Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:17][CH2:16][CH:10]([C:11]([O:13]CC)=[O:12])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Li+].[OH-].O>C1COCC1>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:17][CH2:16][CH:10]([C:11]([OH:13])=[O:12])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCN(c2ccncc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(c2ccncc2)CC1
Temperature: 0 °C

Procedure:
A solution of ester 21-1 (10 g, 42.7 mmol) in THF (50 mL) was treated with 1N LiOH (47 mL, 47.0 mmol) and H2O (50 mL). The resulting solution was concentrated and the aqueous residue cooled to 0° C., then adjusted to pH≈6 with 1N HCl and the resulting solid 21-2, collected by filtration.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][N:7]([CH3:36])[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:13][CH2:12][C:11](=[CH:14][C:15]([NH:17][CH:18]([CH3:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:16])[CH2:10][CH2:9]1>CC(CC)=O>[ClH:1].[CH3:36][N:7]([CH3:6])[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:9][CH2:10][C:11](=[CH:14][C:15]([NH:17][CH:18]([CH3:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:16])[CH2:12][CH2:13]1
Reactant: C[Si](C)(C)Cl
Agent: CC(Cc1c[nH]c2ccccc12)NC(=O)C=C1CCC(c2ccccc2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Chlorotrimethylsilane (0.06 ml, 0.48 mmol) was added to a solution of the more polar diastereoisomer of 2-(4-dimethylamino-4-phenylcyclohexylidene)-N-[2-(1H-indol-3-yl)-1-methylethyl]acetamide (133 mg, 0.32 mmol) in ethyl methyl ketone (5 ml) and the mixture was stirred at RT for 1.5 h. The hydrochloride (Example 5) (66 mg, 46%) thereby precipitated out as a colourless solid with an m.p. of 182-186° C.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>N1C=CC=CC=1>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:1][N:2]2[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]2([CH3:11])[CH3:10])[CH:21]=1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: Nc1cccnc1
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC1(C)CCCC(C)(C)N1Oc1cccnc1
Yield: 51.2 %

Procedure:
The procedure of Example 1 is repeated using 1.95 g (12.5 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 3.90 g (38 mmol) of tert-butyl nitrite, 7.6 mg (0.0125 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 120 mL of pyridine and 2.35 g (25 mmol) of 3-aminopyridine at 70° C. The crude product obtained is purified by vacuum flash chromatography (heptane) to give 1.5 g of the title compound as a colorless oil in 50.8% yield. The structure is confirmed by 1Hnmr and mass spectrographic analyses.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12]Br.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:12][CH2:11][O:10][CH3:9])=[CH:4][CH:3]=1
Reactant: COCCBr
Reactant: Nc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCNc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a 50 mL round-bottomed flask was added 4-fluoroaniline (383 μL, 3971 μmol, Aldrich), 2-bromoethyl methyl ether (552 μL, 3971 μmol, Aldrich), sodium carbonate (667 mg, 7943 μmol), DMF (2 mL). The reaction mixture was stirred at 80° C. for overnight (ca 17 h). The mixture was cooled down to RT. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with water (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 30% EtOAc/hexanes to give 4-fluoro-N-(2-methoxyethyl)benzenamine. MS (ESI pos. ion) m/z: 170 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Br:17][CH2:18][C:19](Br)=[O:20]>C(Cl)Cl>[C:2]1([NH:1][C:19](=[O:20])[CH2:18][Br:17])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CBr)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of aniline (7.40 mmol) in methylene chloride (25 mL) at -50° C. was added successively N,N-diisopropylethylamine (1.58 mL, 8.14 mmol, 1.1 eq) and bromoacetyl bromide (0.72 mL, 7.40 mmol, 1 eq) such that the temperature did not exceed -40° C. On completion of the addition, the cooling bath was removed, and the reaction mixture was allowed to warm to room temperature. After stirring for a further 30 minutes, the mixture was diluted with ether (70 mL) and poured into 1 N sodium bisulfate solution. The phases were separated, and the upper layer was washed successively with water and brine. The organic phase was dried (Na2SO4) and the solvent evaporated to half volume, at which point the product crystallized. The crystals were removed by vacuum filtration to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.C([O-])(O)=O.[Na+].F[C:19](=[O:34])[C@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:21]1[CH:25]=[CH:24][S:23][CH:22]=1>O.C(Cl)Cl>[OH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:19](=[O:34])[C@H:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Reactant: Nc1ccc2c(O)nccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1ccc2c(O)nccc2c1)c1ccsc1
Reaction time: 4 h

