Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (7.0 g, 40 mmols), N-tert-butoxycarbonyl-3-hydroxyphenethylamine (9.5 g, 40 mmols), potassium carbonate (5.5 g, 40 mmols) and N,N-dimethylformamide (100 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an oil of tert-butyl 2-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (15.2 g, 96.6%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([C:11]2[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:9][C:8]2[CH2:7][CH2:6][O:5][C:4]=2[CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:10]2[C:2]([CH3:1])=[CH:3][C:4]3[O:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)=[CH:16][N:15]=1)=[O:22]
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)CCO2
Reactant: O=C(Cl)c1ccccc1F
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)CCO2
Yield: 64.9 %

Procedure:
Similarly, (2-fluorophenyl)-N-[5-(6-methyl(2,3-dihydrobenzo[b]furan-5-yl))-pyrazin-2-yl]carboxamide (167) (6.8 mg, yield: 64.9%, purity>95%) was prepared from 5-(6-methyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (165) (7.5 mg, 0.03 mmol) and 2-fluorobenzoyl chloride (11 μl).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[S:6])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCN=C=S
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCNC(=S)NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Yield: 6.6 %

Procedure:
A solution of propyl isothiocyanate (0.78 g, 7.72 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.256 g, 7.72 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol and then concentrated under vacuum to provide a pale orange syrup. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.22 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-propylthiourea as a white solid, m.p. 113–116° C. Mass spec M+1=433.2.
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([NH2:8])[CH3:7].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.[Na]>CO>[CH2:6]([NH:8][CH:12]1[CH2:13][CH2:14][O:9][CH2:10][CH2:11]1)[CH3:7]
Reactant: O=C1CCOCC1
Reactant: CCN
Agent: O=S(=O)(O)O
Agent: [Na]
Solvent: CO
Product: CCNC1CCOCC1
Reaction time: 16 h

Procedure:
At 0° C. and with efficient cooling, 51 g (0.5 mol) of conc. sulfuric acid were added dropwise to a solution of 105 g (2.3 mol) of ethylamine in 0.5 l of methanol. 50 g (0.5 mol) of tetrahydro-2H-pyran-4-one and 18.8 g (0.3 mol) of sodium cyanoborhydride were then added successively. After 16 hours at room temperature, the methanol was distilled off, an excess of 10% strength aqueous sodium hydroxide solution was added and the aqueous phase was extracted three times with dichloromethane. The combined organic phases were washed neutral with water, dried over magnesium sulfate and filtered and the residue was distilled. Bp. 76-82° C. (20 mbar), yield 24 g. 1H NMR (250 MHz, in CDCl3): δ=0.86 (s, 1H), 1.13 (t, 3H), 1.40 (dq, 2H), 1.84 (m, 2H), 2.68 (m, 3H), 3.40 (dt, 2H), 3.98 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].CN(C)C=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([N:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc(F)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To 2,4-difluoro-phenylamine (a, 2.0 g, 15.5 mmol) in N,N-dimethylformamide (20 mL) potassium carbonate (6.0 g, 45 mmol) and benzyl bromide (5.49 mL, 35 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with hexane to give dibenzyl-(2,4-difluoro-phenyl)-amine as colourless oil (4.34 g, 90%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:7]2[C@H:8]3[C:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)=[C:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>N1C=CC=CC=1>[C:22]([O:1][C@@H:2]1[C@H:7]2[C@H:8]3[C:17]([CH2:18][CH2:19][C@:5]2([CH3:6])[C:4](=[O:21])[CH2:3]1)=[C:16]1[C:11](=[CH:12][C:13](=[O:20])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1[C@@H](O)CC2=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20 g of 15α-hydroxyestra-4,9-diene-3,17-dione in 120 ml of pyridine is combined dropwise with 13.6 ml of benzoyl chloride and the mixture is stirred for one hour at room temperature. Subsequently the mixture is poured into ice water, extracted with dichloromethane, washed with sodium bicarbonate solution and water and concentrated under vacuum. The cooled crude product is chromatographed on silica gel, yielding 26.2 g of 15α-benzoyloxyestra-4,9-diene-3,17-dione.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C@@H:9]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH3:11])=[O:8])[CH2:3]1.[OH:35]O.[OH-].[Na+].Cl>C1COCC1.O>[C:30]([O:29][C:28](=[O:34])[NH:27][C@H:9]([C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]1)=[O:8])[C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:35])=[CH:16][CH:17]=1)[CH3:11])([CH3:31])([CH3:32])[CH3:33]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material from Step A (0.5 g, 1.0 mmol) in THF (10 mL) at 0° C. was added sequentially 30% hydrogen peroxide (0.18 mL, 1.5 mmol) and 3N aqueous sodium hydroxide (0.35 g, 1.0 mmol). After 2 h at this temperature water (30 mL) was added, and the resulting solution was adjusted to pH 5 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined extracts were washed with saturated sodium thiosulfate until the organic phase showed a negative peroxide test. The combined organics were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography (50% ethyl acetate in hexane) to give the title compound as a white foam. LC/MS 389.3 (M+Na).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C>[N:9]1([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1cnc(Br)cn1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Product: Nc1cnc(N2CCCC2)cn1
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of 5-bromopyrazin-2-amine (1.2 g, 6.9 mmol) and pyrrolidine (4 mL, 48 mmol) was microwaved at 180° C., 200 W for 2 h. The reaction was diluted into 125 mL ethyl acetate and extracted with water (3×50 mL) and brine (50 mL). It was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (0 to 3% methanol/methylene chloride) to afford 5-(pyrrolidin-1-yl)pyrazin-2-amine (495 mg, 3. mmol, 43.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.52 (1H, d, J=1.51 Hz), 7.36 (1H, d, J=1.76 Hz), 5.21 (2H, s), 3.24-3.29 (4H, m), 1.90 (4H, ddd, J=6.48, 3.53, 3.34 Hz). MS (LC/MS) R.T.=0.52; [M+H]+=165.29.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1.C(N(CC)CC)C>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:13]([C:29]([F:30])([F:31])[F:32])=[CH:12][N:11]=1
Reactant: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Temperature: 30 °C
Yield: 65.1 %

