Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([I:18])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[OH:17].[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([I:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH3:19])[CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cnc2c(F)cc(I)cc2c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(F)cc(I)cc2c1=O
Temperature: 95 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Ethyl 8-fluoro4-hydroxy-6-iodo-3-quinolinecarboxylate (18.1 g) prepared as an intermediate in Preparation No. 1 is dissolved in DMF (430 mL), and K2CO3 (36.1 g, 261 mmol) and methyl iodide (3.25 mL, 52.3 mmol) are added. The reaction mixture is heated to 95° C. for 6 h, then allowed to stir at room temperature overnight. The mixture is split into two parts. The first part is poured into H2O and extracted with five 100-mL portions of CH2Cl2. The combined organic layers are washed with five 200-mL H2O, dried over MgSO4, filtered, and concentrated in vacuo. The work-up is then repeated on the second portion of the reaction mixture to give a total of 15.8 g of the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]([C:9]1([OH:23])[CH2:12][N:11](C(OCC2C=CC=CC=2)=O)[CH2:10]1)[OH:8]>CO.[Pd]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH:7]([C:9]1([OH:23])[CH2:12][NH:11][CH2:10]1)[OH:8]
Reactant: O=C(OCc1ccccc1)N1CC(O)(C(O)CC2OCCO2)C1
Agent: [Pd]
Solvent: CO
Product: OC(CC1OCCO1)C1(O)CNC1
Yield: 100.1 %

Procedure:
Phenylmethyl 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]-3-hydroxyazetidine-1-carboxylate (235 mg, 0.728 mmol) was dissolved in methanol (5 mL) and treated with 5 wt % palladium on carbon (50 mg) under hydrogen at ambient for 1.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-[2-(1,3-dioxolan-2-yl)-1-hydroxyethyl]azetidin-3-ol (0.729 mmol): MS (EI) for C8H15NO4: 190 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:24]=[C:25]([N:33]=[C:34]=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:21][C:22]([F:36])([F:37])[C:23]1[CH:24]=[C:25]([NH:33][C:34]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:35])[CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)C(=O)C(C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C2=O
Temperature: 30 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 3,5-bis-(trifluoromethyl)phenyl isocyanate (0.51 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature, and then was heated at 30° C. for 7 hours. The reaction mixture was treated with 2N aqueous HCl and the layers separated. The acidic aqueous layer was extracted with two additional portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator to give a yellow oil, which was purified by chromatography on silica gel (10% ethyl acetate/hexane) to yield a yellow oil, which was crystallized from 95% ethanol to yield the title compound as a beige solid (0.36 g, 42% yield), mp=68–72° C.; MS (−) ESI m/z=434 (M−H)−; [α]D25=−21.0° (c=1, EtOH).
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:22][C:23]([C@@H:26]4[CH2:30][O:29]C(C)(C)[O:27]4)([CH3:25])[CH3:24])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[ClH:33]>CO>[ClH:33].[ClH:33].[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:21][CH2:22][C:23]([CH3:25])([CH3:24])[C@@H:26]([OH:27])[CH2:30][OH:29])[CH:14]=[C:15]([F:20])[CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC1(C)OC[C@@H](C(C)(C)COc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)O1
Agent: Cl
Solvent: CO
Product: CC(C)(COc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12)[C@@H](O)CO
Reaction time: 0.5 h

