Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:20]O>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:20])=[O:8]
Reactant: CO
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Yield: 35 %

Procedure:
A solution of crude 5-chloro-2-methyl-3-nitrobenzoic acid (13.2 g) in dry methanol (100 mL) was cooled to 0° C. (3 mL) was added conc. H2SO4 dropwise. After the addition, the mixture was heated to reflux for 16 hr. After removal of solvents under reduced pressure, the crude product was purified by silica gel chromatography (petroleum ether to petroleum ether/EtOAc=50:1) to give the title compound (6.3 g, yield 35% for two steps) as a white solid. LC-MS (ESI) m/z: 230 (M+1)+, 231 (M+2)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.59 (s, 3H), 3.95 (s, 3H), 7.84-7.85 (d, 1H), 7.98-7.99 (d, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N.B.Cl>CCOCC>[OH:10][CH:9]([C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:18][CH:17]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CC(=O)c1ccc(OC(C)=O)cc1
Agent: B
Agent: Cl
Agent: N
Solvent: CCOCC
Product: CCOC(=O)CC(O)c1ccc(OC(C)=O)cc1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
A 250 ml round bottom flask was charged with 11.25 grams (0.045 mol.) of ethyl 4-acetoxy-benzoylacetate and 150 ml of diethyl ether. The solution was stirred and ammonia-borane (1.39 gm., 0.045 mol., Alfa) was added in 4 portions. After being stirred 90 minutes at room temperature 50 ml of ether were added and the reaction mixture was slowly poured into a 400 ml beaker containing 20 ml of 3 N HCl and 100 ml of crushed ice. After 15 minutes the organic phase was separated. The aqueous phase was extracted with ether (2×100 ml). The combined organic phase was washed with brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography, using a 7 cm. diameter column of 250 grams silica gel, packed and eluted with 25% ethyl acetate/petroleum ether. 6.53 grams of ethyl 3-hydroxy-3-(4-acetoxyphenyl)propionate was obtained. The product was identical to that obtained by method A as determined by NMR and elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][F:37]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:33][CH2:34][CH2:35][CH2:36][F:37])=[CH:22][CH:23]=1)(=[O:17])=[O:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: FCCCCBr
Reactant: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCF)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 1 g (2.74 mmol) of [(4-hydroxy-benzenesulfonyl)-(4-methoxy-benzyl)-amino]-acetic acid methyl ester and 1.14 g (8.22 mmol) of K2CO3 in 8 ml of DMF, 0.59 ml (5.47 mmol) of 1-bromo-4-fluorobutane is added dropwise at r.t. After stirring for 18 h at r.t., the reaction mixture is diluted with H2O and extracted with AcOEt. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (AcOEt:n-hexane=3:1) to give {[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)-amino}-acetic acid methyl ester; NMR (CDCl3): 1.86–1.96 (m, 4H), 3.57 (s, 3H), 3.79 (s, 3H), 3.90 (s, 2H), 4.08 (t, 2H, J=6.04 Hz), 4.39 (s, 2H), 4.46 (t, 1H, J=6.04 Hz), 4.55–4.65 (m, 1H), 6.83 (d, 2H, J=8.56 Hz), 6.97 (d, 2H, J=9.08 Hz), 7.15 (d, 2H, J=8.56 Hz), 7.82 (d, 2H, J=9.08 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C:16]([C:21]1[N:26]=[N:25][C:24]([S:27][CH3:28])=[N:23][C:22]=1Cl)([O:18][CH2:19][CH3:20])=[O:17].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:22]3[N:23]=[C:24]([S:27][CH3:28])[N:25]=[N:26][C:21]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CCOC(=O)c1nnc(SC)nc1Cl
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nnc(SC)nc1Nc1ccc2[nH]cc(CCN(C)C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 6-carbethoxy-5-chloro-3-methylthio-1,2,4-triazine [Pesson, M. et al., Eur. J. Med. Chem., 269 (1972)] were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Chromatography afforded the title compound (53%) as an orange solid: mp, 197.0°-199.0° C. with effervescence; 13C NMR (DMSO-d6) δ173.2, 165.5, 150.5, 133.9, 132.5, 127.7, 127.1, 123.9, 116.8, 113.0, 112.2, 111.5, 62.0, 60.0, 45.2, 23.1, 14.0, 13.2; LRMS (m/z, relative intensity) 400 (M30 , 11 ), 386 (5), 195 (11), 163(13), 58 (100). Anal. calcd. for C19H24N6O2S.0.3 H2O: C, 56.22 ; H, 6.11; N, 20.70. Found: C, 55.50; H, 5.89; N, 20.33.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](=O)[CH2:6]Br.[NH2:12][C:13]([NH2:15])=[O:14].C([O-])(=O)C.[NH4+].C(O)(=O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[NH:12][C:13](=[O:14])[NH:15][CH:6]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: NC(N)=O
Reactant: O=C(CBr)c1cccc(Br)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]cc(-c2cccc(Br)c2)[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 3-bromophenacyl bromide (0.5 g, 1.8 mmol), urea (0.32 g, 5.3 mmol), and ammonium acetate (0.40 g, 5.4 mmol) in water (10 mL) was added glacial acetic acid (0.32 g, 5.4 mmol). The reaction mixture was heated at reflux overnight. After cooling to room temperature, the mixture was extracted with three portions of ethyl acetate, and the combined extracts were dried (magnesium sulfate) and concentrated under reduced pressure to give a brown residue which was triturated with diethyl ether to afford the desired product. LC/MS 238.9 and 240.9 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][NH:29][CH2:28]1.Cl.C(N=C=NCCCN(C)C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[CH3:25][N:26]([CH3:32])[C@H:27]1[CH2:31][CH2:30][N:29]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:21])[CH2:28]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CN(C)[C@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CC[C@H](N(C)C)C3)cn2)c1O
Reaction time: 8 h
Yield: 46.2 %