Procedure:
To 6-aminoisoquinolin-1-ol in H2O was added NaHCO3 followed by a solution of (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate in CH2Cl2. The solution was stirred for 4 hours, extracted with EtOAc and NH4Cl(sat)/HCl(1N) and then with NaHCO3 (0.05%), dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, 5% MeOH, CH2Cl2) gave pure (R)-tert-butyl 2-(1-hydroxyisoquinolin-6-ylamino)-2-oxo-1-(thiophen-3-yl)ethylcarbamate (95% ee by Chiracel OD-RH)
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[C:22]([Cl:23])=[C:21]3[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:29])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([Cl:23])[C:13]=1[O:12][C:11]1[CH:30]=[CH:31][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate (45.1 g, 96.5 mmol) was dissolved in dichloromethane (500 ml). Trifluoroacetic acid (100 ml) was added slowly to the solution. The mixture was stirred for 2 hours at ambient temperature. The crude mixture was concentrated and the residue was dissolved in EtOAc (500 ml). The EtOAc solution was washed with saturated NaHCO3 (3×100 ml) and brine (250 ml), dried over MgSO4, filtered, and concentrated to provide 40.3 g of the title compound as a light brown solid (102%).
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[C:9]([Cl:22])=[C:10]([CH:15]=[CH:16][C:17]=1[S:18]([CH3:21])(=[O:20])=[O:19])[C:11]([O:13]C)=[O:12])(=O)C.CO>O>[Cl:22][C:9]1[C:8]([CH2:7][OH:6])=[C:17]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(COC(C)=O)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
6 ml of an aqueous solution containing 1.3 g of sodium hydroxide (93%), was added to 3.9 g of methyl 3-acetoxymethyl-2-chloro-4-methanesulfonylbenzoate and 100 ml of methanol. The mixture was stirred for 30 minutes at room temperature. 50 ml of water was added thereto, and methanol was distilled off under reduced pressure. Then, the reaction mixture was acidified with hydrochloric acid and extracted with chloroform. The extract was concentrated to dryness to obtain 1.3 g of the desired product. Melting point: 240°-245° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:24])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[N:13]=1.S(OC)(O[CH3:29])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:10]=[C:11]([O:24][CH3:29])[N:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:21])[F:22])[N:13]=1
Reactant: O=c1[nH]c(-c2c(F)cccc2F)nn1-c1ccccc1C(F)(F)F
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1nc(-c2c(F)cccc2F)nn1-c1ccccc1C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 3.75 g (11.0 mmol) of 5-(2,6-difluorophenyl)-2-(α,α,α-trifluoro-o-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, 1.05 g (11.0 mmol) of dimethyl sulfate and 3.04 g (22.0 mmol) of potassium carbonate in acetone is stirred at the reflux temperature for 16 hours. The insoluble constituents are then filtered off and the evaporated residue is subjected to chromatography on silica gel using ethyl acetate/n-hexane (1:4) as the eluent. As the first fraction there is isolated the apolar secondary component 3-(2,6-difluorophenyl)-5-methoxy-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole, m.p. 118°-119° C.; mass spectrum: 355(75), 298(39), 159(100); 1H-NMR (CDCl3): 4.13 (s, OCH3). After further elution with ethyl acetate/n-hexane (2:3) and subsequent recrystallization from diethyl ether/n-hexane there is obtained pure 5-(2,6-difluorophenyl)-4-methyl-2-(α,α,α-trifluoro-o-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one, m.p. 98°-99° C., IR spectrum: 1708 cm-1 ; mass spectrum: 355(75), 298(32), 159(100); 1H-NMR (CDCl3): 3.30 (s,N-CH3).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([N:54]([CH2:56][C:57](O)=[O:58])[CH3:55])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([N:54]([CH2:56][C:57]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:58])[CH3:55])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)CN(C)C(=O)OCc1ccccc1
Yield: 64 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-sarcosine. Yield 64%. [α]D =+18.4° (c=1.02, dichloromethane). m.p. 76-77°.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH2:8]Cl)(=O)=O.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:4]1[CH2:7][CH2:8][C:11]([C:10]#[N:14])([C:12]#[N:13])[CH2:2][CH2:3]1
Reactant: N#CCC#N
Reactant: O=S(=O)(CCCl)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC1(C#N)CCSCC1
Yield: 34.9 %