Procedure:
tert-Butyl 4-(3-methoxy-4-((4-((2-(2-methoxy-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I28) (5.52 g, 8.84 mmol) was dissolved in DMF (250 mL) then triethylamine (1 mL) and Pd/C (2.50 g) were added and the mixture stirred at 30° C. under hydrogen. After 16 hours the mixture was filtered through celite and the celite washed with DMF (250 mL). Triethylamine (1 mL) and Pd/C (2.50 g) were added to the combined filtrates and the mixture stirred at 30° C. under hydrogen. After 18 hours the resulting mixture was filtered through celite washing with ethyl acetate (300 mL). The filtrate was divided into two lots; each was poured into water (800 mL) and the resulting mixture extracted with ethyl acetate (3×300 mL). The ethyl acetate extracts from each lot were combined, washed with water (2×500 mL) and brine, dried (sodium sulfate) and evaporated. The two workups were combined and chromatographed (120 g silica cartridge, 0-20% ethyl acetate/petroleum benzine 40-60° C.) to give the title compound (I21) (3.620 g, 65% yield) as a white solid; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.37 (d, J=9.3 Hz, 1H), 7.91 (s, 1H), 7.29-7.18 (m, overlaps with CHCl3), 6.85 (dd. J=8.3, 1.8 Hz, 1H), 6.77 (d, J=1.8 Hz, 1H), 4.26 (s, 2H), 3.93 (s, 3H), 3.68 (s, 3H), 3.19-3.01 (m, 4H), 2.81 (t, J=12.7 Hz, 2H), 2.64 (tt, J=12.0, 3.5 Hz, 1H), 1.85 (d, J=13.3 Hz, 2H), 1.70-1.57 (m, overlaps with water), 1.49 (s, 9H). LCMS Method C: rt 7.14 min; m/z 629.2 [M+H]+, 573.1 [M-tBu+2H]+; m/z 627.2 [M−H].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2C1CCCNC1)[CH3:2].C([Li])CCC.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C:33](=[O:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>O1CCCC1>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][C:33]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[N:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:12]3)([OH:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CCc1cnc2c(C3CCCNC3)cccc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cnc2c(C3(O)CCN(C(=O)OC(C)(C)C)C3)cccc2c1
Temperature: -77 °C
Reaction time: 0.25 h
Yield: 11.5 %

