Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([OH:17])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([N:20]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH3:35])[C@H:15]([CH3:18])[O:14][C:13](=[O:19])[C@@H:12]([N:20]([C:21]([O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:27])[C:28](=[O:29])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2ccccc2)[C@H]1O
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
To a solution of tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-hydroxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (250 mg, 0.521 mmol, 1.00 equiv) in CH2Cl2 (5.2 mL, 0.1 M) at 0° C. (ice water bath) were added proton sponge (335 mg, 1.56 mmol, 3.00 equiv) and trimethyloxonium tetrafluoroborate (116 mg, 0.782 mmol, 1.50 equiv). The resulting white suspension was stirred at 0° C. for 30 minutes (min), removed from the cold bath and stirred at room temperature for 5 h, and then poured into ½ sat'd NaHCO3 solution (20 mL). The mixture was extracted with CH2Cl2 (3×20 mL), and the combined organic phases were washed with 1N HCl (20 mL), dried over Na2SO4, filtered, and concentrated to provide an oil. Purification by automated silica gel column chromatography provided tert-butyl N-[(3S,7S,8R,9S)-7-benzyl-8-methoxy-9-methyl-2-oxo-1,5-dioxonan-3-yl]-N-tert-butoxycarbonylcarbamate (220 mg, 85%) as a colorless, sticky solid: IR (ATR) 2979, 2935, 2831, 1742, 1706, 1455, 1293, 1254, 1170, 1144, 1121, 1098, 1057, 913, 853, 732 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.32-7.24 (m, 2H), 7.22-7.15 (dd, J=5.1, 2.6 Hz, 3H), 5.18-5.06 (dd, J=8.6, 6.3 Hz, 1H), 4.94-4.79 (dq, J=9.1, 6.3 Hz, 1H), 4.16-4.01 (dd, J=11.8, 6.3 Hz, 1H), 3.94-3.76 (dd, J=11.8, 8.7 Hz, 1H), 3.59-3.50 (d, J=10.5 Hz, 1H), 3.50-3.45 (s, 3H), 1.50-1.45 (m, 21H), 3.42-3.32 (dd, J=10.8, 6.2 Hz, 1H), 3.14-3.01 (m, 2H), 2.47-2.31 (t, J=12.4 Hz, 1H), 2.08-1.89 (s, 1H), 1.53-1.43 (s, 18H); 13C NMR (101 MHz, CDCl3) δ 169.94, 152.62, 139.87, 129.25, 128.33, 126.03, 86.42, 83.03, 75.09, 70.91, 59.58, 57.42, 46.62, 35.15, 27.92, 18.92; HRMS-ESI (m/z) [M+Na]+ calc'd for C26H39NO8Na, 516.2568. found, 516.2572.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][NH2:11].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][NH2:11])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(NN)n1
Temperature: 25 °C
Reaction time: 13 h
Yield: 96.1 %