Procedure:
A mixture of 38.2 g of bis(2-chloroethyl)sulfone, 13.2 g of malononitrile, 55.28g of potassium carbonate and 800 ml of acetonitrile is refluxed on a steam bath for 24 hours, then filtered while hot. The filtrate is evaporated and the residue crystallized with charcoal treatment from 100 ml of ethanol, giving 10.6 g of tetrahydro-4H-thiopyran-4,4-dicarbonitrile, 1,1-dioxide as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:20])[NH:7][CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1ccc2cnccc2c1
Solvent: ClCCl
Product: O=c1[nH]ccc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of Intermediate 94 (1.04 g) in methylene chloride (3 ml) was added with a solution of 3-chloroperbenzoic acid (2.16 g) in methylene chloride (3 ml), and stirred for 20 hours. The reaction mixture was added with methylene chloride (200 ml), and washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure. A solution of the residue in acetic anhydride (10 ml) was refluxed by heating for 5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was added with 2.5 N aqueous sodium hydroxide (20 ml), and stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature, and neutralized with 5 N aqueous hydrochloric acid under ice cooling to obtain the precipitated title compound (Intermediate 95, 623 mg).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:11]=[C:10]([F:12])[C:7]([CH2:8][OH:9])=[C:6]([F:13])[CH:5]=1.CCN(CC)CC.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:24][S:21]([O:9][CH2:8][C:7]1[C:6]([F:13])=[CH:5][C:4]([Br:3])=[CH:11][C:10]=1[F:12])(=[O:23])=[O:22]
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1c(F)cc(Br)cc1F
Temperature: 0 °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 4-bromo-2,6-difluorobenzyl alcohol (1.00 g, 4.48 mmol) in dry CH2Cl2 (20 mL) was treated at 0° C. with Et3N (0.81 mL, 5.79 mmol) followed by DMAP (55 mg, 0.45 mmol) and Ms-Cl (0.37 mL, 4.71 mmol). After stirring at 0° C. for 0.5 h and at rt for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-bromo-2,6-difluorophenyl)methyl methanesulfonate as a yellow oil. This material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 1-(azidomethyl)-4-bromo-2,6-difluorobenzene as a yellow oil. LC-MS-conditions 01: tR=1.00 min.
Reaction SMILES: [OH-].[K+].[CH:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\Br)/[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1>O.O.CC(C)=O>[CH:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(/C(Br)=C/c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(C#Cc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
Potassium hydroxide (3.48 mmol), dissolved in water (0.87 M (4.0 ml)), is added over about 30 minutes to a refluxing solution of the alpha-bromochalcone (3.48 mmol) in 0.35 M of 1:1 water/acetone (5 ml each). After 20 minutes of further refluxing, the solution is cooled and diluted with water. The water is extracted with ether, which is dried with MgSO4 and evaporated. Chromatography on silica gel yielded 1,3-diphenylpropynone and its derivatives.
Reaction SMILES: O[C:2]1([C:21]2[C:22]([OH:31])=[CH:23][C:24]3[O:28][N:27]=[C:26]([CH3:29])[C:25]=3[CH:30]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:3]1=[O:20].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:31][C:22]1[C:21]([CH:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:11][C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:3]2=[O:20])=[CH:30][C:25]2[C:26]([CH3:29])=[N:27][O:28][C:24]=2[CH:23]=1
Reactant: COc1ccc(CN2C(=O)C(O)(c3cc4c(C)noc4cc3O)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)C(c3cc4c(C)noc4cc3O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 57 h
Yield: 93.7 %

Procedure:
To a stirred solution of 3-hydroxy-3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (3.70 g; 8.9 mmol) and triethylsilane (8.4 mL, 52.6 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (7.0 mL, 90.8 mmol). The reaction mixture was stirred at ambient temperature for 57 h, concentrated in vacuo to dryness. The residue was washed with diethyl ether-hexanes (1:2) to afford 3-(6-hydroxy-3-methyl-1,2-benzisoxazol-5-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (3.34 g, 93%): mp 195-197° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=9.0 Hz, 2H), 7.19-7.14 (m, 1H), 7.03-6.81 (m, 6H), 6.42 (d, J=9.0 Hz, 1H), 5.46 (s, 1H), 5.04 (Aq, 2H), 3.74 (s, 3H), 2.43 (s, 3H); MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N12CCCN=C1CCCCC2>ClCCl.Cl>[Si:22]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])=[N:7][NH:8]2)=[CH:4][CH:3]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cc(O)ccc12
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(N3C(=O)c4ccccc4C3=O)n[nH]c2c1
Temperature: 50 °C
Yield: 71 %

Procedure:
To a suspension of 15.03 g (53.82 mmol) of 2-({6-hydroxy}-1H-indazol-3-yl)-1H-isoindole-1,3(2H)-dione in 150 ml of dichloromethane, a solution of 20.19 g (0.134 mol) of TBDMS chloride in 75 ml of dichloromethane was added. The resulting mixture was treated dropwise with 12.06 ml (80.73 mmol) of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature, obtaining a clear solution. After 3 hours the reaction mixture was poured in 250 ml of 0.5 N HCl. The aqueous layer was separated and extracted with 120 ml of dichloromethane. Organic extracts were dried over sodium sulfate and the solvent evaporated under vacuum. The moist raw product was stirred in 50 ml of ethyl acetate at 50° C. Then, about one half of the solvent was evaporated under vacuum and the mixture was treated dropwise with 100 ml of cyclohexane. The product was isolated by suction as light yellow solid (15.04 g). Yield=71.0%. mp=207-209° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[CH:14][CH:15]=2)[N:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: Clc1ccc(Nc2nc(Cl)nc3[nH]cnc23)cc1
Yield: 100 %