Procedure:
To a well-stirred solution of the title compound of Example 1, Step 1 (2.10 g, 8.9 mmol) in 30 ml of anhydrous tetrahydrofuran chilled to and maintained at −77° C., a 2.5 M solution of n-butyl lithium in hexanes (3.60 ml, 8.9 mmol; Aldrich Chemical Co.) is added dropwise over a 10 minute period. The reaction was stirred at −77° C. for 15 minutes before adding a solution of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.65 g, 8.9 mmol) in anhydrous tetrahydrofuran (10 ml). The reaction mixture was allowed to warm to ambient temperature and stir at that temperature for 3 hours before quenching by cautious dropwise addition (with cooling) of saturated aqueous sodium bicarbonate (50 ml total). The resulting mixture was thoroughly extracted with three 20 ml of ethyl acetate. The combined organic extracts were, in turn, extracted with an equal volume portion of brine, dried (anhydrous sodium sulfate) and, finally, concentrated in vacuo, yielding a viscous syrup. Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution with methylene chloride/methanol=98:2 in volume) afforded the title compound (352 mg, 11.5% yield) as a viscous yellow oil.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.[C:14](=O)(O)[O-].[Na+]>CO>[CH3:14][O:8][C:7](=[O:9])[C@@H:2]1[CH2:3][CH2:4][C:5](=[O:6])[NH:1]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
To a solution of L-pyroglutamic acid (32.7 g, 0.253 mol) in methanol (600 mL) was added thionyl chloride (2.40 mL, 32.9 mmol), and the resulting solution was stirred at room temperature for 16 h. The reaction mixture was neutralized to pH=7 with saturated aqueous sodium bicarbonate and concentrated in vacuo. The residue was dissolved in methylene chloride, washed with brine, dried over magnesium sulfate, and concentrated. The residue was distilled under high vacuum to give the product as a colorless oil (28.9 g, 80%), b.p. 118-126° C./0.35 mm Hg. 1H NMR (300 MHz, CDCl3): δ 2.36 (m, 4 H), 3.77 (s, 3 H), 4.27 (dd, 1 H, J=5.0, 8.4), 6.78 (s, 1 H).
Reaction SMILES: Br[C:2]1[C:3]([O:14][CH3:15])=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.C(=O)([O-])O.[Na+].[H][H]>CO.[Pd]>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:2][C:3]([O:14][CH3:15])=[CH:4][N:5]=2)[N:10]=1
Reactant: [H][H]
Reactant: COc1ccc2ncc(OC)c(Br)c2n1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cnc2ccc(OC)nc2c1
Yield: 94 %

Procedure:
8-Bromo-2,7-bis(methoxy)-1,5-naphthyridine (11.21 g, 41.673 mmol) was stirred in MeOH (400 mL) with sodium hydrogen carbonate (7.00 g, 83.35 mmol) and 10% palladium on carbon (2.8 g), and the resulting suspension was hydrogenated at 1 atmosphere of hydrogen pressure for 18 h. The mixture was filtered with suction through celite and the solids were washed with ethanol (300 ml). The filtrate was concentrated under reduced pressure and the residue treated with DCM (300 ml) and water (300 ml). The aqueous phase was extracted with DCM (2×300 ml). The combined organic phases were separated, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give 2,7-bis(methoxy)-1,5-naphthyridine as a cream solid (7.45 g, 94%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]3[C:15]([C:18]([NH:20][C:21]4[CH:29]=[CH:28][CH:27]=[C:26]5[C:22]=4[C:23]([CH3:38])=[N:24][N:25]5[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=4)=[O:19])=[CH:16][N:17]=[C:11]3[CH:10]=2)[CH2:4][O:3]1>FC(F)(F)C(O)=O.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][N:12]2[C:15]([C:18]([NH:20][C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[C:23]([CH3:38])=[N:24][N:25]4[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[N:32]=3)=[O:19])=[CH:16][N:17]=[C:11]2[CH:10]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCC6COC(C)(C)O6)ccn45)cccc32)n1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(OCC(O)CO)ccn45)cccc32)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7-((2,2-Dimethyl-1,3-dioxolan-4-yl)methoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (11 mg, 0.02 mmol) was taken up in 50% trifluoroacetic acid/water and stirred at ambient temperature for 1 hour. Concentrated and dried under high vacuum for an hour before treating with excess 2 M hydrochloric acid in diethyl ether. The solution was stirred for an hour and then concentrated to give 7-(2,3-dihydroxypropoxy)-N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide as a colorless residue (8 mg). MS m/z 487.2 (M+1, APCI+).
Reaction SMILES: C([O:3][C:4](=[O:29])/[C:5](=[N:25]\[O:26][CH2:27][CH3:28])/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)C.[OH-].[Na+]>CO.O1CCCC1>[CH2:27]([O:26]/[N:25]=[C:5](/[C:6]1[S:7][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:9][CH:10]=1)\[C:4]([OH:29])=[O:3])[CH3:28]
Reactant: CCO/N=C(\C(=O)OCC)c1ccc(OCCOc2ccc3ccccc3c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCO/N=C(\C(=O)O)c1ccc(OCCOc2ccc3ccccc3c2)s1
Temperature: 55 °C
Yield: 50.8 %