Procedure:
(R)-2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-8-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)-2-methylpropoxy)-6-fluoroquinoline (0.190 g, 0.435 mmol) was added to methanol saturated with HCl and stirred for 30 minutes. The solution was evaporated, DCM was added, and the material triturated and filtered to yield 140 mgs of the desired product as orange solid. MS ESI (+) m/z 397 (M+1) detected.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]3[C:45](=[O:49])[NH:46][CH:47]=[CH:48][C:43]=3[O:42][CH:41]=2)=[CH:36][CH:35]=1.[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[CH2:60][CH2:61]O.Cl>C1COCC1.CC(=O)OCC>[N:34]1[CH:35]=[CH:36][C:37]([C:40]2[C:44]3[C:45](=[O:49])[N:46]([CH2:61][CH2:60][C:51]4[CH:52]=[CH:53][C:54]5[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=5)[N:50]=4)[CH:47]=[CH:48][C:43]=3[O:42][CH:41]=2)=[CH:38][CH:39]=1
Reactant: O=c1[nH]ccc2occ(-c3ccncc3)c12
Reactant: OCCc1ccc2ccccc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1c2c(-c3ccncc3)coc2ccn1CCc1ccc2ccccc2n1
Temperature: 15 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of triphenylphosphine (247 mg, 0.942 mmol) in THF (10 mL), DIAD (0.321 mL, 1.65 mmol) was added. The mixture was cooled to 15° C. 3-(Pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one (100 mg, 0.471 mmol) and 2-(quinolin-2-yl)ethanol from example from example a1 were added. After stirring overnight at room temperature, EA and 2M HCl were added. The phases were separated and extracted with EA. The organic phase was washed with water. The acidic aqueous phase was basified with 2M NaOH and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give 69 mg of the title compound (36.3%) as hydrochloride salt as dark yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][O:24]C(C)=O)=[O:22])=[C:18]([N+:28]([O-:30])=[O:29])[CH:17]=[N:16]1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[N:15]1[C:19]([NH:20][C:21]([CH2:23][OH:24])=[O:22])=[C:18]([N+:28]([O-:30])=[O:29])[CH:17]=[N:16]1
Reactant: CC(=O)OCC(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CO)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
A mixture of 1.5 grams (0.0034 mole) of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)-5-methylcarbonyloxymethylcarbonylamino-4-nitropyrazole, 2.63 mL of a 2N aqueous sodium hydroxide solution, 1.5 mL of ethanol, and 4.7 mL of water was stirred at room temperature for 15 minutes. After the pH was adjusted to 5.0 with dilute hydrochloric acid, ethanol was removed from the mixture by distillation under reduced pressure. The remaining aqueous phase was extracted with methylene chloride, and the extract was washed with water. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.75 gram of 1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)- 5-hydroxymethylcarbonylamino-4-nitropyrazole as a solid (compound 19 of Table 1). The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:11](=O)[CH2:10][CH:9]([C:13]([O:15][CH3:16])=[O:14])[C:7](=O)[CH2:6]1)=[O:4].[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.Cl>CO>[CH3:17][O:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:7]2[CH2:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:11]([NH:23][C:22]3[CH:24]=[CH:25][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH2:10][C:9]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:20]=1
Reactant: COC(=O)C1CC(=O)C(C(=O)OC)CC1=O
Reactant: COc1ccc(N)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)C1=C(Nc2ccc(OC)cc2)CC(C(=O)OC)=C(Nc2ccc(OC)cc2)C1
Yield: 96.9 %

Procedure:
Dimethyl 1,4-cyclohexanedione-2,5-dicarboxylate (9.12 gm; 40 mmol) and methanol (200 ml) were heated to boiling, then 4-methoxyaniline (10.84 gm; 88 mmol) was added followed by conc. hydrochloric acid (400 μl). The mixture was refluxed for 2.5 hours under a nitrogen atmosphere. On cooling, an orange solid precipitated out which was collected by filtration, washed with methanol and dried under vacuum to give 17.0 gm (97%) of dimethyl 2,5-bis{(4-methoxyphenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:15](=[O:25])[CH2:14]1)C(=O)OCC1C=CC=CC=1>CO>[CH3:1][NH:2][CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[C:15](=[O:25])[CH2:14]1
Reactant: CN(C(=O)OCc1ccccc1)C1CCN(c2ccncc2)C(=O)C1
Solvent: CO
Product: CNC1CCN(c2ccncc2)C(=O)C1
Reaction time: 4 h
Yield: 77 %

Procedure:
Benzyl methyl(2-oxo-1-(pyridin-4-yl)piperidin-4-yl)carbamate (300 mg, 0.885 mmol, 1.0 eq.) was dissolved in MeOH and degassed with N2. Pd(OH)2 (240 mg) was then added and hydrogenation was carried out for 4 hours. After monitoring by TLC, the reaction mixture was filtered over Celite, the filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (Alox, 3% MeOH in DCM). Yield: 77% (140 mg, 0.683 mmol)
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[O:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.CN(C)C=O>O>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:28]=1[O:29][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[O:6][C:7]=1[CH3:8])[CH:22]=[O:21]
Reactant: Cc1oc(-c2cccnc2)nc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(-c2cccnc2)oc1C
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A mixture of 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)pyridine (3.00 g), potassium carbonate (1.89 g), vanillin (2.08 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(5-methyl-2-pyridin-3-yl-1,3-oxazol-4-yl)methoxy]benzaldehyde as colorless crystals (3.61 g, 81%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 164-165° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:33])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.F[C:35]1C=CC(C)=C(S(Cl)(=O)=O)[CH:40]=1>>[CH2:35]([O:29][C:28](=[O:30])[C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[CH3:33])(=[O:9])=[O:10])[C:16]=3[CH:17]=2)=[O:22])=[CH:32][CH:31]=1)[CH3:40]
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: Cc1ccc(F)cc1S(=O)(=O)N1CCOc2ccc(C(=O)Nc3ccc(C(=O)O)cc3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2C)CCO3)cc1

