Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:18][CH:2]1[CH2:3][N:4]1[C:13]([CH3:15])([CH3:14])[CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][C:5]1([CH3:17])[CH3:16].[C:19]([OH:28])(=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]>C1(C)C(C)=CC=CC=1>[OH:1][CH:2]([CH2:3][N:4]1[C:5]([CH3:16])([CH3:17])[CH2:6][C:7]2([O:8][CH2:9][CH2:10][O:11]2)[CH2:12][C:13]1([CH3:14])[CH3:15])[CH2:18][O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20][C:19]([O:28][CH2:18][CH:2]([OH:1])[CH2:3][N:4]1[C:5]([CH3:17])([CH3:16])[CH2:6][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:12][C:13]1([CH3:15])[CH3:14])=[O:27]
Reactant: O=C(O)CCCCC(=O)O
Reactant: CC1(C)CC2(CC(C)(C)N1CC1CO1)OCCO2
Solvent: Cc1ccccc1C
Product: CC1(C)CC2(CC(C)(C)N1CC(O)COC(=O)CCCCC(=O)OCC(O)CN1C(C)(C)CC3(CC1(C)C)OCCO3)OCCO2

Procedure:
To 60 ml of xylene were added 10.0 g of 8-(2,3-epoxypropyl)-7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]decane and 2.4 g of adipic acid and the mixture was refluxed for 16 hours, under stirring. After completion of the reaction, the residue obtained by removing xylene from the reaction mixture under a reduced pressure was purified by column chromatography on silica gel (eluent: benzene:ethyl acetate=1:1), giving the desired compound as pale yellow, viscous product. The compound showed Rf value of 0.53 on a thin-layer chromatography on silica gel when developed with ethyl acetate.
Reaction SMILES: COCC1C=C[C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)=C([N+]([O-])=O)C=1.F[C:24](F)(F)C(O)=O>C(Cl)Cl>[CH3:24][C:14]1[CH:13]=[C:12]([CH2:11][O:10][CH3:7])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: O=C(O)C(F)(F)F
Reactant: COCc1ccc(OCc2ccc(OC)cc2)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: COCc1ccc(O)c(C)c1

Procedure:
To a solution of 4-[(methyloxy)methyl]-1-({[4-(methyloxy)phenyl]methyl}oxy)-2-nitrobenzene D118 (1.57 g, 5.18 mmol) in DCM (80 mL) was added trifluoroacetic acid (3.99 mL, 51.80 mmol). After 1 hr the mixture was washed with water (3×25 mL) and then extracted with 10% aq potassium carbonate solution (3×20 mL). The combined extracts were back washed with diethyl ether (20 mL) and then the pH was adjusted to 1 with 2N HCl, the mixture was extracted with DCM (3×25 mL), the combined extracts were washed with water (25 mL) and brine (25 mL), dried(MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5-40% EtOAc in isohexane to afford the title compound as a bright yellow oil. 0.72 g, 76%
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[CH3:24][O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Reaction time: 4 h
Yield: 73.1 %

Procedure:
In 100.4 g of acetic acid, 25.1 g (0.1 mole) of N-benzyloxycarbonyl-L-aspartic anhydride was suspended and 22.7 g (0.1 mole) of L-phenylalanine methyl ester sulfate was added with stirring at 5°-10° C. Successively 17.6 g (0.21 mole) of sodium acetate was added at the same temperature. The reaction was carried out for 4 hours with stirring at the same temperature. Thereafter 87.1 g of water was added to the reaction mixture to adjust the concentration of organic carboxylic acid to 53.5% by weight. After cooling to 0°-5° C., precipitated crystals were filtered, washed and dried. Crystals of N-benzyloxycarbonyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained. The yield was 31.2 g (73.1% yield on L-phenylalanine methyl ester sulfate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:6]([O:8][CH2:9][C:10]([C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]2)=O)=O.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:6]2[O:8][CH:9]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)[N:32]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C(=O)OCC(=O)c2ccc3c(c2)CCC(=O)N3)cc1OC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCC(=O)N4)co2)cc1OC
Temperature: 130 °C
Reaction time: 3 h
Yield: 6.3 %

Procedure:
In 25 ml of acetic acid was dissolved 2 g of 6-[2-(3,4-dimethoxybenzoyloxy)acetyl]-3,4-dihydrocarbostyril. Thereto was added 2 g of ammonium acetate. The mixture was stirred at 130° C. for 3 hours with heating. The solvent was removed by distillation. The residue was dissolved in ethanol. The solution was treated with active carbon, and then recrystallization was conducted to obtain 120 mg of 2-(3,4-dimethoxyphenyl)-4-(3,4-dihydrocarbostyril-6-yl)oxazole as light brown acicular crystals.
Reaction SMILES: [C:1]([NH:5][C:6](=[N:9][S:10](=[O:20])(=[O:19])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[O:7][CH3:8])(OC)=[O:2].[H-].[Na+].O>C1COCC1>[CH2:12]([N:11]1[C:1](=[O:2])[NH:5][C:6]([O:7][CH3:8])=[N:9][S:10]1(=[O:20])=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)NC(=NS(=O)(=O)NCc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(=O)N1

