Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=[O:3])C.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=[C:13]([N+]([O-])=O)[CH2:14][CH3:15]>[Zn].C1(C)C=CC=CC=1>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13](=[O:3])[CH2:14][CH3:15]
Reactant: CC(=O)O
Reactant: CCC(=Cc1ccccc1F)[N+](=O)[O-]
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCC(=O)Cc1ccccc1F
Reaction time: 4 h

Procedure:
100 ml of 90% v/v aqueous acetic acid were added to 7.4 g of 1-(2-fluorophenyl)-2-nitro-1-butene [prepared as described in step (a) above], and then 12.11 g (190 mmole) of a zinc powder were added in portions to the resulting solution, whilst heating. The mixture was then heated under reflux, whilst stirring, for 4 hours. At the end of this time, the reaction mixture was left to stand overnight, and then the crystals which had precipitated were filtered off and washed with toluene. The filtrate was combined with the toluene washings, and the mixture was concentrated by evaporation under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography, using toluene as the eluent, to give 1.85 g of the title compound as a pale brown oil.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]O)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[I:29]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1>O1CCCC1.O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][I:29])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: II
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
The compound (178 mg, 0.42 mmol) prepared in Example 70 was dissolved in tetrahydrofuran (10 ml). Iodine (161 mg, 0.63 mmol), triphenylphosphine (166 mg, 0.63 mmol) and imidazole (86 mg, 1.23 mmol) were added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, water was added. The mixture was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and separated by column chromatography to give the title compound (120 mg, Yield 54%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:27])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:14][C:15]1[CH:20]=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:18]=[CH:17][C:16]=1[CH3:26])=[O:4].O>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:27])=[C:7]2[N:12]([CH:13]=1)[N:11]=[CH:10][N:9]=[C:8]2[NH:14][C:15]1[CH:16]=[CH:26][C:18]([CH3:17])=[C:19]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)=[O:4]
Reactant: COC(=O)c1cn2ncnc(Nc3cc(NS(C)(=O)=O)ccc3C)c2c1C
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cn2ncnc(Nc3ccc(C)c(NS(C)(=O)=O)c3)c2c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of Example 53 (16 mg, 51 μmol) in pyridine (1 mL) at 0° C. was added 4-methyl-3-[(methylsulfonyl)aniline (4.4 μL, 87 μmol). The reaction mixture was stirred for 1 hr at 0° C. and then warmed to 25° C. and stirred for 4 hrs. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×5 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL) and dried (Na2SO4). The crude material was purified by chromatography on silica gel eluting with 2% methanol in chloroform to provide 6.9 mg (30%) of solid. MS: [M+H]+=390.2; 1H NMR (CDCl3): δ 7.93 (s, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.35 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.25 (s, 1H), 3.82 (s, 3H), 3.03 (s, 3H), 2.86 (s, 3H), 2.24 (s, 3H)
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2[CH:13]=[CH:14][CH:15]=CC=2N=N1.[NH2:25][C:26]1[N:34]=[C:33]([C:35](O)=[O:36])[N:32]=[C:31]2[C:27]=1[NH:28][CH:29]([O:45][CH3:46])[N:30]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(C(C)C)CC)(C)C.NCC1CC1>CC(N(C)C)=O>[NH2:25][C:26]1[N:34]=[C:33]([C:35]([NH:8][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[O:36])[N:32]=[C:31]2[C:27]=1[NH:28][CH:29]([O:45][CH3:46])[N:30]2[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC1Nc2c(N)nc(C(=O)O)nc2N1Cc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC1Nc2c(N)nc(C(=O)NCC3CC3)nc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (89 mg, 0.235 mmol) was added to a solution of 6-amino-9-benzyl-8-methoxy-8,9-dihydro-7H-purine-2-carboxylic acid (Example 246) (64 mg, 0.214 mmol) and diisopropylethylamine (75 μl, 0.428 mmol) in dimethylacetamide (0.5 ml) and the reaction mixture stirred at room temperature for 1 hour. Aminomethylcyclopropane (28 μl, 0.321 mmol) was added and the reaction mixture stirred at room temperature for a further 20 hours. The reaction mixture was concentrated in vacuo and water added. The resultant precipitate was collected by filtration, azeotroped with toluene and triturated with methanol to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][O:10][C:11]1[CH:32]=[CH:31][C:14]([O:15]C2C=C(N3CCC4(NCCC4)C3)C=NC=2)=[CH:13][CH:12]=1.COC1C=CC([O-])=CC=1.[Na+]>CN(C)C=O>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:15][C:14]2[CH:31]=[CH:32][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: COc1ccc(Oc2cncc(N3CCC4(CCCN4)C3)c2)cc1