Procedure:
Combined 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (50.0 mg, 0.156 mmol), (S)—N,N-dimethylpyrrolidin-3-amine (26.7 mg, 0.234 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (44.9 mg, 0.234 mmol) in DMF (1561 μl). HOBT (35.9 mg, 0.234 mmol) and DIPEA (136 μl, 0.781 mmol) were added. The reaction was allowed to stir overnight. Then 1N aqueous hydrochloric acid (21 ML) was added and reaction mixture was then purified using preparative HPLC eluting with 0.1% formic acid in water and 5-30% acetonitrile to give the title compound (30 mg, 0.072 mmol, 46.1%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78-1.88 (m, 1H) 2.24 (br. s., 3H) 2.36 (br. s., 3H) 2.42 (s, 3H) 2.88-3.05 (m, 2H) 3.59-3.81 (m, 4H) 7.58 (d, J=7.83 Hz, 1H) 7.64 (s, 1H) 7.95 (d, J=7.83 Hz, 1H) 8.01 (s, 1H) 8.11 (d, J=9.09 Hz, 1H) 8.43 (d, J=8.84 Hz, 1H) 8.62 (s, 1H); ESI-MS m/z (M+H)+ calc'd for C23H24N6O2, 417.20. found 417.5.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7](Cl)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>O>[NH2:2][C:3]1[CH:8]=[C:7]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[O-:11]
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)cc(N)[n+]1[O-]
Agent: Cl
Solvent: O
Product: Cc1cc(N2CCCC2)cc(N)[n+]1[O-]
Temperature: 155 °C
Yield: 51 %