Procedure:
A solution of N-carbomethoxy-N'-benzylsulfamoyl-O-methylisourea (215 g) in anhydrous THF (200 ml) is added dropwise to a stirred suspension of sodium hydride (43 g of 60% dispersion) in anhydrous THF (900 ml) and refluxed for 2 hours under nitrogen. Water (800 ml) is added to the cooled reaction mixture and the aqueous mixture washed with ether. The pH of the aqueous layer is adjusted to about 3.2 and the resulting suspension extracted with methylene chloride. The methylene chloride extract is dried, filtered, and evaporated in vacuo. The residue is taken up in hot isopropyl alcohol, treated with charcoal, filtered hot, concentrated, cooled, the resulting precipitate filtered and dried in vacuo yielding the desired product, M.P.=141°-144° C.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[CH:38]=[N:39][NH:40][CH:41]=5)[CH:28]=[CH:27][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: Fc1ccc(-n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)c(F)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Fc1ccc(-n2ncnc2-c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)c(F)c1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 144. MS (ESI+) 449.0. 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.90-7.83 (m, 1H), 7.74-7.66 (m, 1H), 7.45-7.35 (m, 2H), 7.26 (d, J=1.5, 1H), 7.16 (dd, J=8.3, 1.6, 1H), 4.33 (t, J=4.9, 2H), 3.41 (t, J=4.9, 2H)
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([CH:9]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]1)[CH:6]=[CH:7][CH3:8].Cl>C1C=CC=CC=1.N1C=CC=CC=1>[C:1]([O:14][CH:11]1[CH2:12][CH2:13][CH:9]([CH2:5][CH:6]=[CH:7][CH3:8])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC=CCC1CCC(O)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC=CCC1CCC(OC(C)=O)C1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A solution of 2 ml of acetyl chloride in 5 ml of benzene was added at 0° C. to a solution of 1 g of 3-(2-butenyl)-cyclopentanol in 20 ml of benzene and 2 ml of pyridine and the mixture was stirred at 20° C. for 17 hours and was poured into 2N hydrochloric acid solution with stirring. The decanted aqueous phase was extracted with benzene and the organic phase was washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 1.4 g of 1-acetyloxy-3-(2-butenyl)-cyclopentane.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:28])[N:10]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH2:25][CH2:26][CH3:27])[CH:19]=1)[CH3:4].[CH3:29][O:30][C:31](=[O:40])[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)Br>O1CCCC1>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:28])[N:10]2[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH2:32][C:31]([O:30][CH3:29])=[O:40])=[C:20]([CH2:25][CH2:26][CH3:27])[CH:19]=1)[CH3:4]
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CCCc1cc(Cn2c(=O)ccc3c(CC)nc(CC)cc32)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(Cn2c(=O)ccc3c(CC)nc(CC)cc32)ccc1Oc1ccccc1CC(=O)OC
Reaction time: 0.33 h
Yield: 47.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 51 mg) was added to a solution of compound F (440 mg) in tetrahydrofuran (15 ml) under an atmosphere of argon. The mixture was stirred for 20 minutes and then methyl-α-bromophenylacetate (320 mg) in tetrahydrofuran (5 ml) was added. The mixture was stirred for 18 hours and then volatile material was removed by evaporation. The residue was partitioned between ethyl acetate (25 ml) and water (25 ml) and the organic layer was separated, washed with saturated sodium chloride solution (25 ml) and dried (MgSO4). Volatile material was removed by evaporation and the residue was purified by flash chromatography, eluting with methanol/dichloromethane (1:199 v/v) to give methyl 2-[4-((5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-1-yl)methyl)-2-propylphenoxy]phenylacetate (A) (300 mg) as an oil; NMR: 0.9(t, 3H), 1.2(t, 3H), 1.35(t, 3H), 1.55-1.7(m, 2H), 2.7(t, 2H), 2.8(q, 2H), 3.1(q, 2H), 5.4(s, 2H), 5.6(s, 1H), 6.65(d, 1H), 6.75(d, 1H), 6.9(s, 1H), 6.95(d, 1H), 7.1(s, 1H), 7.3-7.4(m, 3H), 7.5-7.6(m, 2H), 7.95(d, 1H).
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:29])[CH:11]2[NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[C:8]=1[C:30]([O-:32])=[O:31])(=[O:4])[CH3:3].Cl[CH2:34][O:35][C:36](=[O:49])[C@H:37]([CH:46]([CH3:48])[CH3:47])[NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C)C=O.C(OCC)(=O)C>[C:42]([O:41][C:39]([NH:38][CH:37]([CH:46]([CH3:48])[CH3:47])[C:36]([O:35][CH2:34][O:31][C:30]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:28])[CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22]1)[C:10]2=[O:29])=[O:32])=[O:49])=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CSC12)n1cccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)=C(COC(C)=O)CSC12)n1cccc1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared by the general procedure described in W. German Offen. No. 2,236,620 are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 3-[(acetyloxy)methyl]-7-[[2-carboethoxy-2-(1-pyrryl)acetyl]-amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedures to give the title compound.
Reaction SMILES: C1([C@H](N[C@@H:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][C@H:11]2[C:23]([O:25][CH2:26][CH3:27])=[O:24])C)C=CC=CC=1.CC[O-:30].[Na+]>CCO>[O:30]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH:11]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CC[O-]
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N[C@H](C)c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
A mixture of 252D (460 mg, 1.22 mmol) and NaOEt (1.25 mL, 21% wt in EtOH) in EtOH (10 ml) was stirred at 50° C. for 3 hrs, then at RT for about 48 hours. The reaction mixture was concentrated in vacuo, followed by the addition of water. The mixture was acidified with 1N HCl to pH 4–5 and the solid was collected by filtration, washed with water and dried to give 300 mg (yield: 71%) of 252A. It had an analytical HPLC retention time=2.065 min. (Chromolith SpeedROD column 4.5×50 mm, 10–90% aqueous methanol containing 0.1% TFA over 4 min, 4 mL/min, monitoring at 220 nm). Mass (M+1)+=349.
Reaction SMILES: C(O)C.[CH:4]1([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22]4)=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5]1.[OH-].[Na+]>O>[CH:4]1([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22]4)=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)[CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccn(-c2ccc(OC3CCN(C4CCC4)CC3)cc2)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To an ethanol (8 mL) solution of methyl 1-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-1H-pyrrole-3-carboxylate (1.4 g) synthesized in Example 1, 6 N aqueous sodium hydroxide solution (1.32 mL) was added and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was left to cool to room temperature and, after adding water, extracted with chloroform. The aqueous layer was neutralized with hydrochloric acid and extracted with chloroform. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the titled compound as a colorless amorphous substance (1.22 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][OH:20])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[OH-].[Na+].S([O-])([O-])(=O)=O.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>O.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:21][O:22][CH3:23])=[C:10]([CH2:19][O:20][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(CO)c(COC)nc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCn1ncc2c(-c3cncc(C)c3)c(COCC(=O)OC(C)(C)C)c(COC)nc21
Reaction time: 2 h
Yield: 68.1 %

