Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:21][OH:22])[C:3]1[CH:4]=[CH:5][C:6]([F:20])=[C:7]([CH:19]=1)[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[CH3:23][O:24][CH2:25][C:26]1[CH:31]=[C:30]([C:32](O)=O)[CH:29]=[CH:28][C:27]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41]>>[F:20][C:6]1[CH:5]=[CH:4][C:3]([C:2]2[N:1]=[C:32]([C:30]3[CH:29]=[CH:28][C:27]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[C:26]([CH2:25][O:24][CH3:23])[CH:31]=3)[O:22][N:21]=2)=[CH:19][C:7]=1[CH2:8][N:9]([CH3:18])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Product: COCc1cc(-c2nc(-c3ccc(F)c(CN(C)CC(=O)OC(C)(C)C)c3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 60 (256.87 mg; 0.83 mmol) and Intermediate 28 (192.22 mg; 0.75 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a slightly yellow oil. 1H NMR (CDCl3) δ 8.42 (d, J=1.4 Hz, 1H), 8.27 (d, J=5.8 Hz, 1H), 8.19-8.09 (m, 2H), 7.36-7.12 (m, 6H), 4.23 (s, 2H), 3.92 (s, 2H), 3.33 (s, 3H), 3.29 (s, 2H), 2.48 (s, 3H), 2.08 (s, 3H), 1.51 (s, 9H). LC/MS (Method B): 532.3 (M+H)+. HPLC (Method A) Rt 4.85 min (Purity: 98.6%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22]CC2C=CC=CC=2)[CH:17]=1)(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C.C(O)C>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(=O)c2cccc(OCc3ccccc3)c2)[nH]c2cc(Cl)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C(=O)c2cccc(O)c2)[nH]c2cc(Cl)ccc12
Yield: 39.5 %

Procedure:
3-Acetylamino-2-(3-benzyloxybenzoyl)-6-chloroindole (Example 44, 0.42 g, 1.0 mmol) was hydrogenolyzed in the presence of palladium on activated carbon (10%, 0.10 g) in a mixture of ethyl acetate (10 ml) and ethanol (1.0 ml) at atmospheric pressure overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residual solid was recrystallization from ethyl acetate/hexane to afford 0.13 g (40%) of the title compound as a pale yellow solid. m.p.: 130-145° C. 1H-NMR (CDCl3) δ: 11.73 (1H, brs), 9.80-9.65 (2H, m), 7.62 (1H, d, J=8.4 Hz), 7.50-6.98 (5H, m), 1.76 (3H, s) The signal due to H of OH was not observed.
Reaction SMILES: O1CCOCC1.O.C([O:14][C@H:15]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][CH2:18][NH:17][CH2:16]1)(=O)C(C)(C)C.O.[OH-].[Li+]>C(Cl)(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C@H:15]([OH:14])[CH2:16][NH:17][CH2:18][CH:19]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)O[C@@H]1CNCC=C1c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: O[C@@H]1CNCC=C1c1ccc(F)cc1
Yield: 46 %

Procedure:
To a 1,4-dioxane (11 mL)-water (6.5 mL) solution of the crude product of (S)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-3-yl pivalate synthesized in Reference Synthesis Example 137, lithium hydroxide monohydrate (1.54 g, 36.7 mmol) was added and the resultant mixture was stirred at 115° C. for 3 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with chloroform was performed. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=32/1→13/7) to obtain the title compound (383 mg, two step yield 46%).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([Cl:48])=[C:22]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[CH2:32][NH:33][C:34](=[O:47])[CH:35]=[CH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43](=[O:46])[NH:44][CH3:45])=[CH:39][CH:38]=2)[CH:23]=[CH:24][C:25]=1[Cl:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:48][C:21]1[C:20]([CH2:19][OH:18])=[C:25]([Cl:26])[CH:24]=[CH:23][C:22]=1[N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][NH:33][C:34](=[O:47])[CH:35]=[CH:36][C:37]1[CH:38]=[CH:39][C:40]([C:43](=[O:46])[NH:44][CH3:45])=[CH:41][CH:42]=1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CO)c2Cl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.3 %