Procedure:
A quantity (1.95 g., 0.01 mole) of 2-amino-4-chloro-6-methylpyridine-1-oxide hydrochloride (prepared in Part B, Example 1, above) with 10 ml. pyrrolidine and 10 ml. water was sealed in a reinforced bottle and heated in an oil bath at the temperature 155° C. for 5 hrs. After cooling, this reaction mixture was diluted with water and extracted with three 50-ml. portions of methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate, treated with charcoal, and filtered. The methylene chloride was removed from the filtrate by evaporation under reduced pressure, and the residue thus obtained was triturated with acetone and collected on a filter. The solids on the filter were crystallized from about 400 ml. acetonitrile. There was thus obtained 0.98 g. (51% yield) of 2-amino-6-methyl-4-pyrrolidinylpyridine-1-oxide as fine white needles having a melting point at 282° C. (with decomposition). The crystals became pink colored after exposure to light for several days.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH2:5][CH2:6][CH2:7][NH:8]C(OC(C)(C)C)=O)[CH2:2][CH3:3].Cl.O1CCOCC1>CO>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][NH2:8])[CH2:17][CH3:18]
Reactant: CCCN(CCC)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCN(CCC)CCCN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.4 %

Procedure:
The compound (2.67 g) obtained in Example 22-2 was dissolved in anhydrous methanol (2.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (20.0 ml), followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with dichloromethane. The extract was washed with distilled water and saturated saline solution, and then the organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off, thereby obtaining the subject compound (726 mg) as a pale-yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:14]1([NH:20][C:21](=[O:22])[NH:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[O:7])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C=Cc1ccccc1N
Solvent: c1ccccc1
Product: COC(=O)C=Cc1ccccc1NC(=O)Nc1ccccc1
Reaction time: 12 h

Procedure:
Methyl 2-aminocinnamate (2) (6.35 g, 35.8 mmol) was dissolved in 150 ml of benzene and phenylisocyanate (5.12 g, 43.0 mmol) was slowly dropped thereto at a room temperature. The reaction mixture was stirred for 12 hours to obtain a solid precipitate. Then, the precipitate was washed with ether in order to obtain the title compound (3) in the form of a white crystal (10.2 g, 96%) (mp 184° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:17][C:18]3[N:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[CH:20][CH:19]=3)=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[CH3:27][S:28]([NH:31][C:24]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][C:6]2[C:5]3[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:23]=1)=[O:26])(=[O:30])=[O:29]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc2c(Cc3cccc(C(=O)O)n3)c(-c3ccccc3)[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc2c(Cc3cccc(C(=O)NS(C)(=O)=O)n3)c(-c3ccccc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
Under an argon atmosphere, to a solution of 6-(6-methyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylic acid (838 mg) in dichloromethane (17.4 mL) were added methane sulfonamide (279 mg), 4-dimethylaminopyridine (718 mg), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.13 g) successively, and this mixture was stirred at room temperature for 24 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, followed by extraction with dichloromethane. The organic layer was washed with 1 mol/L hydrochloric acid, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (740 mg).
Reaction SMILES: [N:1]1[N:5]2[C:6]([CH:10]([OH:12])[CH3:11])=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1>O1CCCC1>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([O:12][CH:10]([C:6]2[N:5]3[N:1]=[CH:2][N:3]=[C:4]3[N:9]=[CH:8][CH:7]=2)[CH3:11])=[CH:47][CH:46]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(O)c1ccnc2ncnn12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(Cl)cc1)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (+)-1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (0.27 g), diethylazodicarboxylate (0.29 g), triphenylphosphine (0.44 g) and 4-chlorophenol (0.22 g) in dry tetrahydrofuran (40 ml) was stirred at ambient temperature for 2 days. Further diethylazodicarboxylate (0.15 g) and triphenylphosphine (0.22 g) was added to the solution, which was stirred overnight until the reaction was complete. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). This solution was washed with 1M sodium hydroxide (40 ml) followed by brine (20 ml) and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using as eluent a mixture of triethylamine and ethyl acetate (in the ratio 1:100 respectively) to give (+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.33 g.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:21])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:42]1[C:46](=[O:47])[C:45]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:44]2[C:43]1=[O:52]>O1CCCC1>[CH2:1]([O:8][CH2:9][C@H:10]([O:21][N:42]1[C:43](=[O:52])[C:44]2=[CH:51][CH:50]=[CH:49][CH:48]=[C:45]2[C:46]1=[O:47])[CH2:11][CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O[C@@H](CCOCc1ccccc1)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1O[C@H](CCOCc1ccccc1)COCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.9 %