Procedure:
As in Example 306, a solution of (E)-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy) ethoxy]-2-thiopheneacetic acid ethyl ester (0.131 g) in methanol (2 mL) and tetrahydrofuran (2 mL) was treated with 4N sodium hydroxide (0.5 mL) and the stirred mixture was heated at 55° C. for 45 minutes. After the usual work up, the isolated product was crystallized from ethyl acetate-hexane to afford 0.062 g of (E)-alpha-(ethoxyimino)-5-[2-(2-naphthalenyloxy)ethoxy]-2-thiopheneacetic acid, mp 17°-108° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]#[N:18])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl.[CH2:20]([O:22]CC)[CH3:21]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17](=[NH:18])[O:22][CH2:20][CH3:21])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: CCOCC
Reactant: COc1cc(/C=C/C#N)ccc1-n1cnc(C)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylonitrile (700 mg) in ethanol (6 mL) was saturated with hydrogen chloride gas under ice-cooling, and then the reaction solution was stirred at 0° C. overnight. Diethyl ether (10 mL) was added to the reaction solution. The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. Ethyl acetate and a saturated sodium bicarbonate solution were added to the resulting residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate-ethanol system) to obtain 127 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]([Br:39])[CH:37]=[O:38])[CH:31]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:30]2=[O:48])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[CH:36]([Br:39])[CH:37]=[O:38])[CH:31]([NH:40][C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[C:30]2=[O:48])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CSC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Br)C=O)CS(=O)C12
Reaction time: 0.5 h

Procedure:
A solution of 85% pure meta-chloroperbenzoic acid (4.31 g) in methylene chloride (50 cc) is added dropwise, over a period of 30 minutes, to a solution, cooled to between 0° and -5° C., of 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (mixture of the diastereoisomers at the substituent in the 3-position) (14.69 g) in methylene chloride (150 cc). After 30 minutes at -5° C., the reaction mixture is poured into a mixture of a semi-saturated solution of sodium bicarbonate (100 cc) and methylene chloride (200 cc). The organic phase is washed with distilled water (150 cc) and a semi-saturated solution of sodium chloride (150 cc) and then dried over sodium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 20° C. to give crude 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8 -oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (mixture of the diastereoisomers at the substituent in the 3-position) (13.35 g) in the form of a hard, light brown foam. The crude product obtained is divided into 2 batches, which are chromatographed on a column (height: 30 cm, diameter: 5 cm) of silica gel (0.04-0.063 mm), elution being carried out under a pressure of 0.4 bar (40 kPa) with a mixture of cyclohexane and ethyl acetate (40/60 by volume), and 125 cc fractions being collected. Fractions 7 to 10 from both chromatographic separations are combined and concentrated to dryness under reduced pressure (30 mm HG; 4 kPa) at 20° C. to give 2-benzhydryloxycarbonyl-3-(1-bromo-2-oxoethyl)-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (mixture of the diastereoisomers at the substituent in the 3-position) (2.43 g) in the form of a hard yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:39][C:38](=[O:40])[NH:37][CH:36]=2)=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[C:17]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]4[O:39][C:38](=[O:40])[NH:37][CH:36]=4)=[CH:33][CH:34]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2CCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: Nc1ccc(-c2c[nH]c(=O)o2)cc1
Product: COc1cn(C(CC2CCC2)C(=O)Nc2ccc(-c3c[nH]c(=O)o3)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
103 mg (purity 94%, 0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-cyclobutylpropanoic acid (racemate) and 55 mg (0.28 mmol, 1.1 eq.) of 5-(4-aminophenyl)-1,3-oxazol-2(3H)-one were reacted according to General Method 1. The crude product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 36 mg (27% of theory)