Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([NH:11][C@H:12]([C:24]([OH:26])=[O:25])[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=1)(=[O:16])=[O:15])(=[O:10])[CH3:9].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:8]([NH:11][C@H:12]([C:24]([OH:26])=[O:25])[CH2:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])(=[O:10])[CH3:9]
Reactant: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Sc2ccccc2)cc1)C(=O)O
Temperature: 9 °C
Reaction time: 2 h

Procedure:
Thiophenol (7.27 g, 71.0 mmol) was added to a solution of the title compound of Example 11b (17.0g, 59.0 mmol) and K2CO3 (24.4 g, 177 mmol) in DMF (200 mL). After heating at 9 degrees C. for 2 hours, the mixture was concentrated under a stream of N2. The solution was acidified to pH=1 with 1M KHSO4, extracted into EtOAc (2×) and the organic phases were washed with brine and dried over MgSO4. The solution was concentrated in vacuo to yield the title compound as a white solid and was carried on without additional purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]1[C:31](=O)[CH:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:33].[O-]CC.[Na+]>C(O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:16]=[C:31]([CH:32]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH3:33])[C:19]4[CH2:20][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:22][CH2:23][C:18]=4[N:15]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: CC(C(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(C(C)c4ccccc4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 36.9 %

Procedure:
1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (700 mg, 3.25 mmol, example 9e), tert-butyl 4-oxo-3-(2-phenylpropanoyl)piperidine-1-carboxylate (1293 mg, 3.90 mmol) and sodium ethoxide (221 mg, 3.25 mmol) in ethanol (6 mL) were heated to 110° C. in a microwave reactor for 4 h. The solvent was evaporated and the crude was dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO4 and the solvent was evaporated under reduced pressure. Purification by flash chromatography using dichloromethane and methanol (0-10%) as eluent gave tert-butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(1-phenylethyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (612 mg, 36.9%). MS (ES+) m/z 511 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[C:11](=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:25]N1C(=O)CCC1=O>ClC(Cl)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]([C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])[C:11](=[O:24])[C:10]=1[Br:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OCc2ccccc2)cc(=O)n1-c1c(Cl)cccc1Cl
Solvent: CC(Cl)Cl
Product: Cc1cc(OCc2ccccc2)c(Br)c(=O)n1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(benzyloxy)-1-(2,6-dichlorophenyl)-6-methylpyridin-2(1H)-one (0.1 g, 0.278 mmol) and N-bromosuccinimide (0.055 g, 0.3 mmol) in dichloroethane (3.0 mL) was stirred at room temperature for 1 h, and heated at 60° C. under argon for 30 min. The reaction mixture was then diluted with dichloroethane (15 mL), washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure. 1H NMR (CD3OD) δ: 7.64 (m, 2H), 7.55 (m, 3H), 7.38 (m, 3H), 6.65 (s, 1H), 5.34 (s, 2H), and 2.00 (s, 3H); ES-MS m/z=439 (MH+); HR-MS, m/z calc C19H16NO2Cl2Br, 439.9635, found 439.9669.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:16])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[C:21]([N+:30]([O-:32])=[O:31])[CH:20]=1>O1CCOCC1>[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][C:8](=[O:16])[O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:21]([N+:30]([O-:32])=[O:31])[CH:20]=1
Reactant: NCCCOc1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NCCCOc1ccc(F)cc1[N+](=O)[O-])Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
Triethylamine (2.90 ml, 21.4 mmol) and phenyl chlorocarbonate (2.52 ml, 20.0 mmol) were added to a dioxane solution (43 ml) of 3-(4-fluoro-2-nitrophenoxy)propylamine (4.03 g, 18.8 mmol), while being cooled with ice, and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane: ethyl acetate=30:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 5.92 g of powdery yellow phenyl [3-(4-fluoro-2-nitrophenoxy)propyl]carbamate (yield: 94%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:25](O)=[O:26]>>[CH:25]([C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1])=[O:26]
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: COC(=O)Cc1ccc(O)c(C=O)c1