Procedure:
To a solution of 1-[3-(tert-butyldiphenylsilyloxymethyl)-2,4-dichlorophenyl]-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (620 mg) in tetrahydrofuran (6 ml) was added 1N solution of tetrabutylammonium fluoride in tetrahydrofuran (2.5 ml). The mixture was stirred at ambient temperature for 6 hours and partitioned between ethyl acetate and water. The organic layer was isolated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with methanol to give 1-(2,4-dichloro-3-hydroxymethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (197 mg) as a brownish powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:41])[C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:31][CH:30]=2)=[CH:20][CH:19]=1)[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:41])[C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:31][CH:30]=2)=[CH:20][CH:19]=1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O)OCc1ccccc1
Yield: 73.9 %

Procedure:
In a similar manner to that described in Example 2, methyl (S)-2-benzyloxycarbonylamino-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (200 mg), which is the product of Example 167, was reacted with aqueous sodium hydroxide solution (1N, 0.72 ml) and the reaction mixture was treated to give the title compound (144 mg) as a mass of foam.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:37])=[C:5]([C:28]([O:35]C)=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:32][O:31][C:30]1[C:3](=[O:2])[C:4]([CH3:37])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])[C:28](=[O:35])[C:29]=1[O:33][CH3:34]
Reactant: COc1c(C)c(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(Oc3cccnc3)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 53 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyloxy)benzoyl]piperidine (0.050 g, 0.099 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.135 g, 0.247 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) to obtain the titled compound (0.025 g, 0.0525 mmol, 53%).
Reaction SMILES: [CH:1]([CH:4]([CH:8]([CH3:10])[CH3:9])[C:5]([NH2:7])=[O:6])([CH3:3])C.[CH3:11]OC(C)(C)C>>[CH2:1]([C@@H:4]([CH:8]([CH3:9])[CH3:10])[C:5]([NH2:7])=[O:6])[CH2:3][CH3:11]
Reactant: COC(C)(C)C
Reactant: CC(C)C(C(N)=O)C(C)C
Product: CCC[C@H](C(N)=O)C(C)C
Reaction time: 0.01 h

Procedure:
Assay of plasma samples: to test tubes containing 2 μg of the internal standard (diisopropyl acetamide), 0.5 ml of plasma (thawed at room temperature) and 5 ml of tert-butyl methyl ether (TBME) was added. The test tubes were vigorously vortexed for 30 sec and centrifuged at 3000 g for 10 minutes. The organic phase was separated and dried under reduced pressure using a vortex evaporator. Samples were then reconstituted with 150 μl of chloroform and dried under reduced pressure without vortexing. The sample was again reconstituted with 30 μl of chloroform, of which 2 μl were injected into the GC apparatus.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[N:6][C:5]([Cl:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(C)C>[Cl:10][C:5]1[N:6]=[C:7]([CH:8]=[N:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:2]([NH2:1])=[N:3][C:4]=1[S:11][CH3:12]
Reactant: NCc1ccccc1
Reactant: CSc1nc(N)c(C=O)nc1Cl
Solvent: CC(C)O
Product: CSc1nc(N)c(C=NCc2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 2 ml of heated isopropanol there was dissolved 2-amino-5-chloro-3-formyl-6-(methylthio)pyrazine (60 mg; 0.3 mMol) prepared in Step A above. Benzylamine (35 mg; 0.33 mMol) was then added, and the reaction mixture was heated for 2 minutes on a steam bath, and then allowed to cool to room temperature. The reaction mixture was redissolved in 5 ml of isopropanol, a 20% excess of benzylamine was added, and stirring was continued overnight at room temperature. Product precipitated, was filtered and dried (38 mg).
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C@@H:21]([CH2:22][CH2:23][C@@H:24]3[C@@H:33]2[CH2:32][CH2:31][C@@:29]2([CH3:30])[C@H:25]3[CH2:26][CH2:27][C@@H:28]2[C:38]#[C:39][C:40](=[O:42])[CH3:41])[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1.O>ClCCl>[O:42]=[C:40]([CH3:41])[C:39]#[C:38][C@H:28]1[CH2:27][CH2:26][C@H:25]2[C@H:24]3[C@H:33]([CH2:32][CH2:31][C@:29]12[CH3:30])[C@:34]1([CH3:37])[C@H:21]([CH2:20][C@H:19]([OH:18])[CH2:36][CH2:35]1)[CH2:22][CH2:23]3
Reactant: CC(=O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4[3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-yl]-3-butyn-2-one (40 mg, 0.07 mmol) in anhydrous dichloromethane (2.8 mL) was treated with HF pyridine (0.008 mL, 0.28 mmol) at 0° C. and the resulting mixture was stirred at RT for 2 h. Addition of water at 0° C. was followed by extraction with methylene chloride. The organic layer was washed with brine and was dried with Na2SO4 and the solvent was evaporated in vacuo. Subsequent purification of the residue with flash column chromatography using dichloromethane/ethyl acetate 95/5 as eluent afforded the desired compound named above.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCC)C>[CH2:19]([O:1][N:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)CC(O)CC(C)(C)N1OCc1ccccc1
Yield: 14.9 %

