Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[NH2:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12]>[OH-].[Na+]>[CH2:5]([O:4][C:2]([NH:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:3])[CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
11.2 ml (85.3 mmol) of isobutyl chloroformate are added to a solution of 10 g (85.3 mmol) of (L)-valine in 100 ml of 2N sodium hydroxide solution and the solution is stirred at RT for 18 h. The reaction solution is washed with methylene chloride, acidified with 4N hydrochloric acid and extracted with methylene chloride. The organic extracts are washed with brine and filtered through cotton wadding to yield the title compound in the form of a colourless resin after concentration by evaporation. 1H-NMR (200 MHz, CD3OD): 0.95 (m, 12H), 1.9 (m, 1H), 2.15 (m, 1H), 3.85 (d, J=7 Hz, 2H), 4.05 (d broad, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:4][N:3]=1.C1C(=O)N([I:19])C(=O)C1>CN(C=O)C>[I:19][C:6]1[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][NH:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc(C)n[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)c1n[nH]c(C)c1I
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.3 %

Procedure:
To a stirred solution of ethyl 3-methylpyrazole-5-carboxylate (3.11 g, 20.17 mmol) in DMF (50 mL) under Ar at 0° C. was added NIS (5.90 g, 26.2 mmol). The reaction mixture was stirred 20 hr at rt and quenched with 500 mL of water. The resulting precipitate was collected to afford the title product (5.61 g, 20.03 mmol, 99% yield) as a white solid. tR: 3.75 min (HPLC 1); tR: 0.78 min (LC-MS 2); ESI-MS: 281 [M+H]+ (LC-MS 2)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[C:14]([NH:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)(=[O:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:24][C:20]1[CH:19]=[C:18]([NH:17][C:14](=[O:16])[CH3:15])[CH:23]=[CH:22][CH:21]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Reactant: CC(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a mixture of 3,4-dinitrofluorobenzene (1.0 g, 5.4 mmol, 1.0 eq.) and 3-acetamidophenol (0.8 g, 5.4 mmol, 1.0 eq.) in 10 mL of anhydrous DMF, K2CO3 (0.7 g, 5.4 mmol, 1.0 eq) was added. The reaction mixture was heated to 120° C. and stirred for 16 h. The mixture was cooled to RT and EtOAc was added (100 mL). After washing with H2O (100 mL), the organic layer was dried (MgSO4), filtered and concentrated. The resulting crude material was purified by column chromatography (20-100% EtOAc in hexanes) to obtain pure N-[3-(3,4-dinitro-phenoxy)-phenyl]-acetamide.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:18])=[CH2:17])=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[Br:1][CH2:17][C:16]([C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)=[CH2:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(C)c1ccc(F)cc1
Solvent: ClC(Cl)Cl
Product: C=C(CBr)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 44.3 %

Procedure:
To a solution of N-bromo succinimide (8.6 g, 48.48 mmol) in chloroform (60 mL) was added 1-fluoro-4-isopropenyl-benzene (6 g, 44.11 mmol) at RT. The reaction mixture was stirred at 60° C. for 15 h. The progress of reaction was monitored by TLC. The reaction mixture was cooled to RT and filtered. The residue was rinsed with DCM (50 mL). The combined filtrate was concentrated under reduced pressure to obtain crude product that was purified by column chromatography using silica (100:200) and pure hexane to yield 4.2 g of 1-(1-bromomethyl-vinyl)-4-fluoro-benzene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:19][S:20]([O:18][CH2:17][C:14]1[CH:13]=[N:12][C:11]([NH:10][C:4]2[C:5](=[O:9])[N:6]([CH3:8])[N:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:16][CH:15]=1)(=[O:22])=[O:21]
Reactant: Cn1nc(Cl)cc(Nc2ccc(CO)cn2)c1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(Cl)cc(Nc2ccc(COS(C)(=O)=O)cn2)c1=O