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (10 g, 0.061 mol) in dry THF (500 ml) was added anhydrous hydrazine (1.96 g, 0.061 mol) followed by potassium carbonate (12.7 g, 0.092 mol). The reaction mixture was stirred at room temperature for 13 h and filtered. The filtrate was evaporated under reduced pressure to afford 9.3 g (45%) of the titled compound as a solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH:6]=[CH:7][CH:8]=1)#[N:2].C([O-])=O.[NH4+]>CO.O1CCCC1.[Zn]>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[NH2:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(C#N)c1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N)cc1-c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Zinc dust (20.26 g, 310 mmol) was added in portions over five minutes to a solution of 2-(3-cyanophenyl)-4-nitroanisole (15.7 g, 62 mmol) and ammonium formate (19.48 g, 310 mmol) in methanol (500 mL) and tetrahydofuran (500 mL). The reaction was complete after stirring for one hour at room temperature. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified using flash chromatoghraphy on silica gel eluting with 5% methanol in dichloromethane to give 3-(3-cyanophenyl)-4-methoxyaniline (10 g, 44 mmol) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C1N=C[N:15](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[NH4+].[NH4+].O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)c(C(N)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a solution of 2-bromo-5-methoxybenzoic acid (21.6 mmol) in DMF (20 mL) was added N,N-carbonyldiimidazole (54.1 mmol). The reaction mixture was allowed to stir at rt for 30 min and then ammonium carbonate (97.4 mmol) was added in portions over several minutes. The reaction mixture was allowed to stir until for 5 days and then poured into water. A white precipitate formed. The mixture was extracted with EtOAc. The organic solutions were combined, washed sequentially with water, 1N HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4 filtered and concentrated to give 2-bromo-5-methoxybenzamide (18.5 mmol, 85%), which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][C:15]([NH2:18])=[C:14]4[O:19][C:20]([C:22]5[C:30]6[C:25](=[CH:26][N:27]=[CH:28][CH:29]=6)[S:24][CH:23]=5)=[CH:21][C:13]=34)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[C:40](O)(=[O:49])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[NH2:18][C:15]1[N:16]=[CH:17][C:12]([C:10]2[CH:9]=[N:8][N:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:40](=[O:49])[CH2:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:6][CH2:5]3)[CH:11]=2)=[C:13]2[CH:21]=[C:20]([C:22]3[C:30]4[C:25](=[CH:26][N:27]=[CH:28][CH:29]=4)[S:24][CH:23]=3)[O:19][C:14]=12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3csc4cnccc34)oc12
Reactant: O=C(O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(-c2cnn(C3CCN(C(=O)CCc4ccccc4)CC3)c2)c2cc(-c3csc4cnccc34)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-piperidin-4-yl-1H-pyrazol-4-yl)-2-thieno[2,3-c]pyridin-3-yl-furo[2,3-c]pyridin-7-ylamine (20.8 mg, 0.05 mmol) in DMF (0.5 mL) was added diisopropylethylamine (0.05 mL, 6.5 mmol), dihydrocinnamic acid (0.06 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride (13.5 mg, 0.07 mmol). The resulting solution was allowed to stir at room temperature overnight. The mixture was concentrated and then purified by MDP to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 9.50 (s, 1H), 9.10 (s, 1H), 8.59 (d, J=6.1 Hz, 1H), 8.72 (d, J=6.1 Hz, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 7.88 (s, 1H), 7.87 (s, 1H), 7.28 (s, 5H), 4.54 (m, 1H), 4.04 (m, 2H), 3.10 (m, 2H), 2.99 (m, 2H), 2.67 (m, 2H), 2.19 (m, 2H), 1.95 (m, 2H); MS (ESI): 549.64 [M+H]+; HPLC tR=0.86 min (HPLC: Analytical—2 min).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[O:5][C:4]([CH:8]=[CH2:9])=[N:3]1.[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH2:15]>COC(C)(C)C>[CH3:11][O:12][CH:13]([O:16][CH3:17])[CH2:14][NH:15][C:6]([C:2]([NH:3][C:4](=[O:5])[CH:8]=[CH2:9])([CH3:10])[CH3:1])=[O:7]
Reactant: COC(CN)OC
Reactant: C=CC1=NC(C)(C)C(=O)O1
Solvent: COC(C)(C)C
Product: C=CC(=O)NC(C)(C)C(=O)NCC(OC)OC

Procedure:
62.62 g (0.45 mol) of 4,4-dimethyl-2-vinyl-4H-oxazol-5-one (azalactone) are introduced into 275 g of tert-butyl methyl ether. 47.34 g (0.45 mol) of aminoacetaldehyde dimethyl acetal are slowly added with stirring. The product is formed as a white precipitate, which is filtered off, washed with tert-butyl methyl ether and dried, giving 106 g (96.5% of theory) of a white product of melting point 80-82° C.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)/[C:5](=[CH:13]/[C:14]([OH:16])=O)/[CH2:4]1)[CH3:2].[Cl:17]CCl>>[CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)/[C:5](=[CH:13]/[C:14]([Cl:17])=[O:16])/[CH2:4]1)[CH3:2]
Reactant: CCC1C/C(=C\C(=O)O)c2cc(F)ccc21
Reactant: ClCCl
Product: CCC1C/C(=C\C(=O)Cl)c2cc(F)ccc21