Procedure:
A mixture of 2.58 g (0.015 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 27.64 g (0.30 mol) of toluene under a nitrogen atmosphere is heated in a pressure vessel for 53 hours. The reaction mixture is diluted with diethyl ether and the resultant mixture is washed with 10 w/v % ascorbic acid (1×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from heptane to give 0.59 g (30% yield) of a white solid melting at 86-87° C.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.[Br:19][C:20]1[N:25]=[C:24](Br)[CH:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(O)C>[Br:19][C:20]1[N:25]=[C:24]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[CH2:7][CH2:8]2)[CH:23]=[CH:22][N:21]=1
Reactant: Brc1ccnc(Br)n1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2ncccc2n1C1CCN(c2ccnc(Br)n2)CC1

Procedure:
1.4 g (4.8 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one-dihydrochloride, 1.1 g (4.8 mmol) 2,4-dibromo-pyrimidine, a spatula tip of DMAP and 3.3 mL (19.1 mmol) DIPEA in 35 mL ethanol were stirred at RT. After the reaction had ended the precipitate was suction filtered, washed with a little ethanol and dried.
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH:14]3[CH2:15][CH:11]4[CH:12]([CH2:13]3)[CH:10]24)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH:22](Cl)[CH3:23]>CS(C)=O>[CH3:16][N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[CH2:22][CH2:23][O:8][C:7](=[C:9]1[CH:14]2[CH2:15][CH:11]3[CH:12]([CH2:13]2)[CH:10]13)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(Cl)C1CCCN1C
Reactant: O=C(c1ccccc1)C1C2CC3C(C2)C31
Solvent: CS(C)=O
Product: CN1CCCC1CCOC(=C1C2CC3C(C2)C13)c1ccccc1
Temperature: 25 °C

Procedure:
5.28 g. (0.11 mol) of a 50% sodium hydride/mineral oil dispersion were purified as in Example 6, followed by the dropwise addition while stirring under nitrogen of 80 ml. of dimethyl sulphoxide. The reaction mixture was then heated for 30 minutes at 70°-80° C. until the evolution of hydrogen stopped, after which it was cooled to room temperature and a solution of 19.83 g. (0.1 mol) of tricyclo-(2.2.1.02.6)-hept-3-yl phenyl ketone in 25 ml. of dimethyl sulphoxide added dropwise to it. After stirring for another hour at 35°-40° C., 16.25 g. (0.11 mol) of N-methyl pyrrolidyl-2-ethyl chloride in 15 ml. of dimethyl sulphoxide were added and the mixture stirred for another 2.5 hours at 35° to 40° C. The reaction mixture was then poured into 300 ml. of water, the oil precipitated was extracted with ether and the ether phase dried with anhydrous sodium sulphate. Filtration and concentration of the solvent by evaporation in vacuo left an oily residue which was converted into the hydrochloride in chloroform with 2N hydrochloric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:19](=[O:22])[CH2:20][CH3:21])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and propionyl chloride the title compound was obtained as a light yellow solid (5%), MS: m/e=322 (M+H+).
Reaction SMILES: [NH2:1][OH:2].CO.Cl[C:6]1[N:11]=[CH:10][N:9]=[C:8]2[N:12]([CH3:23])[N:13]=[C:14]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:7]=12>C(O)C>[OH:2][NH:1][C:6]1[N:11]=[CH:10][N:9]=[C:8]2[N:12]([CH3:23])[N:13]=[C:14]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:7]=12
Reactant: NO
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Solvent: CO
Solvent: CCO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(NO)ncnc21
Reaction time: 0.5 h

Procedure:
A solution containing 0.7 grams of anhydrous hydroxylamine in 50 millilitres if methanol was added to a solution containing 1.4 grams of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidine dissolved in 600 millilitres of ethanol, at a temperature of 30° C. and the mixture was allowed to stand for 30 minutes at room temperature. The mixture was gently heated at reflux for a further 15 minutes and cooled. The crystalline product was washed with ether and dried. Recrystallisation from dimethylformamide gave 4-hydroxyamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d] pyrimidine, having melting point 294° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[N:11][CH:12]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: Oc1ccccc1O
Solvent: ClCCl
Product: Oc1ccccc1Oc1ccc(Cl)cn1