Procedure:
Intermediate 180b was treated with methanesulfonyl chloride and diisopropylethylamine in methylene chloride at 0° C. to give 180c.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[CH:6][C:5]=1[NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)(=[O:3])[NH2:2].[OH-].[Na+]>CCO>[CH2:11]([O:10][C:8]1[CH:9]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:14][C:15]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)=[N:2][C:1]2=[O:3])[CH2:12][CH3:13]
Reactant: CCCOc1ccc(NC(=O)c2cccnc2)c(C(N)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCOc1ccc2[nH]c(-c3cccnc3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-(2-carbamoyl-4-propoxy-phenyl)-nicotinamide (980 mg, 3.27 mmol) in EtOH (20 mL) was treated with NaOH (654 mg, 16.37 mmol). The resulting mixture was stirred at room temperature for 18 h. After the reaction was completed, the volatiles were removed in vacuo. The residue was partitioned between H2O (50 mL) and ethyl acetate (50 mL). The aqueous layer was neutralized to pH 7 by slowly adding aq. citric acid and then a precipitate formed. The precipitate was collected and dried to give 1.00 g of iv-a as a grey solid (quantitative yield). LCMS m/z=282.1 (M+1) (Method B) (retention time=1.60 min).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][CH:6]=1)=[O:4].O[CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15]>S(=O)(=O)(O)O.C(OCC)(=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:9]=[C:8]([CH2:11][NH:12][C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[O:7][CH:6]=1)=[O:4]
Reactant: O=C(NCO)C(F)(F)F
Reactant: CNC(=O)c1ccoc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CNC(=O)c1coc(CNC(=O)C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To a suspension of N-methyl-3-furancaboxamide (0.404 g) (prepared as described in Synthetic Communications (1992), 22(16), 2381-92) in concentrated aqueous sulphuric acid (10 ml) at 0-5° C. was added N-(hydroxymethyl)-trifluoroacetamide (0.483 g). The suspension was allowed to warm to 20° C. and stirred for 1 h. The mixture was poured onto ice (100 g) and diluted with ethyl acetate (150 ml). The phases were separated and the organic phase washed with saturated sodium hydrogen carbonate (50 ml×2), brine (30 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo to give a yellow solid. The residue was purified by silica SPE (10 g) eluting with 4:1 to 1:3 cyclohexane:ethyl acetate to give the title compound as a white solid (0.286 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:15](=[O:17])[O:16][C:5]=2[CH:4]=1.[ClH:18].[Cl:19][CH2:20][CH2:21][N:22]1[CH2:28][CH:27]2[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]2)[CH2:23]1.C(N(CC)CC)C>C(O)C>[ClH:19].[ClH:18].[CH:27]12[CH2:29][CH2:30][CH:24]([CH2:25][CH2:26]1)[CH2:23][N:22]([CH2:21][CH2:20][N:12]1[CH2:13][CH2:14][C:9]3[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:16][C:15](=[O:17])[C:10]=3[CH2:11]1)[CH2:28]2
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Reactant: ClCCN1CC2CCC(CC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 51.4 %

Procedure:
A mixture of 8-methoxy-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.31 g, 0.01 mole), 3-(2-chloroethyl)-3-azabicyclo(3.2.2)nonane hydrochloride (2.49 g, 0.01 mole) and triethylamine (3.03 g) in absolute ethanol (50 ml) is refluxed for 24 hours. The reaction mixture is filtered. Hydrogen chloride gas is bubbled through the filtrate. The product is filtered off, washed with ethanol and sucked dry. Recrystallization from methanol gave the product (2.34 g), mp 265°-270° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[C:15]([CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]2)=[N:14][C:13]2[C:8]1=[N:9][C:10](Cl)=[N:11][C:12]=2[N:27]1[CH2:32][CH2:31][O:30]CC1)(=O)[CH3:2].C1(S([N:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45](B(O)O)=[CH:44]2)(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:30][CH2:31][CH2:32][N:27]1[C:15]([CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([C:23]([OH:26])([CH3:24])[CH3:25])[CH2:21][CH2:22]2)=[N:14][C:13]2[C:12]1=[N:11][C:10]([C:45]1[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[NH:43][CH:44]=1)=[N:9][C:8]=2[N:7]1[CH2:2][CH2:1][O:4][CH2:5][CH2:6]1
Reactant: CC(=O)OCCn1c(CN2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: O=S(=O)(c1ccccc1)n1cc(B(O)O)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(O)C1CCN(Cc2nc3c(N4CCOCC4)nc(-c4c[nH]c5ccccc45)nc3n2CCO)CC1
Temperature: 95 °C
Reaction time: 18 h
Yield: 26.8 %

