Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C:12](=[O:27])[CH2:11][CH2:10]1.[BH4-].[Na+].[Cl-].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][C@@H:16]2[F:26])([CH3:14])[C@@H:12]([OH:27])[CH2:11][CH2:10]1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
5.0 g of 7α-(5-chloropentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 100 ml of methanol and mixed in portions at 0° C. with 0.96 g of sodium borohydride. After 30 minutes of stirring at 0° C., the reaction mixture is added to semi-saturated sodium chloride solution, extracted 3 times with ethyl acetate and washed once with saturated common salt solution. After drying on magnesium sulfate, it is concentrated by evaporation in a vacuum. Preparative column chromatography on silica gel with a hexane-ethyl acetate gradient yields 4.29 g of 7α-(5-chloropentyl)-11β-fluor-estra-1,3,5(10)-triene-3,17β-diol.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH2:11](O)[CH3:12]>>[ClH:1].[NH2:2][CH2:3][C:4](=[O:10])[CH2:5][CH2:6][C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: CCO
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CCOC(=O)CCC(=O)CN
Reaction time: 2 h

Procedure:
From ethanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 2 h. The yield was 1.0 g (85%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Nc1ccc(O)cc1
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)cc1
Yield: 59.5 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (2 g, 8 mmol), 4-aminophenol (1.24 g, 11 mmol) and 1,4-dioxan (50 ml) were heated at reflux for 2 hours, then the solid filtered off and converted to free base. Recrystallisation from ethanol and then methanol gave 3-butyryl-4-(4-hydroxyphenylamino)-8-methoxyquinoline (1.6 g), m.p. 270°-272°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N=C=NCCCN(C)C)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1ccccn1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
To a solution of 4-methoxyphenyl acetic acid (5 g; 30.08 mmol) in 30 ml of dichloromethane, under nitrogen, it was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.34 g; 33.09 mmol) in small portions. After 10 minutes 2-aminopyridine (2.83 g; 30.08 mmol) was added and stirred for 4 hours at rt. The reaction mixture was concentrated and partitioned between ethyl acetate and 0.5N HCl. The organic phase was washed with 0.5N HCl (2×) and 0.5N NaOH (2×). The pH of the acidic/aqueous phase was adjusted to ˜7 with 0.5N NaOH and extracted twice with ethyl acetate. The basic/aqueous phase was also extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to afford 2-(4-methoxyphenyl)-N-pyridin-2-ylacetamide (7 g; 92% yield), which was used in the next step without further purification. MS: m/z 243 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.I[CH2:14][C:15]([F:18])([F:17])[F:16].[H-].[Na+]>C(OCC)(=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: FC(F)(F)CI
Reactant: O=c1[nH]ccc2ccc(Br)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1c2cc(Br)ccc2ccn1CC(F)(F)F
Temperature: 25 °C
Yield: 22 %

Procedure:
To a stirred solution of 7-bromoisoquinolin-1(2H)-one (5 g, 22.3 mmol) and iodotrifluoroethane (4.9 g, 23.4 mmol) in dimethylacetimide cooled to 5° C. was added sodium hydride 60% wt (0.89 g 22.3 mmol) portion wise over 5 minutes. After complete addition reaction mixture allowed to warm up to room temperature over 2 hours and then heated at 50° C. for 24 hours. Reaction mixture was evaporated to leave a residue, which was diluted with ethyl acetate (200 ml) and water (200 ml). The aqueous layer was further extracted with ethyl acetate (2×50 ml) and organic layers were combined and washed with saturated aqueous bicarbonate (200 ml), brine (200 ml) and dried over Magnesium sulfate powder, filtered and concentrated under reduced pressure to leave a residue and purified using column chromatography eluting with 50% ethyl acetate/petrol ether to give a yellow solid which was still impure by LCMS (1.53 g, 22% yield)
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10]N=[CH:8][CH:7]=2)=[CH:2]1.I[C:13]1[CH:18]=CC(CCC)=[CH:15][CH:14]=1.O1C=CC(B(O)O)=C1>>[CH2:13]([C:18]1[CH:10]=[CH:11][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:7][CH:8]=1)[CH2:14][CH3:15]
Reactant: CCCc1ccc(I)cc1
Reactant: c1cc(-c2ccoc2)ccn1
Agent: OB(O)c1ccoc1
Product: CCCc1ccc(-c2ccoc2)cc1