Procedure:
This compound was prepared in an analogous manner to Example 18h with replacement of (E)-2-(6-fluoro-3-methyl-1-indanylidene)acetic acid with (E)-2-(3-ethyl-6-fluoro-1-indanylidene)acetic acid (5.7 g, 25.88 mmol). The product residue was dissolved in dichloromethane and used without purification in Example 26.
Reaction SMILES: I[C:2]1[CH:14]=[C:13]([C:15]([CH3:22])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:16])[CH:12]=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[C:23]([C:27]1[CH:28]=[CH:29][C:30]2[NH:31][C:32]3[C:37]([C:38]=2[CH:39]=1)=[CH:36][C:35]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:34][CH:33]=3)([CH3:26])([CH3:25])[CH3:24].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[C:23]([C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:2]3[CH:14]=[C:13]([C:15]([CH3:22])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:16])[CH:12]=[CH:11][C:3]=3[O:4][CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][O:6]3)[C:32]3[C:37]([C:38]=2[CH:39]=1)=[CH:36][C:35]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:34][CH:33]=3)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)CC(C)(C)c1ccc(OC2CCCCO2)c(I)c1
Reactant: CC(C)(C)c1ccc2[nH]c3ccc(C(C)(C)C)cc3c2c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(C)(C)c1ccc(OC2CCCCO2)c(-n2c3ccc(C(C)(C)C)cc3c3cc(C(C)(C)C)ccc32)c1

Procedure:
To a 50 mL three necked round bottom flask equipped with a stir bar and condenser under N2 atmosphere add 20 mL of dry toluene, 5.00 g (12.01 mmol) of 2-(2-iodo-4-(2,4,4-trimethylpentan-2-yl)phenoxy)tetrahydro-2H-pyran (P5), Preparation 5; 3.56 g (12.01 mmol) of 3,6-di-t-butyl carbazole (P1), Preparation 1; 0.488 g (2.56 mmol) of CuI, 7.71 g (36.22 mmol) of K3PO4, and 0.338 g (3.84 mmol) of N,N′-dimethylethylenediamine. Reflux the reaction mixture for 48 hours, cool it, filter it through a bed of silica gel, rinse the silica gel with tetrahydrofuran (THF), and concentrate the organics to give a crude residue. Crystallize the crude residue using acetonitrile to yield 4.57 g (67.01%) of (P6) as a white solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:2]1.[Cl:16]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:16][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc(-c2ccoc2)c1
Solvent: CC(=O)O
Product: COC(=O)c1cccc(-c2ccoc2Cl)c1
Temperature: 110 °C
Yield: 20.5 %

Procedure:
A solution of methyl 3-(furan-3-yl)benzoate (1.0 g) in acetic acid (5 ml) was stirred at 110° C., and to this was slowly added N-chlorosuccinimide (0.66 g). The mixture was heated at 110° C. for 1.5 hours and then cooled to room temperature. The reaction mixture was poured onto water and the product was extracted with ethyl acetate, washed successively with water, hydrochloric acid, and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane:toluene (2:1) to afford methyl 3-(2-chlorofuran-3-yl)benzoate (0.24 g).
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([S:22]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30](C(OCC)=O)[CH:29]=[CH:28]3)(=[O:24])=[O:23])[CH:3]=1.C1([OH:45])C=CC=CC=1>>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([S:22]([C:4]3[CH:3]=[C:2]([OH:45])[C:7]4[O:8][C:9]5[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C:10]=5[C:6]=4[CH:5]=3)(=[O:24])=[O:23])=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: Oc1ccccc1
Reactant: CCOC(=O)n1ccc2cc(S(=O)(=O)c3cc(Cl)c4oc5c(c4c3)CN(C(=O)OC(C)(C)C)CC5)ccc21
Product: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(S(=O)(=O)c4ccc5[nH]ccc5c4)cc3c2C1
Yield: 65 %