Procedure:
4-{[4-(5-Fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=468.9 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 5-fluoro-2-methyl-benzenesulfonyl chloride and yielded 4-{[4-(5-fluoro-2-methyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: Br[CH2:2][CH2:3]Br.[S:5]([O-:8])([O-:7])=[O:6].[Na+:9].[Na+]>O>[CH2:2]([S:5]([O-:8])(=[O:7])=[O:6])[CH2:3][S:5]([O-:8])(=[O:7])=[O:6].[Na+:9].[Na+:9]
Reactant: O=S([O-])[O-]
Reactant: BrCCBr
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])CCS(=O)(=O)[O-]
Yield: 65.1 %

Procedure:
A mixture of 1,2-dibromoethane (37.6 g, 0.20 tool) and sodium sulfite (63.0 g, 0.5 mol) in water (225 mL) was heated at reflux temperature for 20 h. After the mixture was cooled in the refrigerator, crystals were collected. The crude product was repeatedly recrystallized from water-ethanol. The trace amount of inorganic salts was removed by treating the aqueous solution with a small amount of silver(I) oxide and barium hydroxide. The basic solution was neutralized with Amberlite-120 ion-exchange resin and treated three times with Amberlite-120(sodium form) ion-exchange resin. After removal of the water, the product was recrystallized from water-ethanol to afford the title compound (30.5 g).
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([O:10][C:11](=[O:21])[NH:12][CH:13]1[CH2:18][CH2:17][CH:16]([CH:19]=[O:20])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7]>C1COCC1>[C:6]([O:10][C:11](=[O:21])[NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([CH:19]([C:11]2[O:10][C:1]3[CH:3]=[CH:8][CH:6]=[CH:7][C:2]=3[N:12]=2)[OH:20])[CH2:17][CH2:18]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)[Mg]Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(C=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(O)c2nc3ccccc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methoxy-benzoxazole (1490 mg, 10 mmol, obtained by methylation of 4-hydroxybenzoxazole (J. Med. Chem. (1987), 30, 62) in THF (60 ml) was added dropwise a solution of i-PrMgCl (5 ml, 2M solution in THF). The red mixture was stirred at 0° C. for 1 h before dropwise addition of (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (1360 mg, 6 mmol) dissolved in THF (10 ml). The reaction was stirred at 0° C. for 30 min and at RT for 1 h. The reaction mixture was quenched with aq. ammonium chloride solution and extracted EtOAc. The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by chromatograpy on SiO2 (hex/EtOAc 2:1, 1:1) affording 1300 mg (59%) of product as yellow oil.
Reaction SMILES: [O-:1][N+:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:17]([O:16][C:14]([N:8]([CH2:9][CH2:10][CH2:11][OH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N+:2]=1[O-:1])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: [O-][n+]1ccccc1NCCCO
Product: O=C(OCc1ccccc1)N(CCCO)c1cccc[n+]1[O-]

Procedure:
3-[N-benzyloxycarbonyl-N-(1-oxido-2-pyridinyl)amino] propanol was prepared by reaction of 3-[N-(1-oxido-2-pyridinyl)amino] propanol (obtained as described in MILLER, W. H. et al. Bioorg. Med. Chem. Lett. 1999, 9 1807-1812) with benzyl chloroformate according to the standard procedure.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:30]=[C:14]3[CH:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[CH2:16][CH2:17][CH2:18][CH2:19][N:13]3[N:12]=2)[CH:8]=[CH:7][C:6]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1.CN(C=[O:41])C>>[CH3:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[N:30]=[C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:27])([F:29])[F:28])([OH:41])[CH2:16][CH2:17][CH2:18][CH2:19][N:13]3[N:12]=2)[CH:8]=[CH:7][C:6]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1
Reactant: COc1nc(-c2nc3n(n2)CCCCC3c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: COc1nc(-c2nc3n(n2)CCCCC3(O)c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reaction time: 96 h

Procedure:
Sodium hydride (60%) was added to a solution of 2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-9-(2-trifluoromethylphenyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepine obtained in Examples 74 and 75 (83 mg) in DMF (5 mL) with stirring under ice-cooling until bubbling was stopped. Thereafter, the mixture was stirred at room temperature in an oxygen atmosphere. After four days, ice water, chloroform and a saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with toluene and concentrated under reduced pressure. The residue was diluted again with toluene and concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with chloroform and then air-dried to obtain 36.8 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][NH:12]3)[N:5]=[C:4]2[N:17]([CH3:20])[N:18]=[CH:19][C:3]=12.[CH3:21][S:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[NH:12]1[C:13]2[C:9](=[C:8]([C:6]3[N:5]=[C:4]4[N:17]([CH3:20])[N:18]=[CH:19][C:3]4=[C:2]([NH:26][CH2:25][CH2:24][CH2:23][S:22][CH3:21])[CH:7]=3)[CH:16]=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: Cn1ncc2c(Cl)cc(-c3cccc4[nH]ncc34)nc21
Reactant: CSCCCN
Product: CSCCCNc1cc(-c2cccc3[nH]ncc23)nc2c1cnn2C