Agent: COc1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2cncc(Br)c2)cc1

Procedure:
In an alternative approach to the synthesis of pyridine-substituted pyridyl diazaspiroalkanes, 3,5-dibromopyridine can be converted into the corresponding 5-alkoxy-3-bromo- and 5-aryloxy-3-bromopyridines by the action of sodium alkoxides or sodium aryloxides. Procedures such as those described by Comins et al., J. Org. Chem. 55: 69 (1990) and Hertog et al., Recueil Trav. Chim. Pays-Bas 74: 1171 (1955) are used. This is exemplified by the preparation 7-(5-(4-methoxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane. Reaction of 3,5-dibromopyridine with sodium 4-methoxyphenoxide in N,N-dimethylformamide gives 3-bromo-5-(4-methoxyphenoxy)pyridine. Coupling of 3-bromo-5-(4-methoxyphenoxy)pyridine with 1-benzyl-7-(3-pyridyl)-1,7-diazaspiro[4.4]nonane in the presence of sodium tert-butoxide, and a catalytic amount of tris(dibenzylideneacetone)dipalladium(0) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, in toluene, followed by hydrogenolysis of the benzyl protecting group, will provide 7-(5-(4-methoxyphenoxy)-3-pyridyl)-1,7-diazaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([OH:16])=O)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.Cl.[CH3:18][NH:19][CH3:20].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([N:19]([CH3:20])[CH3:18])=[O:16])[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)NC(=O)C(C(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-7-methoxy-2-oxo-3-quinolinecarboxylic acid (3.74 g), dimethylamine hydrochloride (3.44 g), 1-hydroxybenzotriazole (2.85 g), and triethylamine (8.5 g) in acetonitrile (400 ml) was added WSC (6.5 g). The reaction mixture was stirred at room temperature for 24 hr and concentrated. The residue was diluted with ethyl acetate and the organic layer was washed with 1 N aqueous hydrochloric acid, 10% aqueous potassium carbonate, and saturated aqueous sodium chloride, dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the titled compound (1.63 g).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:12]([Cl:22])=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:14]([O:16][CH3:17])=[O:15].O>C(#N)C>[Cl:22][C:12]1[C:11]([CH:10]=[O:5])=[C:20]([Cl:21])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Cl)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At reflux, 696.2 g (2.97 mol) of aqueous 50% strength N-methylmorpholine N-oxide solution were added to a solution of 312.0 g (0.99 mol) of methyl 3-bromomethyl-2,4-dichlorobenzoate in 2 l of acetonitrile. After stirring for 48 hours at room temperature, the reaction solution was stirred into 6 l of water. The precipitate was filtered off with suction, washed with water and dried under reduced pressure. 141.3 g of methyl 2,4-dichloro-3-formylbenzoate were obtained.
Reaction SMILES: [F:1][CH:2]([F:18])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[N:29]=1)[C:24](O)=[O:25]>>[F:18][CH:2]([F:1])[CH2:3][N:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])[C:24](=[O:25])[C:23]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[N:29]=[C:21]([C:20]([F:35])([F:19])[F:34])[CH:22]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: Fc1ccccc1-c1ccncc1NCC(F)F
Product: O=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)N(CC(F)F)c1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 90, from (2,2-difluoro-ethyl)-[4-(2-fluoro-phenyl)-pyridin-3-yl]-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 68 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (44%). MS (ESI): m/z=494.09 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([O:36]C)=[O:35])=[O:30])[CH:11]=1)=[O:9].O.[OH-].[Li+]>O1CCCC1.O>[F:45][C:2]([F:1])([F:44])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=2)[C:34]([OH:36])=[O:35])=[O:30])[CH:11]=1)=[O:9]
Reactant: COC(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoate (360 mg, 0.58 mmol, 1.00 equiv) in tetrahydrofuran/water (2:3) (35 mL), and lithium hydroxide hydrate (251.2 mg, 5.98 mmol, 10.25 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 50 mL of water adjusted to pH 2-3 with hydrogen chloride (2 mol/L). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 325 mg (92%) of 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)-benzoic acid as a yellow oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[NH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>C1COCC1>[CH2:6]([C@H:13]1[CH2:17][O:16][C:15](=[O:18])[N:14]1[C:28](=[O:29])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