Procedure:
As described in Example 1(d) for the preparation of 4-furan-3-yl-pyridine, 1-iodo-4-propylbenzene (500 mg, 2.03 mmol) was coupled to 3-furanboronic acid to furnish in high yield 3-(4-propylphenyl)-furan as a light brown oil that was unstable and used immediately without further purification. 1H NMR (CDCl3): ∂ 7.69 (t, 1H, J=0.9 Hz), 7.46 (t, 1H, J=1.7 Hz), 7.40 (d, 2H, J=8.1 Hz), 7.18 (d, 2H, J=7.8 Hz), 6.68 (t, 1H, J=0.9 Hz), 2.59 (t, 2H, J=7.5 Hz), 1.66-1.60 (m, 2H), 0.95 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([O:9]C1C=CC([N+]([O-])=O)=CC=1)=O)=[O:5].[Br:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]([NH:31][C:28]1[CH:27]=[CH:26][C:25]([Br:24])=[CH:30][N:29]=1)=[O:9])=[O:5]
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(NC(=O)c1c(F)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Product: O=C(NC(=O)c1c(F)cccc1Cl)Nc1ccc(Br)cn1

Procedure:
To a solution of 2-chloro-6-fluorobenzamidocarboxylic acid, 4-nitrophenyl ester, in an inert organic solvent is added 5-bromo-2-aminopyridine. The reaction mixture is stirred at an elevated temperature for a period of time, and is then evaporated to dryness under vacuum. The product named in the heading above, identical to the product of Example 2, is isolated and purified by recrystallization.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Reactant: N#Cc1ccc(N)cc1
Product: COc1cccc2c(Nc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-5-methoxy-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 371(MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1(=O)[O:13][C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12>C(O)(=O)C>[C:8]1(=[O:13])[N:1]([CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])[C:11](=[O:12])[C:10]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:9]12
Reactant: NCCCC(=O)O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CC(=O)O
Product: O=C(O)CCCN1C(=O)c2ccccc2C1=O

Procedure:
A 2 liter nitrogen flushed flask fitted with a mechanical stirrer and a reflux condenser was charged with 103 g (1 mole) of 4-aminobutyric acid (GABA), 148 g (1 mole) of phthalic anhydride and 250 ml of glacial acetic acid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:28]=[CH:27][C:21]([O:22][CH:23]2[CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I.C(OCC)(=O)C>[C:14]([C:18]1[CH:28]=[CH:27][C:21]([O:22][CH:23]2[CH2:26][N:25]([C:2]3[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:13])[CH3:12])[CH3:9])=[CH:4][CH:3]=3)[CH2:24]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)N[C@@H](C)c1ccc(I)cc1
Reactant: CC(C)(C)c1ccc(OC2CNC2)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CC(=O)N[C@@H](C)c1ccc(N2CC(Oc3ccc(C(C)(C)C)cc3)C2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Under an argon atmosphere a mixture of 0.28 g (0.97 mmol) (S)—N-[1-(4-iodo-phenyl)-ethyl]-acetamide (III.1), 0.20 g (0.98 mmol) 3-(4-tert-butyl-phenoxy)-azetidine, 0.0093 g (0.049 mmol) CuI, 0.41 g (1.95 mmol) K3PO4 and 0.12 g (1.95 mmol) ethyleneglycol in 1.0 mL isopropanol is stirred for 12 h at 80° C. 100 mL Ethyl acetate are added and the mixture is washed with ammonia solution (5%, 2×). The aq. layer is extracted with ethyl acetate (1×) and the combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by HPLC (XBridge, MeOH/water (+0.3% NH4OH)) to yield the desired product.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O-2].[Zn+2:7].O>>[Zn+2:7].[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[NH2:1][CH2:2][C:3]([O-:5])=[O:4]
Reactant: NCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: NCC(=O)[O-]
Reaction time: 1 h