Procedure:
[1-Ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (57 mg), toluene (0.3 ml), 50% aqueous NaOH solution and tetrabutylammonim sulfate (32 mg) were stirred at room temperature. tert-Butyl bromoacetate (53 mg) was added dropwise and stirring was continued for 2 hours. Water (3 ml) was added and organic layer was separated. Water layer was extracted with EtOAc (×2). Organic layer was combined and dried over MgSO4. The solvent was evaporated to give dark brown oil. The crude compound was purified by flash column chromatography on silica gel (CHCl3:MeOH=50:1) to give tert-butyl {[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]methoxy}acetate (53 mg) as colorless oil
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH:38]3[CH2:40][CH2:39]3)(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)O)cnn23)c1
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 66.2 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.095 g, 0.19 mmol) obtained in step 4 and cyclopropanesulfonamide (0.12 g, 0.95 mmol), the title compound (0.076 g, 66%) was obtained.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([CH:21](O)[OH:22])[O:19][CH:20]=2)[N:11]=1.[CH3:29][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:22])[CH3:29])[O:19][CH:20]=2)[N:11]=1
Reactant: C[Mg]Br
Reactant: O=C(Nc1cnn(Cc2coc(C(O)O)n2)n1)OCc1ccccc1Cl
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1nc(Cn2ncc(NC(=O)OCc3ccccc3Cl)n2)co1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(2-dihydroxymethyl-oxazol-4-ylmethyl)-2H-[1,2,3]triazol-4-yl]-carbamic acid 2-chloro-benzyl ester (19 mg, 0.05 mmol) in THF (1.0 mL) was treated at −65° C. with methylmagnesium bromide (0.15 mL of a 1M solution in THF, 0.15 mmol). The reaction mixture was then stirred at −65° C. for 1 h. The reaction mixture was then slowly warmed to rt and stirred at this temperature for 45 min. Sat. aq. NH4Cl was then added and the aq. layer was extracted with EA (3×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The residue was purified by FC (EA) to give the title compound as a yellow oil. TLC: rf (EA)=0.30. LC-MS-conditions 02: tR=0.89 min, [M+H]+=378.30.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Cl:9][C:4]1[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: C1CNCCN1
Product: Clc1ccc(N2CCNCC2)cc1Cl
Yield: 48.2 %