n-Butyllithium (15.4 ml, 24.7 mmol, 1.6 M) was added to a solution of (S)-4-benzyl oxazolidinone (4.00 g, 22.5 mmol) in dry THF (100 ml) at −78° C. and stirred for 30 min. Then p-methoxyphenyl acetyl chloride (6.50 ml, 29.3 mmol) in THF (50 ml) was added to the reaction mixture at −78° C. The reaction mixture was allowed to warm up to room temperature and stirred overnight. It was then quenched with saturated ammonium chloride solution (50 ml) and extracted with ethyl acetate (3×50 ml). The crude compound was purified by column chromatography over silica gel (60-120 mesh) using ethyl acetate (7%) in petroleum ether as eluent to afford 6.0 g (82.5%) of (S)-4-benzyl-3-(2-(4-methoxyphenyl)acetyl)oxazolidin-2-one as an off-white color solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[C:5](=[O:21])[CH2:6][C:7]([CH3:20])=[CH:8][CH2:9][CH2:10][C:11]([CH3:19])=[CH:12][CH2:13][CH2:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.O>C1(C)C=CC=CC=1>[CH3:19][C:11]1=[CH:12][CH2:13][CH2:14][C:15]([CH3:18])=[CH:16][CH:17]=[C:4]([CH:2]([CH3:1])[CH3:3])[C@@H:5]([OH:21])[CH2:6][C:7]([CH3:20])=[CH:8][CH2:9][CH2:10]1
Reactant: CC1=CC=C(C(C)C)C(=O)CC(C)=CCCC(C)=CCC1
Agent: C/C1=C\C=C(\C(C)C)[C@@H](O)C/C(C)=C/CC/C(C)=C/CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CC=C(C(C)C)[C@@H](O)CC(C)=CCCC(C)=CCC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under argon atmosphere, to a solution of the ketone, 2-(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-cyclotetradecatetraene-1-on (137 mg, 0.48 mmol) prepared in Reference Example 8 in dry toluene (25 ml) is dropwise added a 1 M solution of diisobutylaluminum hydride in toluene (0.6 ml) while stirring on a refrigerant bath at -70° C. After 1 hour, disappearance of the starting compound is confirmed. To the mixture is added water (0.25 ml) and the mixture is stirred enough after removing the bath. The mixture is dried over anhydrous magnesium sulfate, stirred, filtered and concentrated. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate =12:1) to give the desired Sarcophytol A (125 mg, 88%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.C(N(CC)CC)C.[CH3:44][C:45]1[O:49][C:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:47][C:46]=1[CH2:56][C:57]1[O:58][C:59]2[CH:65]=[CH:64][C:63]([CH:66]=[O:67])=[CH:62][C:60]=2[CH:61]=1>ClCCl>[OH:67][C@H:66]([C:63]1[CH:64]=[CH:65][C:59]2[O:58][C:57]([CH2:56][C:46]3[N:47]=[C:48]([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:49][C:45]=3[CH3:44])=[CH:61][C:60]=2[CH:62]=1)[C@H:15]([O:16][CH2:17][CH3:18])[C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:19]
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=O)ccc2o1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc2oc(Cc3nc(-c4ccccc4)oc3C)cc2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of (S)-4-benzyl-3-(ethoxyacetyl)oxazolidin-2-one (1.0 g, 3.8 mmol) in dichloromethane (10 ml), cooled to 0° C., was added freshly distilled dibutylboron triflate (1.1 ml, 4.6 mmol) dropwise, followed by triethylamine (0.69 m), 4.9 mmol). After 5 minutes the solution was cooled to -78° C. and a precooled solution of 2-(5-methyl-2-phenyl-4-oxazolyl) methyl-5-benzofurancarboxaldehyde (1.33 g, 4.2 mmol) in dichloromethane (5 ml) was added. After 20 minutes the mixture was warmed to 0° C. and stirred at that temperature for 1 hour then quenched with a solution of pH 7 buffer (10 ml) in methanol (30 ml), followed by a solution of 30% hydrogen peroxide (10 ml) in methanol (30 ml), and stirred at 0° C. for 1 hour. The mixture was then diluted with water and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried over sodium sulfate and concentrated. The product was purified by flash chromatography (hexanes/ethyl acetate, 1:1) and obtained as a yellow solid (1.16 g, m.p. 66° C.).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH2:18][CH2:19][CH:20]([OH:22])[CH3:21].Cl>C1COCC1>[OH:22][CH:20]([CH3:21])[CH2:19][NH:18][S:2]([C:5]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)Cl
Reactant: CC(O)CN
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCC(C)O
Temperature: 0 °C
Yield: 63.5 %

Procedure:
A solution of methyl 2-chlorosulfonyl-6-nitrobenzoate (2.80 g, 10 mmol) in 100 ml of THF was cooled in an ice-bath and stirred while a solution of 1-amino-2-propanol (1.65 g, 22 mmol) in 10 ml of THF was added dropwise over a period of 50 minutes. After stirring an additional 30 minutes in the ice-bath, the reaction mixture was acidified by the addition of 3 ml of 1.2 N HCl. The THF was evaporated under reduced pressure and the residue taken up in 100 ml of ethyl acetate. After extracting with 4×20 ml of saturated NaCl solution, the ethyl acetate solution was dried over Na2SO4 and the solvent evaporated. The residue was crystallized from a mixture of ethyl acetate and hexane to give 2.02 g (63.5%) of yellow crystalline product, m.p., 93.5°-95°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=O.[CH:11]([CH:13]=[CH2:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[OH:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[O:1][CH2:14][C:13]([CH:11]=[O:12])=[CH:4]2
Reactant: C=CC=O
Reactant: O=Cc1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=CC1=Cc2cc(O)ccc2OC1

Procedure:
3 g (21.7 mmol) of 2,5-dihydroxybenzaldehyde and also 2.2 ml (32.6 mmol) of acrolein are added to a suspension of 6 g (43.5 mmol) of potassium carbonate in 50 ml of 1,4-dioxane; the medium is then heated at reflux for 12 hours. The salts are filtered off over Celite; the solvent is then evaporated in vacuo. The residue obtained is taken up in water; the aqueous phase is then extracted with ether. After drying over magnesium sulphate and evaporation of the solvent in vacuo, the crude product is triturated in dichloromethane to yield the title compound in the form of a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[N:11][C:12]([NH:15][C:16]([C:18]3[CH:23]=[C:22]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]4)[CH:21]=[CH:20][C:19]=3[NH:30][C:31]([C:33]3[CH:34]=[C:35]([CH:47]=[CH:48][CH:49]=3)[CH2:36][S:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:32])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)OC(C)(C)C)c3)nc2)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2cnc(NC(=O)c3cc(N4CCCCC4)ccc3NC(=O)c3cccc(CSCCC(=O)O)c3)nc2)cc1C
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 8.1 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-(2-(5-(3,4-dimethylphenyl)pyrimidin-2-ylcarbamoyl)-4-(piperidin-1-yl)phenylcarbamoyl)benzylthio)propano ate (340 mg, 0.5 mmol, 1.00 equiv) in dichloromethane (18 mL), and trifluoroacetic acid (8.9 mL). The resulting solution was stirred for ca. 5.5 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by HPLC reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 25.3 mg (8%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 11.35 (s, 1H), 11.26 (s, 1H), 8.72 (s, 2H), 8.25 (d, J=9 Hz, 1H), 7.86 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.56˜7.741 (m, 3H), 7.37 (s, 1H), 7.28˜7.13 (m, 3H), 4.34 (s, 1H), 3.84 (s, 2H), 3.31 (m, 4H), 2.60˜2.55 (m, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 1.71˜1.58 (m, 6H). MS (ES, m/z): 624 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:9]2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][N+:16]([O-:38])=[CH:17][CH:18]=3)[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)=[N:9]2)=[CH:28][CH:29]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(Cn2cc(-c3ccncc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2cc(-c3cc[n+]([O-])cc3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
100 mg (0.26 mmol) of 4-[1-(4-methoxybenzyl)-3-(3-nitrophenyl)-1H-pyrazol-4-yl]-pyridine were dissolved in 3 mL of dichloromethane and 80 mg (0.52 mmol) of m-chloroperbenzoic acid were added. The mixture was stirred at room temperature for 4 hours, diluted with the same solvent and washed with aqueous sodium hydrogenocarbonate. The organic layer was then dried over sodium sulphate and evaporated to afford, after crystallization from ethylacetate, 49 mg (47%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[CH:3]=1.[CH2:10]([Mg]Br)[CH2:11][CH3:12].[Cl-].[NH4+].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:10][CH2:11][CH3:12])[CH:3]=1
Reactant: CCC[Mg]Br
Reactant: BrCc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Under nitrogen stream, to a solution of 1-bromo-3-bromomethylbenzene (25 g) in tetrahydrofuran (200 ml) were sequentially added dropwise n-propylmagnesium bromide (60 ml, 2M solution in tetrahydrofuran) and lithium tetrachlorocuprate (5 ml, 0.1M solution in tetrahydrofuran) at −78° C. Then, this reaction mixture was stirred at 0° C. for 2 hours. Under ice-cooling, to this reaction mixture were sequentially added a saturated aqueous solution of ammonium chloride (100 ml) and water (100 ml), and the mixture was extracted with ethyl acetate (200 ml). The resulting aqueous layer was again extracted with ethyl acetate (100 ml), the combined organic layer was washed with a saturated aqueous solution of sodium chloride (100 ml), and dried over anhydrous sodium sulfate. This organic layer was concentrated under reduced pressure, the resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=1/0 to 100/1) to give the titled compound (8.5 g).