Procedure:
Glycine zinc salt was prepared by the following procedure. Glycine (300 g; 4 moles) and 162.8 g (2 moles) of zinc oxide were put in a portable universal mixer and mixed for about 5 minutes. Then 162.8 g (34 moles) of water was added, and the mixing was continued for about 1 hour. Then, the mixture was dried at 110° C. to obtain glycine zinc salt as crystals. The crystals were mechanically pulverized and observed under a scanning electron microscope. When the largest particle among those particles which appeared in the visual field has a particle diameter of 10 micrometer, it was determined that the crystals had been finely pulverized to an average particle diameter of not more than 10 micrometers. The above pulverization to an average particle diameter of not more than 10 micrometers was effected by using a jet pulverizer, and the pulverization was repeated.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](=[S:11])=[S:10]>CN(C=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]=2[S:11][C:9]1=[S:10]
Reactant: S=C=S
Reactant: Nc1cccnc1Cl
Solvent: CN(C)C=O
Product: S=c1[nH]c2cccnc2s1
Yield: 90 %

Procedure:
A mixture of 6.43 g (50.0 mmols) of 3-amino-2-chloropyridine, 50 ml of carbon disulfide and 50 ml of DMF was heated under reflux for 6 days. An excess of carbon disulfide was evaporated under reduced pressure, and the residue was poured into 300 ml of ice water with stirring. The precipitated crystals was taken out by filtration and dried to afford 7.57 g (yield: 90%) of pyrido[3,2-d]thiazo-line-2-thione.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH2:7][CH:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:9]3[CH2:18][CH2:17][CH2:16][CH:10]3[C:11]=2[CH:12]=[C:13]([OH:15])[CH:14]=1)=[O:4].[OH-].[Na+]>C(O)C>[OH:15][C:13]1[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH2:7][CH:8]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:9]3[CH2:18][CH2:17][CH2:16][CH:10]3[C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21
Yield: 81.1 %