Procedure:
To a solution of (S)-1,4-dibenzyloxy-2-hydroxybutane (5 g, 17.5 mmol) in dry tetrahydrofuran (100 ml) was added triphenylphosphine (5.1 g, 19.2 mmol) and N-hydroxyphthalimide (3.1 g, 19.2 mmol). The solution was treated dropwise with diethyl azadicarboxylate (3 ml, 19.2 mmol). A red colouration appeared, gradually fading and the solution became warm. The solution was stirred at room temperature for 48 hours and the solvent removed under vacuum. The residue was dissolved in ethylacetatehexane 1:1 (100 ml) and refrigerated. A white solid crystallised out and was filtered off. The solution was evaporated to dryness and the residue chromatographed on silica, eluting with ethylacetate-hexane 1:2 to give (R)-N-(1,4-dibenzyloxybut-2-oxy)phthalimide (4.6 g, 61%), [α]D25 +16.4° (c 1.3 in ethanol); IR: υmax (film) 3090, 3060, 3030, 2930, 2860, 1810, 1790, 1730, 1610, 1495, 1465, 1450, 1370, 1240, 1190, 1120, 1100, 1080, 1030, 1015, 980, 880, 785, 740, 700 cm-1 ; 1H NMR: δH (CDCl3) 2.1 (2H, m, CH2), 3.75 (4 H, m, 2×CH2), 4.5 (5H, m, 2×CH2 plus CH), 7.1-7.9 (14 H, m, 2×C6H5 plus C6H4); m/z (FAB) MH+ 432.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:53](O)=[O:54])[CH:50]([CH3:52])[CH3:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:14]=1)[C:53](=[O:54])[C@H:49]([CH:50]([CH3:51])[CH3:52])[NH:48][C:46]([O:45][CH2:44][CH:42]1[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:43]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:47])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: COc1cc(-c2cc(CNCCO[Si](C)(C)C(C)(C)C)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(CCO[Si](C)(C)C(C)(C)C)C(=O)[C@@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(C)C)ccn2)cc(OC)c1OC

Procedure:
N-[2-(tert-Butyldimethylsilyloxy)ethyl]-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amine (679 mg) and N-(9-fluorenylmethoxycarbonyl)-L-valine (865 mg) were treated in the same manner as in Preparation Example 9 to obtain the title compound.
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[N:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cn[nH]1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ncc(OCc2ccc(Cl)cn2)cc1=O
Yield: 91 %

Procedure:
5-(5-Chloro-pyridin-2-ylmethoxy)-2-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one is prepared following preparation 1c employing 5-(5-chloro-pyridin-2-ylmethoxy)-2H-pyridazin-3-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:16]([O-])=O>C(O)C.[Ni]>[NH2:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=2
Reactant: COc1cc2ncc([N+](=O)[O-])c(Cl)c2cc1OC
Agent: [Ni]
Solvent: CCO
Product: COc1cc2ncc(N)c(Cl)c2cc1OC
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A solution of 4-chloro-6,7-dimethoxy-3-nitroquinoline (1.07 g, 4 mmol) in ethanol (40 ml) containing Raney Nickel (1 g) was stirred under hydrogen at atmospheric pressure for 3 hours. The volatiles were removed by evaporation. The residue was triturated with petroleum ether, collected by filtration and dried under vacuum to give 3-amino-4-chloro-6,7-dimethoxyquinoline (925 mg, 97%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH:12]=[CH2:13])[C:5]=1[OH:14])=[O:3]>[Pd]>[CH3:13][CH2:12][CH2:11][C:6]1[C:5]([OH:14])=[C:4]([C:2]([CH3:1])=[O:3])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: C=CCc1c(O)ccc(C(C)=O)c1O
Agent: [Pd]
Product: CCCc1c(O)ccc(C(C)=O)c1O