Procedure:
To a degassed suspension of 2-(2-chloro-8-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-6-morpholino-9H-purin-9-yl)ethyl acetate (110 mg, 0.23 mmol), 1-(phenylsulfonyl)-3-indoleboronic acid (83 mg, 0.27 mmol), 2 M Na2CO3 aqueous solution (0.23 mL, 0.46 mmol) in toluene (3 mL) and ethanol (1 mL) was added Pd(PPh3)4 (10 mg, 0.009 mmol). The suspension was then stirred under nitrogen at 95° C. for 18 hours. The reaction mixture was then diluted with EtOAc and water. The layers were then separated. The aqueous layer was extracted three times with EtOAc. The combined organic extracts were washed with water, dried over Na2SO4, filtered and concentrated. The crude mixture was filtered through a pad of silica gel (10% MeOH in DCM) and the filtrate was concentrated to give a yellow paste which was then taken up in ethanol (10 mL). To the solution was added a 1 M aqueous solution of NaOH (2 mL, 2 mmol). After 2 hours of stirring at 65° C., the reaction mixture was concentrated and purified by RP-HPLC to give 107 (32 mg, 40%). LCMS: M+H+=520.3. 1H-NMR (400 MHz, DMSO-d6): δ 11.5 (s, 1H), 8.54 (m, 1H), 8.20 (s, 1H), 8.11 (d, 1H), 7.44 (m, 1H), 7.14 (m, 2H), 4.44 (t, 2H), 4.27 (s, br, 4H), 3.85 (t, 2H), 3.78 (m, 4H), 3.72 (s, 3H), 2.91 (m, 2H), 1.98 (m, 2H), 1.67 (m, 2H), 1.21 (m, 3H), 1.01 (s, 6H)
Reaction SMILES: N[C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.N([O-])=O.[Na+].[ClH:19]>O>[Cl:19][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Cl
Reactant: Nc1ccc(C(=O)O)c2c1OCCO2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)c2c1OCCO2
Temperature: 40 °C
Yield: 62 %

Procedure:
29.3 g of 8-amino-1,4-benzodioxane-5-carboxylic acid, 120 ml of water and 30 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermometer. The mixture was heated to 40° C. and then cooled to 5° C. and a solution of 10.5 g of sodium nitrite in 20 ml of water was added in portions with the temperature being maintained at from 5°-10° C. The mixture was agitated and then poured into a solution of 12 g of cuprous chloride in 45 ml of hydrochloric acid (d=1.18) with the temperature being maintained below 30° C. The precipitate was dried off, washed in 300 ml of water and 25 g of sodium bicarbonate. The solution was filtered and treated with hydrochloric acid. The precipitate was dried off, washed with water and dried. 20 g of 8-chloro-1,4-benzodioxane-5-carboxylic acid were obtained (M.P.: 195° C.; yield: 62%).
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.[CH3:17]O>CCOCC.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(F)cc1