Procedure:
Combine 8-Hydroxy-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-6-carboxylic acid methyl ester (0.013 g, 0.038 mmol), ethanol (3 ml), and NaOH (1.5 ml, 2N) and heat at 45° C. for 1.5 hours. Acidify with 1 N HCl and extract with ethyl acetate. Wash 1× with water, dry over anhydrous sodium sulfate and concentrate in vacuo to yield the titled compound (0.010 g, 84%) as a white residue. 1H NMR (CD3OD) 7.1 (d, J=7.5 Hz, 2H), 7.08 (s, 1H), 6.8 (s, 1H), 6.7 (d, J=7.5 Hz, 2H), 3.4 (m, 1H), 3.15 (m, 1H), 3.0 (m, 2H), 2.55(m, 1H) 2.2 (m, 1H), 1.6-1.2. MS m/z 323 (M−1).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].Cl[C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=2[N:19]=1.O>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([CH2:4][O:5][C:9]2[CH:10]=[CH:11][C:12]3[CH2:13][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16][O:17][C:18]=3[N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(Cl)ccc2C1
Reactant: OCC1CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2nc(OCC3CC3)ccc2C1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a solution of cyclopropylmethanol (0.14 mL) in toluene (4 mL) was added sodium hydride (0.14 g), and the resulting mixture was stirred at 70° C. for 15 min under a nitrogen atmosphere. A mixture of tert-butyl 8-chloro-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.50 g), BINAP (0.033 g), Pd2(dba)3 (0.024 g) and toluene (4 mL) was added, and the resulting mixture was stirred at 100° C. for 2 hr under an argon atmosphere. The reaction solution was poured into water, and the resulting product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→40% ethyl acetate/hexane) to give tert-butyl 8-(cyclopropylmethoxy)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.33 g, 59%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16](Br)=[C:15]([Br:18])[N:14]=[C:13]2[CH:19]2[O:23][CH2:22][CH2:21][O:20]2)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.O1CCCC1.C([Mg]Br)C.Cl>CCOCC.C(OCC)(=O)C.CN(C)C=O>[Br:18][C:15]1[N:14]=[C:13]([CH:19]2[O:23][CH2:22][CH2:21][O:20]2)[N:12]([CH2:11][C:3]2[C:2]([Cl:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=2)[CH:16]=1
Reactant: Clc1cc2c(cc1Cn1c(C3OCCO3)nc(Br)c1Br)OCO2
Agent: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Clc1cc2c(cc1Cn1cc(Br)nc1C1OCCO1)OCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 g of the product obtained in Stage A above is introduced into 200 ml of tetrahydrofuran and 10 ml of ethyl magnesium bromide in a 3M solution in ether is added dropwise. The reaction medium is maintained under agitation for 20 minutes at ambient temperature. 10 ml of dimethylformamide is then added to the reaction medium obtained and agitation is carried out for 2 hours at ambient temperature. The medium is hydrolyzed by the addition of 200 ml of dilute hydrochloric acid, extraction is carried out with ethyl acetate, followed by washing with water then drying and after impasting in isopropyl ether, 7.6 g of expected product is recovered, which is used as it is for the following stage.
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7][CH:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH:4]=1.[C:22](Cl)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>N1C=CC=CC=1>[C:22]([O:1][CH2:2][C:3]1[S:11][C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[O:7][CH:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH:4]=1)(=[O:38])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCc1cc2c(s1)-c1ccccc1OC2c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OCc1cc2c(s1)-c1ccccc1OC2c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 5.9 g 4H-2-hydroxymethyl-4-phenyl-thieno[3,2-c][1]benzopyran and 5.8 g of palmitoyl chloride in 50 ml pyridine is stirred at room temperature for 4 h. After filtration, one adds 400 ml water to the filtrate. The precipitate which appears is collected. This material is dissolved in methylene chloride and this organic phase is washed with hydrochloric acid solution, then with water, dried and evaporated. The residue is purified by column chromatography on silicagel using a mixture of n-hexane and methylene chloride as eluant. Pure 4H-2-palmitoyloxymethyl-4-phenyl-thieno[3,2-c][1]benzopyran is obtained as a white powder; m.p. 64°-65° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.Cl.[NH2:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:16]([NH:18][CH:19]1[CH2:21][CH2:20]1)=[O:17]>>[Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:7]([NH:12][C:13]2[CH:14]=[C:15]([C:16](=[O:17])[NH:18][CH:19]3[CH2:21][CH2:20]3)[CH:22]=[CH:23][C:24]=2[CH3:25])=[O:9])[S:5][CH:6]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: Cc1c(Br)csc1C(=O)O
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C

Procedure:
The compound a was prepared by coupling commercially available 4-bromo-3-methylthiophene-2-carboxylic acid with 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO 04/071440) using the method described in Example 128. HPLC Ret time=3.12 min. LCMS [M+H]+ 393.13.
Reaction SMILES: Cl.N=C1C=CN([C:9]2[N:10]=[CH:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=4)[C:16](=[O:29])[N:15]([CH2:30][CH3:31])[C:13]=3[N:14]=2)C=C1.C(=O)([O-])[O-].[K+].[K+].[NH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>CS(C)=O>[N:42]1[CH:43]=[CH:44][C:39]([NH:38][C:9]2[N:10]=[CH:11][C:12]3[CH:18]=[C:17]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=4)[C:16](=[O:29])[N:15]([CH2:30][CH3:31])[C:13]=3[N:14]=2)=[CH:40][CH:41]=1
Reactant: Nc1ccncc1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(-n3ccc(=N)cc3)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 100 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 330 g (0.75 mol) of 2-(4-imino-4H-pyridin-1-yl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride in 1.5 L of dimethylsulfoxide were added in one portion 114 g (0.825 mol) of powdered potassium carbonate, followed by the addition of a solution of 2.8 g (0.03 mol; 0.05 eq) 4-aminopyridine in 50 mL of dimethylsulfoxide. The reaction mixture was heated to 100° C., and aliquots were removed after 1 hour and analyzed by reverse phase high pressure liquid chromatography (RP-HPLC) (YMC-AQ column, 60:40 CH3CN/0.02 M SDS, pH 2.2, 1.0 mL/min, 254 nm). After 40 minutes, the reaction was shown to produce the title compound, plus a dimer-like compound of the formula
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])[C:11]3=[O:28])=[CH:4][C:3]=2[O:2]1>[Pt]=O.CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH:20]([OH:21])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:11]3=[O:28])=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Cn1c(=O)n(-c2ccc3c(c2)OCO3)c2ncccc21)c1ccccc1
Agent: O=[Pt]
Solvent: CO
Product: O=c1n(CC(O)c2ccccc2)c2cccnc2n1-c1ccc2c(c1)OCO2