Procedure:
Beginning with 4-bromo-1,2-dichlorobenzene (200 mg, 0.88 mmol) and piperazine (91 mg, 1.06 mmol), 98 mg of the title compound was recovered by the procedure described in Example 1.
Reaction SMILES: O.NN.[CH2:4]([N:11]1[CH2:15][CH2:14][C:13]([CH2:19][N:20]2C(=O)C3C(=CC=CC=3)C2=O)([CH2:16][O:17][CH3:18])[CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(O)C>[CH2:4]([N:11]1[CH2:15][CH2:14][C:13]([CH2:19][NH2:20])([CH2:16][O:17][CH3:18])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COCC1(CN2C(=O)c3ccccc3C2=O)CCN(Cc2ccccc2)C1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COCC1(CN)CCN(Cc2ccccc2)C1
Yield: 89.5 %

Procedure:
Hydrazine hydrate (85% solution in water, 0.372 g, 6.32 mmol) is added to a solution of 2-(1-benzyl-3-methoxymethylpyrrolidin-3-ylmethyl)isoindole-1,3-dione (Example A20, 1.581 g, 4.34 mmol) in ethanol (50 mL). The resulting mixture is refluxed for 4.5 hours, cooled and acidified with concentrated hydrochloric acid. The precipitate is removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in ethanol/water (2:1) and the insoluble material is removed by filtration. The filtrate is basified to pH 10 with 1N sodium hydroxide solution and extracted with dichloromethane. The combined organic extracts are dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (0.910 g). 1H NMR (200 MHz, CDCl3): δ 7.41–7.15 (m, 5H), 3.57 (s, 2H), 3.33 (s, 3H), 3.30 (s, 2H), 2.71 (s, 2H), 2.64–2.51 (m, 2H), 2.42–2.24 (m, 2H), 1.68–1.52 (m, 2H), 1.38–1.10 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>ClC(Cl)C>[Cl:1][C:2]1[N:7]=[N:6][C:5](/[N:8]=[C:9](\[Cl:16])/[C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Cl)nn1)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: FC(F)(F)/C(Cl)=N/c1ccc(Cl)nn1
Temperature: 25 °C

Procedure:
A solution of 3.8 g (17 mmol) of the crude product of Step A and 4.2 g (22 mmol) of phosphorous pentachloride in 200 mL of dichloroethane was heated at reflux temperature under nitrogen. After 6 h the reaction was cooled to ambient temperature then concentrated in vacuo to yield a crude oil which was carried on to Step C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.ClC1C=C[C:21]([C:24]2[O:28][N:27]=[C:26]([C:29](O)=O)[C:25]=2C)=CC=1>>[Cl:1][C:2]1[C:3]([C:14]([NH:27][C@@H:26]2[CH2:29][CH2:21][C@H:24]([OH:28])[CH2:25]2)=[O:16])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1
Reactant: Cc1c(C(=O)O)noc1-c1ccc(Cl)cc1
Reactant: O=C(O)c1noc(-c2ccc(Cl)cc2)c1Cl
Product: O=C(N[C@@H]1CC[C@H](O)C1)c1noc(-c2ccc(Cl)cc2)c1Cl

Procedure:
Using 4-chloro-5-(4-chlorophenyl)isoxazole-3-carboxylic acid, synthesised according to Example 1, in place of 5-(4-chlorophenyl)-4-methylisoxazole-3-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].[CH3:20][C:21]([CH3:23])=O>O>[N+:14]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:21]([CH3:23])([CH3:20])[O:19][CH:17]([CH3:18])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(C)=O
Reactant: CC(O)c1cc(-c2cccc([N+](=O)[O-])c2)ccc1N
Solvent: O
Product: CC1OC(C)(C)Nc2ccc(-c3cccc([N+](=O)[O-])c3)cc21

Procedure:
Prepared from 1-(4-amino-3′-nitro-biphenyl-3-yl)-ethanol and acetone in the same fashion as that of Example 4. Yellow solid: mp 188-189° C.; Anal. Calc. For C17H18N2O3.0.35 H2O: C, 67.02; H, 6.19; N, 9.20. Found: C, 66.7; H, 5.89; N, 9.03.