Procedure:
4-Chloro-6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine 7 (100 mg) and 3-(methylthio)propylamine (3 equiv.) were heated in microwave at 170° C. for one hour following General Procedure B. Volatiles were removed in vacuo; the residue was purified by prep HPLC to give [6-(1H-indazol-4-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl]-(3-methylsulfanyl-propyl)-amine (94 mg) as a white solid. 3-Chloroperoxybenzoic acid (MCPBA, 94 mg, 2.2 equiv.) in 2 ml dry DCM was added at 0° C. The reaction mixture was allowed slowly to warm up to room temperature over 3 hours and extracted with DCM, washed with saturated aqueous sodium hydrogen carbonate and purified by flash chromatography (methanol/DCM) to give 116 (27 mg) as a white solid. NMR (CDCl3): 2.39 (2H, m), 3.00 (3H, s), 3.25 (2H, t), 3.74 (2H, m), 4.20 (3H, s), 5.20 (1H, br t), 6.77 (1H, s), 7.50-7.54 (1H, m), 7.59 (1H, d), 7.70 (1H, d), 7.97 (1G=H, s), 8.82 (1H, s), 10.20 (1H, br). MS: MH+ 385.19 (100%)
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[N:18][S:19][C:20]=2[C:21]([O:23]CC)=[O:22])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+]>O>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[N:18][S:19][C:20]=2[C:21]([OH:23])=[O:22])=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1snnc1-c1ccc(OCC(O)CNC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccc(-c2nnsc2C(=O)O)cc1

Procedure:
To a solution of 200 mg. of 4-[4(3-t-butylamino-2-hydroxypropoxy)phenyl]-5-carboethoxy-1,2,3-thiadiazole in 15 ml. of methanol is added a solution of 100 mg. of sodium hydroxide in 2 ml. of water, and the reaction mixture is refluxed for 4 hours. It is then cooled, evaporated to a small volume under vacuo, diluted with 25 ml. of water and extracted with ethyl acetate to eliminate the unsaponified product. The aqueous phase is passed through a column of 10 g. of ion exchange resin sold by the Dow Chemical Company under the trademark Dowex 50, acidic type (H+) eluting the column first with water and thereafter with 10% acetic acid solution. The combined acidic eluates are concentrated to a small volume under reduced pressure at low temperature and then lyophilized, to yield 4-[4(3-t-butylamino-2-hydroxypropoxy)phenyl]-5-carboxy-1,2,3-thiadiazole.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:1]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CNCC3)nc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CN(Cc2ccccc2)CC3)nc1
Yield: 25.7 %

Procedure:
Combine 6-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide (94 mg, 0.35 mmol), benzaldehyde (37 μL, 0.37 mmol), sodium triacetoxyborohydride (96 mg 0.46 mmol), acetic acid (21 μL, 0.37 mmol), and 1,2-dichloroethane (5 mL) then stir at room temperature for 18 hours. Dilute the reaction with saturated aqueous sodium bicarbonate solution and extract with 5% methanol in dichloromethane (3×25 mL). Dry the combined 5% methanol in dichloromethane extracts with sodium chloride/magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 100 mg of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 1% conc. ammonium hydroxide/10% ethanol in chloroform to yield 6-(2-benzyl-1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide 2039910 (30 mg, 0.09 mmol): m/z=360.12 (M+1); 1H NMR (CDCl3, 300.00 MHz): 8.50 (d, 1H); 8.09-8.05 (m, 1H); 7.34-7.20 (m, 5H); 7.09 (d, 1H); 6.87-6.82 (m, 2H); 6.71 (d, 1H); 5.80 (s, 2H); 3.63-3.57 (m, 4H); 2.87-2.69 (m, 4H), HPLC=96%@2.98 m (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nm).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[S:33])[NH:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34]I>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:18][CH2:19][N:20]([C:23]([S:33][CH3:34])=[N:24][C:25]5[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=5[CH3:32])[CH2:21][CH2:22]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(NC(=S)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Reactant: CI
Solvent: ClCCl
Product: CSC(=Nc1cc(C)ccc1C)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1

Procedure:
A solution of 14-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-N-(2,5-dimethylphenyl)-1-piperidinecarbothioamide (i.e. the product of Step C) (476 mg, 1.0 mmol) and methyl iodide (0.25 mL, 4.0 mmol) in dichloromethane (2 mL) was agitated at room temperature for 3 h. The reaction mixture was then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (MgSO4), and concentrated to give a foamy white solid (480 mg). The solid was crystallized from methyl acetate/petroleum ether to give the title compound, a compound of the present invention, as a white powder (320 mg) melting at 114-116° C.