Procedure:
A mixture of 431 mg. of 1,3-dihydro-3-(3,4-methylenedioxyphenyl)-1-phenacylimidazo[4,5-b]pyridin-2-one in 30 ml. of methanol was hydrogenated over 25 mg. of platinum oxide. The catalyst was removed by filtration and the filtrate was evaporated to dryness to give a glass which could not be crystallized.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)(=[O:14])=[O:13])(=[O:8])[O:5]CC)[CH3:2].C[Si](Br)(C)C>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][NH:11][S:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]1)(=[O:13])=[O:14])(=[O:5])[OH:8])[CH3:2]
Reactant: CCOP(=O)(CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCN(C(=O)OC(C)(C)C)CC1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCOP(=O)(O)CCNS(=O)(=O)CCCCc1ccccc1OCCCCC1CCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6-9 (0.09 g, 0.142 mmol) in CH2Cl2 cooled to 0° was treated with TMSBr (0.054, 0.355 mmol) and the resulting solution was stirred at rt for 16 hours with cooling. Et2N (100 μl) was added and the solvent was removed. The residue was dissolved in 10% aqueous acetone (5 ml), concentrated, and suspended in toluene to give a solid. This was purified by flash chromatography on silica gel eluting with 10:1:1 EtOH/H2O/NH4OH to give pure 6-10.
Reaction SMILES: C(C1C=C(C2ON=C(C3C=C(C)C(OCC(O)CNC(=O)CO)=C(C)C=3)N=2)C=CC=1)=O.[CH:32]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[CH2:43][CH3:44])[C:37]([OH:39])=O)=[O:33].[CH2:45]([C:47]1[CH:62]=[C:61]([C:63](=[NH:66])[NH:64]O)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]>>[CH2:45]([C:47]1[CH:62]=[C:61]([C:63]2[N:66]=[C:37]([C:36]3[CH:40]=[CH:41][C:42]([CH2:43][CH3:44])=[C:34]([CH:32]=[O:33])[CH:35]=3)[O:39][N:64]=2)[CH:60]=[C:59]([CH3:67])[C:48]=1[O:49][CH2:50][C@@H:51]([OH:58])[CH2:52][NH:53][C:54](=[O:57])[CH2:55][OH:56])[CH3:46]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Reactant: CCc1ccc(C(=O)O)cc1C=O
Agent: Cc1cc(-c2noc(-c3cccc(C=O)c3)n2)cc(C)c1OCC(O)CNC(=O)CO
Product: CCc1ccc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)cc1C=O
Yield: 24.7 %

Procedure:
The title compound (233 mg) is prepared in analogy to rac-N-(3-{4-[5-(3-formyl-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide, starting from 3-formyl-4-ethyl-benzoic acid (360 mg, 2.02 mmol) and N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide (657 mg, 2.02 mmol). LC-MS**: tR=0.72 min; [M+1]+=468.21; 1H NMR (D6-DMSO): δ 1.23 (t, J=7.5 Hz, 3H), 1.26 (t, J=7.5 Hz, 3H), 2.35 (s, 3H), 2.74 (q, J=7.5 Hz, 2H), 3.17 (q, J=7.3 Hz, 2H), 3.21-3.29 (m, 1H), 3.40-3.48 (m, 1H), 3.70-3.80 (m, 2H), 3.84 (d, J=5.8 Hz, 2H), 3.93-4.01 (m, 1H), 5.32 (d, J=5.0 Hz, 1H), 5.56 (t, J=5.8 Hz, 1H), 7.68-7.73 (m, 2H), 7.81 (s, 2H), 8.37 (dd, J=8.0, 1.8 Hz, 1H), 8.61 (d, J=1.8 Hz, 1H), 10.38 (s, 1H).