Procedure:
The product of step A was converted to the phenol derivative using the procedure of Example 54, step A. Purification by flash column chromatography (SiO2, 3:7 hexane/ethyl acetate) provided tert-butyl 8-((1H-indol-5-yl)sulfonyl)-6-hydroxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (90 mg, 65%) as a yellow solid: 1H NMR (CDCl3, 400 MHz) δ 8.98 (s, 1H), 8.22 (s, 1H), 7.77-7.17 (m, 4H), 6.51 (s, 1H), 4.49 (s, 2H), 3.80-3.67 (m, 2H), 2.80-2.63 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: COC([O:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([O:12][CH2:13][C@H:14]([CH3:17])[CH2:15][CH3:16])=[O:11])=[CH:8][CH:7]=1)=O.N>C(O)C>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][C@H:14]([CH3:17])[CH2:15][CH3:16])=[O:11])=[CH:18][CH:19]=1
Reactant: CC[C@@H](C)COC(=O)c1ccc(OC(=O)OC)cc1
Agent: N
Solvent: CCO
Product: CC[C@@H](C)COC(=O)c1ccc(O)cc1

Procedure:
Compound 4, 10.5 g, 39 mmol; ethanol, 200 ml; aqueous ammonia, 50 ml.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]3[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[C:30](I)=[N:29]3)[C@@H:22]([CH3:39])[CH2:21]2)=[C:14]([F:40])[CH:13]=1>O1CCCC1.C(OCC)(=O)C.[Cl-].[Cl-].[Zn+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:38])[CH2:27][N:28]3[C:32]4=[N:33][CH:34]=[CH:35][CH:36]=[C:31]4[C:30]([C:2]4[O:1][CH:5]=[CH:4][N:3]=4)=[N:29]3)[C@@H:22]([CH3:39])[CH2:21]2)=[C:14]([F:40])[CH:13]=1
Reactant: COc1cc(N2CCN(C(=O)Cn3nc(I)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Reactant: c1cocn1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncco4)c4cccnc43)[C@@H](C)C2)c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
To a solution of oxazole (40 μL, 0.54 mmol, 3 equiv) in tetrahydrofuran (1 mL) under nitrogen atmosphere, was added dropwise n-butyl lithium (2.5 M in Hexane, 220 μL, 0.54 mmol, 3 equiv.). The resultant mixture was stirred at −78° C. for an additional 30 min followed by the addition of ZnCl2 (0.5M in THF, 1.5 mL, 0.72 mmol, 4 equiv.). The reaction solution was allowed to warm to 0° C. and stirred 1 hr followed by the addition of 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-ethanone (100.2 mg, 0.18 mmol, 1 equiv) and palladium tetrakis(triphenylphosphine) (22.3 mg, 0.018, 0.1 equiv). The reaction mixture was then heated to reflux for 48 hr, cooled to room temperature and diluted with ethyl acetate (150 mL). The reaction mixture was washed with water (20 mL), brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to provide the crude product. Purification by preparative HPLC provided the desired product 1-[4-(4-chloro-2-fluoro-5-methoxy-phenyl)-2-(S)-methyl-piperazin-1-yl]-2-(3-oxazol-2-yl-pyrazolo[3,4-b]pyridin-1-yl)-ethanone as a white powder (38.5 mg): LCMS (ES) M+H 485.5, Rf 2.56 min (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C., 1 ml/min flow rate, a 2.5 min gradient of 20% to 100% B with a 1.1 min wash at 100% B; A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][C:18]=1[CH3:26].O[N:28]=[C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH3:38])[NH2:30].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:25][N:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[N:28]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1ccccc1C(N)=NO
Reactant: COc1ccc(-c2ccc(C(=O)O)cc2C)c(OC)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(-c3nc(-c4ccccc4OC)no3)cc2C)c(OC)c1

Procedure:
Oxalyl chloride (112 μL; 1.32 mmol; 3 eq.), Intermediate 28 (120 mg; 0.44 mmol; 1 eq.), Intermediate 1 (73 mg; 0.44 mmol, 1 eq.) and DIEA (228 μL; 1.32 mmol; 3 eq.) were reacted according to general procedure 2. Purification by precipitation from DCM/n-pentane afforded the title compound as a yellow solid.
Reaction SMILES: [Na].[CH3:2][CH:3]([C:5](C)([OH:23])[CH:6]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:4].[CH3:25]O>>[CH3:25][C:3]([CH3:2])([CH:5]([OH:23])[CH:6]([N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH3:4]
Reactant: CC(C)C(C)(O)C(CCCCOc1ccccc1)n1cncn1
Reactant: CO
Agent: [Na]
Product: CC(C)(C)C(O)C(CCCCOc1ccccc1)n1cncn1

