:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>CCOCC>[CH2:1]([O:8][C@H:9]1[C@H:15]2[CH2:16][N:17]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C@@H:10]1[C@H:11]([O:14]2)[O:12][CH3:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@@H]2CN[C@H]1[C@H]2OCc1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CO[C@H]1O[C@@H]2CN(C(=O)OCc3ccccc3)[C@H]1[C@H]2OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.1 %

Procedure:
Methyl 3-O-benzyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside (13α) (870 mg, 3.70 mmol) was stirred with a 3:2 mixture of ether and saturated aqueous sodium bicarbonate (60 ml). Benzyl chloroformate (1.57 ml, 11.1 mmol) was added to the mixture which was stirred at room temperature for 12 hours. The ether layer was separated and the aqueous phase further extracted with ether (4×25 ml). The combined extracts were dried, filtered and the solvent removed. Purification by flash chromatography (ether-hexane 1:10-1:3) afforded methyl 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-α-D-lyxofuranoside (1.04 g, 76%) as a white crystalline solid, m.p. 74°-75° C., Rf 0.2 (ether-hexane 1:3); [α]20D +12.0° (c, 0.98 in chloroform); νmax (chloroform) 2940, 1695 (C=O), 1420, 1260, 1230, 1090 and 750 cm-1 ; 1H NMR δ 3.38, 3.41 (3H, 2× s, CH3); 3.3-3.7 (2H, m, 5,5'-H); 4.05-4.90 (5H, m, H-3, H-2, H-4, CH2Ph); 5.12-5.20 (3H, m, H-1, CH2 -Z); 7.2-7.4 (10H, m, 2×H-Ph). 13C NMR δ 50.71 (t, C-5); 55.15, 55.33 (2×q, Me); 59.63, 60.17 (2×d, C-2); 66.95, 67.08 (2×t, CH2 -Z); 72.28 (t, CH2Ph); 75.09, 75.49, 77.93, 78.48 (4×d, C-3, C-4); 105.67, 105.90 (d, C-1); 127.83, 127.92, 128.15, 128.64 (4×d, HC-Ph); 136.68, 137.46 (2×s, C-Ph); 155.68, 155.81 (2×s, C=O). m/z: 91 (100%), 108 (25%), 158 (20%), 370 (M+H+, 10%). (Found C, 67.98; H, 6.39; N, 3.60. C21H23NO5 requires C, 68.28; H, 6.28; N, 3.79). Methyl 3-O-benzyl-2,5-dideoxy-2,5-imino-β-D-lyxofuranoside (13β) (829 mg, 3.53 mmol) was treated likewise giving methyl 3-O-benzyl-N-benzyloxycarbonyl-2,5-dideoxy-2,5-imino-β-D-lyxofuranoside (1.18 g, 90%) as a clear oil, Rf 0.35 (ether-hexane 1:3); [α]20D -75.2° (c, 0.83 in chloroform); νmax (film) 2930, 1705 (C=O), 1425, 1275, 1255, 1105 and 750 cm-1 ; 1H NMR δ 3.36, 3.42 (3H, 2×s, CH3); 3.50 (1H, 2×d 5-H); 3.67 (1H, 2×d, H-5'); 4.02-4.06 (1H, m, H-3); 4.29 (1H, bs, H-2); 4.49, 4.54 (1H, bs and dd, H-4); 4.52-4.65 (2H, m, CH2Ph); 5.0-5.2 (2H, 2×dd, CH2Ph); 5.21 (1H, s, H-1); 7.28-7.38 (10H, m, H-Ph). 13C NMR δ 50.02 (t, C-5); 55.70, 55.89 (2×q, Me); 60.17, 59.52 (2×d, C-2); 66.79 (t, CH2 -Z); 72.00, 72.10 (t, CH2Ph); 77.56, 78.08, 78.52, 79.18 (4×d, C-3, C-4); 104.71, 105.11 (2×d, C-1); 128.79, 127.96, 128.33, 128.61, 128.78 (5×d, HC-Ph); 137.09, 137.22 (2×s, C-Ph); 156.20, 156.45 (2×s, C=O). m/z: 91 (100%), 370 (M+H+, 60%), 202 (30%). (Found C, 68.08; H, 6.39; N, 3.40. C21H 23 NO5 requires C, 68.28; H, 6.28; N, 3.79).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1Br.C(N)C1C=CC=CC=1.O.C[C:33]([N:35](C)[CH3:36])=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[N:14]=2)=[N:6][C:7]=1[N:35]([CH3:36])[CH3:33]
Reactant: Cn1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(=O)N(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: NCc1ccccc1
Product: CN(C)c1nc(-c2ccc(=O)n(C)n2)c(-c2ccccc2)nc1N
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-methyl-3(2H)-pyridazinone (150 mg) and benzylamine (0.138 ml) in DMA (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (4 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel. By elution with a mixture of n-hexane and EtOAc (60:40 v/v) was obtained 6-[5-amino-6-(dimethylamino)-3-phenyl-2-pyrazinyl]-2-methyl-3(2H)-pyridazinone as a solid (83 mg) and by elution with a mixture of n-hexane and EtOAc (20:80 v/v) was obtained 6-[5-amino-6-(benzylamino)-3-phenyl-2-pyrazinyl]-2-methyl-3(2H)-pyridazinone as a solid (48 mg).
Reaction SMILES: CC1(C)C2C=C(C#CC3C=CC=CC=3C(O)=O)C=CC=2C(C2C=CC=CC=2)=CC1.[CH3:30][C:31]1([CH3:59])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([O:49]CC)=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[CH:33][CH2:32]1>>[CH3:30][C:31]1([CH3:59])[C:40]2[CH:39]=[C:38]([C:41]#[C:42][C:43]3[CH:53]=[CH:52][C:46]([C:47]([OH:49])=[O:48])=[CH:45][CH:44]=3)[CH:37]=[CH:36][C:35]=2[C:34]([C:54]2[S:55][CH:56]=[CH:57][N:58]=2)=[CH:33][CH2:32]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3c2nccs2)cc1
Agent: CC1(C)CC=C(c2ccccc2)c2ccc(C#Cc3ccccc3C(=O)O)cc21
Product: CC1(C)CC=C(c2nccs2)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-phenylnaphth-2-yl)ethynyl]benzoic acid (Compound 97), 177 mg (0.43 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-thiazolyl)naphth-2-yl)ethynyl]benzoate (Compound 88) was converted to the title compound (white solid) using 91 mg (4.3 ml, 2.14 mmol) of LiOH (0.5M aqueous solution).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[CH:5]=[C:6]([CH:12]=1)[O:7][CH2:8][CH2:9][CH:10]=[O:11]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Sulfur trioxide pyridine complex (1.12 mg, 7.0 mmol) was added to a solution of 3-[5-methyl-3-(2-nitrophenylsulfonyloxy)phenoxy]propanol (920 mg, 2.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a pale yellow oil (780 mg, 85%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.85 (m, 2H), 7.70 (m, 1H), 6.64 (s, 2H), 6.57 (s, 1H), 4.22 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.0 Hz, 2H), 2.27 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>ClCCl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(Br)c(C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COc1ccc(Br)c(CBr)c1
Reaction time: 4 h
Yield: 72.1 %