Procedure:
The chromone derivative of formula I is readily prepared according to the following reaction scheme: ##STR2## by reacting 2,4-dihydroxyacetophenone (II) with allylbromide in the presence of potassium carbonate and acetone to obtain 4-allyloxy-2-hydroxyacetophenone III which, upon heating at 180°-220° C., undergoes rearrangement to form 3-allyl-2,4-dihydroxyacetophenone (IV). The dihydroxy intermediate then is catalytically reduced in the presence of palladium/carbon catalyst to form 2,4-dihydroxy-3-propylacetophenone (V). Intermediate (V) then is treated with epichlorohydrin in refluxing ethanolic potassium hydroxide to form 4-(2,4-epoxypropoxy)-2-hydroxy-3-propylacetophenone (VI) and with diethyl oxalate in the presence of sodium ethoxide to form ethyl 7-hydroxy-8-propyl-4-oxo-4H-1-benzopyran-2-carboxylate (VII). Intermediates (VI) and (VII) are reacted under a nitrogen atmosphere at 140°-150° C. in the presence of Triton B (Rohm & Hass, Philadelphia, Pa.) and the resulting ester treated with sodium bicarbonate to form 7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid (VIII). This intermediate, preferrably the sodium salt, then is iodinated in the presence of potassium triiodide to form the desired 7-[3-(4-acetyl-3-hydroxy-6-iodo-2-propylphenoxy)-2-hydroxypropoxy]-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid (I).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]([O:13]C)=O)=[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[NH2:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:3](=[O:21])[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:5]2[C:11](=[O:13])[N:22]([CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[C:8](=[O:10])[C:6]2=[CH:7]1
Reactant: COC(=O)c1c(C(=O)O)cn(C)c(=O)c1-c1ccncc1
Reactant: NCCc1ccc2ccccc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 1-methyl-2-oxo-1,2-dihydro-3-(4-pyridyl)-4-methoxycarbonyl-pyridine-5-carboxylic acid (500 mg, 1.7 mmol, see Example b3)), 2-aminoethyl quinoline (358 mg, 2.0 mmol), PyBOP (1.2 g, 2.2 mmol) and DIPEA (671 mg, 5.2 mmol) in DCM (20 ml) was stirred at r.t. overnight. The solvent was removed, the residue was purified by column chromatography on silica gel (PE:EA=10:1) to give the title compound as a white solid (600 mg, 84%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[S:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl.[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH2:37])[CH3:33]>CCO>[CH2:32]([O:34][C:35](=[O:38])[CH2:36][NH:37][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][C:6]=2[NH:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[S:20][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=2)[N:11]=1)[CH3:33]
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(Cl)ccc23)cc1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2n1
Temperature: 25 °C

Procedure:
The product from Example 24a (47 mg, 0.10 mmol) was reacted with the glycine ethyl ester hydrochloride (84 mg, 0.10 mmol) in 2 mL of EtOH in a sealed tube at 150° C. for 1 h. Cooled to room temperature and concentrated. Adjusted to pH 7 with 1M HCl and extracted with EtOAc, dried over Na2SO4, filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid solid (12 mg, 19%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.22 (t, J=6.99 Hz, 3H) 2.04 (s, 3H) 2.33 (s, 3H) 4.15 (q, J=7.23 Hz, 2H) 4.27 (d, J=6.25 Hz, 2H) 6.08 (d, J=6.99 Hz, 1H) 7.04 (d, J=5.52 Hz, 1H) 7.07 (d, J=6.62 Hz, 1H) 7.19-7.30 (m, 4H) 7.57 (d, J=8.46 Hz, 2H) 8.04 (t, J=6.62 Hz, 1H) 8.53 (d, J=9.19 Hz, 1H) 8.72 (t, J=5.88 Hz, 1H) 10.08 (s, 1H) 10.43 (s, 1H) 13.43 (d, J=5.88 Hz, 1H); MS (ESI+) m/z 502(M+H−TFA)+.