Procedure:
The procedure is carried out as in Example 1, starting with 472.5 mg of 2,6-dichloropurine, 5 ml of butanol and 398.0 mg of para-chloroaniline. 700.3 mg of the expected product are thus obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:5].CCN(C(C)C)C(C)C.F[C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][C:31]=1[N+:40]([O-:42])=[O:41]>CN(C=O)C.CCOC(C)=O>[O:9]1[CH2:10][CH2:11][N:6]([C:4](=[O:5])[CH2:3][C@@H:2]([NH:1][C:30]2[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][C:31]=2[N+:40]([O-:42])=[O:41])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:8]1
Reactant: N[C@@H](CSc1ccccc1)CC(=O)N1CCOCC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of (R)-3-amino-1-morpholino-4-(phenylthio)butan-1-one (INTERMEDIATE 72, 375.5 mg, 1.34 mmol) in DMF (2.5 ml) and DIPEA (1.20 Ml, 6.87 mmol) was added 4-fluoro-3-nitrobenzenesulfonamide (INTERMEDIATE 18, 325.8 mg, 1.48 mmol), and the resulting dark solution was stirred at 50° C. overnight, under a nitrogen atmosphere. The mixture was diluted with EtOAc (50 ml) and washed with water and brine (30 ml each), dried (Na2SO4), filtered, and evaporated under reduced pressure. The concentrate was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/DCM) to give the title product (532.5 mg, yield: 83%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:27]=[CH:26][C:16]([CH2:17]P(=O)(OCC)OCC)=[CH:15][CH:14]=3)[N:12]=2)[CH:9]=1.[O:28]([CH2:36][CH2:37][O:38][C:39]1[CH:46]=[C:45]([N+:47]([O-:49])=[O:48])[CH:44]=[CH:43][C:40]=1[CH:41]=O)[Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].CCOC(C)=O.CCCCCC>C1COCC1>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][C:16](/[CH:17]=[CH:41]/[C:40]4[CH:43]=[CH:44][C:45]([N+:47]([O-:49])=[O:48])=[CH:46][C:39]=4[O:38][CH2:37][CH2:36][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:26][CH:27]=3)[N:12]=2)[CH:9]=1
Reactant: CCOP(=O)(Cc1ccc(-c2cn3cc(C)ccc3n2)cc1)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc([N+](=O)[O-])ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc([N+](=O)[O-])cc4OCCO[Si](C)(C)C(C)(C)C)cc3)cn2c1
Yield: 64.3 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (40 mg, 60% dispersion in mineral oil, 1.00 mmol), diethyl [4-(6-methylimidazo[1,2-a]pyridin-2-yl)benzyl]phosphonate (0.300 g, 0.837 mmol) and 2-([2-tert-butyldimethylsiloxy]ethoxy)-4-nitrobenzaldehyde (0.272 g, 0.837 mmol) in dry THF (30 ml) to give the title compound (0.285 g, 64%) as an orange solid after work-up and flash chromatography (2:1 EtOAc/Hexane).
Reaction SMILES: [C:1]([C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([OH:18])=[C:5]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=1)#[CH:2].[OH2:26]>C1COCC1.OS(O)(=O)=O.[Cl-].[Na+].O.C(=O)(O)[O-].[Na+]>[C:1]([C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([OH:18])=[C:5]([C:19]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:20])[N:4]=1)(=[O:26])[CH3:2]
Reactant: O
Reactant: C#Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3ccccc3)c12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(=O)c1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-ethynyl-7-hydroxy-3-phenylisoxazolo[4,5-c]pyridine-6-carboxamido)acetic acid (60 mg, 0.178 mmol) was dissolved in 6.6 mL of THF. Water (0.7 mL) was added, followed by 1.5 mL of a saturated solution of HgSO4 in 1% H2SO4. The reaction mixture was stirred at room temperature for 16 h. Brine (10 mL) was added and the mixture was extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated to give a purple solid. The solid was taken up in 25 mL of saturated sodium bicarbonate solution and washed several times with EtOAc. The aqueous layer was acidified to pH 3 with 4M hydrochloric acid and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 65 mg of crude solid. The solid was purified by flash chromatography (0-100% EA/hexanes+2% acetic acid) to give 20 mg of the title compound. MS: (−) m/z 354.22 (M−1).