Procedure:
To a stirred solution of 4-bromo-3-methylanisole (100 g, 497 mmol) in dry dichloromethane (500 mL) was added N-bromosuccinimide (97 g, 545 mmol) followed by benzoyl peroxide (6 g, 25 mmol). The reaction was gently refluxed with a 150 watt flood lamp with reflector placed approximately 12 inches from the reaction flask. After 24 h the reaction was concentrated by rotary evaporation to half its volume and allowed to sit for 4 h. The white precipitate which formed was filtered off and rinsed with a small volume of dichloromethane. The filtrate was concentrated to dryness and the remaining solid was triturated with hexanes and filtered. Drying under vacuum gave the title compound (100.25 g, 72%) as white needles: GC tR=6.56 min (HP 530 μm×20 m methylsilicone column, He carrier flow 20 mL/min, 100° C. initial temp., 1 min initial time, 10° C./min rate, 200° C. final temp., 1 min final time); 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J=10 Hz, 1 H), 6.99 (d, J=3 Hz, 1 H), 6.73 (dd, 1H), 4.55 (s, 2H), 3.80 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([CH2:5][OH:6])[CH2:3][NH2:4].[O:7]=[C:8]1[C:13]2[CH:14]=[CH:15]O[C:12]=2[CH2:11][CH2:10][CH2:9]1>C(O)C>[O:7]=[C:8]1[CH2:9][CH2:10][CH2:11][C:12]2[N:4]([CH2:3][CH:2]([OH:1])[CH2:5][OH:6])[CH:15]=[CH:14][C:13]1=2
Reactant: O=C1CCCc2occc21
Reactant: NCC(O)CO
Solvent: CCO
Product: O=C1CCCc2c1ccn2CC(O)CO
Temperature: 150 °C

Procedure:
9.4 g of 2,3-dihydroxypropylamine were added to a solution of 13.6 g of 4-oxo-4,5,6,7-tetrahydrobenzofuran in 200 cm3 of ethanol. The reaction medium was heated at 150° C. for 9 hours. After evaporation of the solvent and purification of the crude product on silica gel (ethyl acetate/methanol=9/1 ), 11.2 g of 4-oxo-4,5,6,7-tetrahydro-1-N-(β,γ-dihydroxypropyl)indole were recovered in the form of an oil.