Procedure:
Under nitrogen, a mixture of 15.0 grams (0.136 mole) of catechol, and 22.0 grams of 2,5-dichloropyridine was heated as a melt at 140°-150° for 12 hours. The resulting black residue was dissolved in a minimum amount of methylene chloride, i.e., about 50 ml, chromatographed through a silica gel column using methylene chloride as the eluent. The 2-(5-chloropyridin-2-yloxy)phenol was isolated in the latter fraction, whereas starting material 2,5-dichloropyridine eluted with the solvent front. Yield 8.0 grams, m.p. 97°-100°; NMR (CDCl3): δ6.70-7.70 (m's, ArH and OH), 8.0 (d, ArH); ir (Nujol): 3.20-2.80 (OH), 6.30 (C=N), 13.30 microns.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[NH:5][C:6](=O)[C:7]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:8]=2[N:9]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:35]>C(Cl)(Cl)Cl>[Cl:35][C:6]1[C:7]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][C:8]=2[N:9]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=1
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Reflux a mixture of 2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one (0.500 g, 1.49 mmol), 2,6-lutidine (0.69 mL), and POCl3 (0.555 mL) in CHCl3 (10 mL) for 5 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (MgSO4) and concentrate under reduced pressure. Purified the crude by flash column chromatography on a silica gel (EtOAc eluent) and concentrate under reduced pressure to give 4-chloro-2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:17][C:18]2[CH:22]=[C:21]([CH3:23])[O:20][N:19]=2)[C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2].FC1C=C(C=CC=1F)CNC(C1C2C(=CC(OC(C)C)=CC=2)N(CC2OC=CN=2)C=1C(C)C)=[O:31]>>[CH:1]([C:4]1[N:5]([CH2:17][C:18]2[CH:22]=[C:21]([CH3:23])[O:20][N:19]=2)[C:6]2[C:11]([C:12]=1[C:13]([OH:31])=[O:14])=[CH:10][CH:9]=[C:8]([O:15][CH3:16])[CH:7]=2)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ncco3)c2c1
Reactant: COc1ccc2c(C=O)c(C(C)C)n(Cc3cc(C)on3)c2c1
Product: COc1ccc2c(C(=O)O)c(C(C)C)n(Cc3cc(C)on3)c2c1

Procedure:
The title compound was prepared from 2-isopropyl-6-methoxy-1-((5-methylisoxazol-3-yl)methyl)-1H-indole-3-carbaldehyde (Compound 213) by General Procedure K.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9]CC)=[O:8])[O:3]1.O[Li].O.Cl.O1CCOCC1>C1COCC1.O.CO>[O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([OH:9])=[O:8])[O:3]1
Reactant: CCOC(=O)c1c[nH]c(=O)o1
Agent: Cl
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-oxo-2,3-dihydrooxazole-5-carboxylate (300 mg, 1.909 mmol) in THF (5 ml) was added LiOH.H2O (352 mg, 8.4 mmol) as a solution in water (5 ml). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. To the residue was added 4M HCl in dioxane (6 ml, 24.0 mmol) and the solid was sonicated for ˜1 minute. The solvent was removed under reduced pressure to afford a yellow solid. The solid was redissolved in MeOH and concentrated under reduced pressure. The solid was dried in the vacuum oven to afford the title compound;
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[CH:12][N:11]=2.S(=O)(=O)(O)O>O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:8](=[O:9])[CH2:3][CH2:2][CH3:7])=[CH:12][N:11]=2
Reactant: Fc1ccccc1-c1nc2cccnc2o1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCC(=O)c1cnc2oc(-c3ccccc3F)nc2c1

Procedure:
Using the procedure described in Example 1, but replacing 2-phenyloxazolo[4,5-b]pyridine by 2-(2-fluorophenyl)oxazolo[5,4-b]pyridine (J. Med. Chem. 1978, 21, 11, 1158+) and using 8.4 ml of concentrated sulfuric acid in 16.8 ml of water and 16.8 ml of acetic acid, and after purification on a column of silica (40 to 63μ; 70-230 mesh; eluent: ethyl acetate/toluene, 1:9), the product of the title is obtained.