Procedure:
A catalytic amount (0.5 mL) of concentrated sulfuric acid was added to a solution of 4-fluorophenylacetic acid (30.8 g, 0.20 mol) in 500 mL of methanol. The solution was stirred at reflux for 4 hours. The volatile materials were removed under reduced pressure to furnish a colorless oil which was dissolved in ether/ethyl acetate and washed with 2 N aqueous Na2CO3, brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an oil which was dried overnight under high vacuum (yield: 33.6 g; 95%). 1H NMR (300 MHz, CDCl3) δ 3.59 (s, 2H), 3.65 (s, 3H), 7.01 (t, J=9 Hz, 2H), 7.20-7.28 (m, 2H). MS (DCI/NH3) m/z 186 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][CH:22]([OH:38])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].[Na+].[I:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46]Br)=[CH:44][CH:43]=1>>[I:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][O:38][CH:22]([C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:3]([O:4][C:5]([CH3:13])([CH3:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:2]([Cl:1])[C:18]=2[Cl:19])=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl
Reactant: BrCc1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(OCc2ccc(I)cc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
Tert-butyl 2-(4-(3-(4-iodobenzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,3-dichlorophenoxy)-2-methylpropanoate is prepared from tert-butyl 2-(2,3-dichloro-4-(3-hydroxy-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate using 1.1 equivalents of sodium hydride and 1.1 equivalents of 4-iodobenzyl bromide according to general procedure H.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][CH2:19]CS([O-])(=O)=O)=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].CCN(C(C)C)C(C)C.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:13]([CH2:17][CH2:18][CH2:19][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[N:14][O:15][N:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCCS(=O)(=O)[O-]
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCN1CCOCC1
Temperature: 70 °C
Yield: 53.2 %

Procedure:
3-(4-[(3-Chloro-4-fluorophenyl)amino]carbonyl-1,2,5-oxadiazol-3-yl)propylmethanesulfonate (19 mg, 0.051 mmol) was dissolved in anhydrous ACN (100 μL) followed by addition of DIPEA (44 μL, 0.26 mmol) and morpholine (6.7 μL, 76.8 μmol). The reaction was stirred and heated at 70° C. for 3 h. The reaction was concentrated and purified with silica gel chromatography (60-100% ethyl acetate/hex) to give the desired product (10 mg, 54%). LCMS for C16H19ClFN4O3(M+H)+: m/z=369.1.
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:43])[CH2:37][C:38]5[S:39][CH:40]=[CH:41][CH:42]=5)[CH:30]=4)=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[CH:17]=[CH:16][N:15]=2)[CH:8]=1)=O.O[Li].O>C1COCC1.O.C(Cl)Cl>[NH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:29]4[CH:30]=[C:31]([NH:35][C:36](=[O:43])[CH2:37][C:38]5[S:39][CH:40]=[CH:41][CH:42]=5)[CH:32]=[CH:33][CH:34]=4)=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(CNC(=O)C(F)(F)F)c3)n2)c1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: NCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Temperature: 50 °C
Yield: 94 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(3-{[4-(2-{3-[(2-thienylacetyl)amino]phenyl}-pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}phenyl)methyl]acetamide (71 mg, 0.11 mmol) in THF (3 mL) was added LiOH hydrate (10 mg, 0.21 mmol) in water (0.5 mL). The solution was heated to 50° C. for 2 h, and then diluted with DCM, washed with 1N Na2CO3, dried over Na2SO4, and concentrated to generate the title compound in 94% yield. 1H NMR (400 MHz, d6-DMSO) 610.37 (s, 1H), 9.51 (s, 1H), 8.83 (d, J=6.8 Hz, 1H), 8.53 (d, J=8.8 Hz, 1H), 8.24 (d, J=5.4 Hz, 1H), 7.90 (s, 1H), 7.74-7.76 (m, 2H), 7.55 (d, J=8.1 Hz, 1H), 7.38-7.50 (m, 3H), 7.28 (d, J=7.5 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H), 7.12 (t, J=6.8 Hz, 1H), 6.94-6.98 (m, 3H), 6.46 (d, J=5.3 Hz, 1H), 3.88 (s, 2H), 3.67 (s, 2H). ES-LC/MS m/z=532 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([N+]([O-])=O)=[CH:10][CH:9]=[CH:8][C:7]=1[S:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:22]([CH3:42])=[CH:21][C:20]=1[OH:43])(=[O:17])=[O:16].C(O)(C)C.[Cl-].[NH4+:49]>[Fe].[O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+2].[Fe+2].O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:49])=[CH:8][C:7]=1[S:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:22]([CH3:42])=[CH:21][C:20]=1[OH:43])(=[O:16])=[O:17]
Reactant: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2OCCOC)c(O)cc1C
Reactant: [NH4+]
Agent: [Fe+2]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)O
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc(N)ccc2OCCOC)c(O)cc1C