Procedure:
72 g of solid sodium borohydried are added, a little at a time, to a stirred solution of 600 g of 2,3-dimethyl-4-(1,2,4-triazol-1-yl)-8-phenoxy-octan-3-ol in 1,000 ml of methanol; during the addition, the mixture reaches the refluxing temperature. When the exothermic reaction has subsided, the mixture is evaporated to dryness under reduced pressure. 500 ml of water are added to the residue and the batch is extracted three times with 300 ml of methylene chloride at a time. The combined organic phases are dried over magnesium sulfate and filtered, and the filtrate is concentrated under reduced pressure. 200 ml of diisopropyl ether are added to the residue, and 360 g of colorless crystals, of melting point 79°-81° C., are isolated from this mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][CH3:13])[C:7]3=[CH:14][C:15]([C:17]([O:19]CC)=[O:18])=[N:16][N:6]3[C:5](=[O:22])[C:4]=2[CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][CH3:13])[C:7]3=[CH:14][C:15]([C:17]([OH:19])=[O:18])=[N:16][N:6]3[C:5](=[O:22])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1cc2n(CC)c3ccc(Cl)cc3c(=O)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1c2ccc(Cl)cc2c(=O)n2nc(C(=O)O)cc12

Procedure:
From 11.2 g of 7-chloro-4-ethyl-4,9-dihydro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid, ethyl ester, 100 ml of 1 N aqueous sodium hydroxide and 250 ml of methanol, following the procedure of Example 14, there if obtained 7-chloro-4-ethyl-4,9-dihydro-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid; mp 267°-268° C. (d), after crystallization from dimethylformamide/methanol.
Reaction SMILES: [C:1]([C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([NH:12][C@H:13]([C@H:17]([OH:19])[CH3:18])[C:14]([OH:16])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=1)#[N:21].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1.CN(C=O)C>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:28][NH:29][C:14](=[O:16])[C@H:13]([NH:12][C:6]2[C:7]3[CH:11]=[CH:10][S:9][C:8]=3[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C@H:17]([OH:19])[CH3:18])=[O:27])=[CH:30][CH:31]=1)#[N:21]
Reactant: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)O
Reactant: N#Cc1ccc(C(=O)NN)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: C[C@@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a mixture of (2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoic acid (1.0 g, 3.62 mmol), 4-cyanobenzhydrazide (590 mg, 3.66 mmol), HOBt (495 mg, 3.66 mmol) in THF:DMF (1:1) (40 mL) was added EDC (1.05 g, 5.48 mmol) and Et3N (0.80 mL, 5.74 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min., then at room temperature overnight. The reaction was quenched by adding water and extracted with EtOAc (500 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent and purification of the residue gave the title compound 4-cyano-N′-((2R,3R)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (1.25 g, 82%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.10 (d, J=8.6 Hz, 2H), 7.93 (d, J=8.6 Hz, 2H), 7.83 (d, J=5.5 Hz, 1H), 7.71 (d, J=5.5 Hz, 1H), 7.67 (d, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 6.35 (d, J=7.8 Hz, 1H), 4.26 (m, 2H), 1.42 (d, J=6.3 Hz, 3H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:42])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:39][CH3:40])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:38])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:41])[CH:12]=1.C(=O)(O)[O-].[Na+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:42])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:41])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:38])[CH:23]=1)[CH2:39][CH3:40])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCCCCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 100 °C
Yield: 25.2 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.50 mL, 1.0 mmol) was added to a solution of the mixture containing {5-[4-(1-ethyl-1-{4-[2-(1-hydroxy-cycloheptyl)-(E)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (65.3 mg) in methanol (1.0 mL), and the mixture was stirred with microwave heating at 100° C. for five minutes. A sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate and washing with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (Shiseido CAPCELL PAK C18 MGII, 20 mm I.D.×50 mm, methanol:20 mM ammonium acetate solution=55:45 to 100:0, 20 mL/min). A sodium bicarbonate solution was added to the eluate, followed by extraction with ethyl acetate and washing with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the target compound as a colorless oil (16.0 mg, 30% in two steps).