Procedure:
32 g of 2-[2'-(2-methoxyethoxy)nitrobenzenesulfonamido]-4-hexadecyloxy-5-methylphenol was added to 300 ml of isopropyl alcohol together with 24 g of iron dust, 12 g of tri-iron tetroxide, 0.6 g of ammonium chloride, and 25 ml of water, and refluxed for 1 hour on a steam bath under stirring. After completion of the stirring, the mixture was hot-filtered and, after cooling the mother liquor, crystals thus formed were collected by filtration, washed with 50 ml of isopropyl alcohol, and air-dried. Yield: 23 g; m.p. 142° to 144° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[CH:5]2.C([Li])(C)(C)C.[C:26]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)(=[O:28])[CH3:27].Cl>O1CCCC1>[OH:35][C:32]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:16])[CH3:17])[CH:6]=[CH:5]3)[CH2:33][CH2:34][N:29]([C:26](=[O:28])[CH3:27])[CH2:30][CH2:31]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)ccc21
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(=O)N1CCC(O)(c2ccc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 21 %

Procedure:
5-Bromo-1-triisopropylsilyl-1H-indole (13.7 g, 38.9 mmol) in tetrahydrofuran (250 ml) at -78° C. was treated with t-butyllithium (45.8 ml, 77.8 mmol, 1.7M solution in pentanes) and stirred at this temperature for 15 minutes. The yellow solution formed was added to 1-acetyl-4-piperidone (5.49 g, 38.9 mmol) in tetrahydrofuran (250 ml) at -78° C., and the mixture allowed to warm to room temperature. Hydrochloric acid (40 ml, 1M) was added and the mixture extracted with ethyl acetate (2×500 ml). The extracts were combined, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography using ethyl acetate as eluant, to give 1-[4-hydroxy-4-(1-triisopropylsilyl-1H-indol-5-yl)piperidin-1-yl]ethanone (3.39 g, 21%) as a white solid; δH (DMSO-d6) 1.10 (18H, d, J 7.9 Hz, 6×CH3), 1.70 (3H, m, 3×CH), 2.00 (2H, m, piperidinyl H), 2.05 (3H, s, COCH3), 2.45 (1H, m, piperidinyl H), 3.00 (1H, m, piperidinyl H), 3.30 (1H, m, piperidinyl H), 3.50 (1H, m, piperidinyl H), 3.70 (1H, m, piperidinyl H), 4.30 (1H, m, piperidinyl H), 5.00 (1H, s, OH), 6.60 (1H, d, J 2.8 Hz, ArH), 7.30 (1H, d, J 7.8 Hz, ArH), 7.35 (1H, d, J 2.2 Hz, ArH), 7.50 (1H, d, J 7.9 Hz, ArH), and 7.70 (1H, s, ArH).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[N+:28]([O-:30])=[O:29])C.[OH-].[K+].Cl>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:31])=[O:3])=[C:6]([N+:28]([O-:30])=[O:29])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.1 %

Procedure:
In a solution of 0.36 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-nitrobenzoic acid ethyl ester in 8 ml of ethanol, a solution of 0.40 g of potassium hydroxide in 2 ml of water was added, and stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was poured in 15 ml of water, adjusted to pH 4 with concentrated hydrochloric acid, then extracted with ethyl acetate (20 ml×2), the organic phase was washed with water, and then dehydrated with saturated sodium chloride aqueous solution and dried over over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 0.40 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-nitro benzoic acid as pale yellow oily substance. The substance was dissolved in 10 ml of chloroform, and 0.24 g of 2-picolylamine, 0.01 g of 4-(N,N-dimethylamino)pyridine and 0.35 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride were added, and stirred at room temperature for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:1 to 1:0 gradient), and 0.14 g of the aimed product was obtained as colorless resinous substance.