Procedure:
Methyl (4-hydroxyphenyl)acetate (1.66 g) is dissolved in trifluoroacetic acid (20 ml), thereto is added hexamethylenetetramine (700 mg), and the mixture is heated under reflux for 2 hours. The reaction solution is concentrated under reduced pressure, thereto is poured ice-water, and then the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate =9/1, then 4/1) to give the title compound (1.08 g). ESI-MS M/Z:193[M−H]−
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[N:23](COCC[Si](C)(C)C)[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[CH:14][CH:13]=2)[C:4]1=[O:36])[CH3:2].[ClH:37]>CCO>[ClH:37].[NH:20]1[C:21]2[CH:35]=[CH:34][CH:33]=[CH:32][C:22]=2[N:23]=[C:19]1[O:18][C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3=[N:7][CH:8]=[CH:9][CH:10]=[C:11]3[N:3]([CH2:1][CH3:2])[C:4]2=[O:36])=[CH:17][CH:16]=1
Reactant: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Agent: Cl
Solvent: CCO
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4[nH]3)cc2)c2ncccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
2-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (1.861 g) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.4 g) and sodium hydride (0.263 g) in DMF(dry) (10 mL) at room temperature. The mixture was heated at 200° C. for 1 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.60 g) as a colorless solid. A mixture of 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (194 mg) and 2 M HCl in EtOH (6.0 mL) was stirred at 70° C. for 4 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was recrystallized from EtOH-ether to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (154 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].I[CH2:20][CH2:21][CH3:22]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH:21]([CH3:22])[CH3:20])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)c(Cl)c1
Reaction time: 18 h
Yield: 104.6 %

Procedure:
Methyl 3-chloro-4-hydroxybenzoate (available from Pfalz % Bauer, 50 g, 0.27 mole), K2CO3 (74 g, 0.54 mole) and iodopropane (29.5 ml, 0.23 mole) were stirred at room temperature in DMF (100 mL). After 18 h hours, the solvent was removed by evaporation under vacuum and the residue was chromatographed over a column of silica 60 in EtOAc/hexane (1:1) to give the title compound as an oil (55 g, 90%). 1H NMR (400 MHz, CDCl3) δ 8.05 (1H, d), 7.89 (1H, dd), 6.94 (1H, d), 4.60-4.72 (1H, m), 3.89 (3H, s), 1.41 (6H, d); m/z (API-ES) 229 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH2:5][CH:6]([C:9]#[N:10])[C:7]#[N:8].[H-].[Na+].Br[CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[F:14])[CH2:5][C:6]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])([C:7]#[N:8])[C:9]#[N:10]
Reactant: N#CC(C#N)Cc1ccc(F)c(F)c1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(F)c(F)c1
Yield: 21.3 %

Procedure:
Using 1.00 g of (3,4-difluorobenzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.20 g of sodium hydride (60% in oil), and 1.38 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.32 g of 2-(3,4-difluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (19)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[NH2:31][CH2:32][CH2:33][OH:34]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][NH:6][C:7]([C:9]1[N:31]([CH2:32][CH2:33][OH:34])[CH:11]=[C:12]([Br:24])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: O=C(NCc1cccc(Cl)c1)c1occ(Br)c(=O)c1OCc1ccccc1
Reactant: NCCO
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(NCc1cccc(Cl)c1)c1c(OCc2ccccc2)c(=O)c(Br)cn1CCO
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (2.0 g) obtained in Example 161, Step 1 in tetrahydrofuran (10 ml)-ethanol (10 ml) was added 2-aminoethanol (0.33 ml) and the mixture was stirred at room temperature and at 50° C. respectively for 30 min. The solvent was evaporated and the residue was crystallized from ethyl acetate-diisopropyl ether to give 3-benzyloxy-5-bromo-1-(2-hydroxyethyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (1.95 g).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([N:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Li]CCCC.[B:28](OC)([O:31]C)[O:29]C.Cl>C1COCC1>[C:10]1([CH3:13])[CH:11]=[CH:12][C:7]([N:6]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:5]2[CH:4]=[CH:3][C:2]([B:28]([OH:31])[OH:29])=[CH:22][CH:21]=2)=[CH:8][CH:9]=1
Reactant: COB(OC)OC
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 4-bromo-N,N-di-p-tolylaniline (Compound 25) (12.55 g, 35.6 mmol) in anhydrous THF (100 mL), was added n-BuLi solution (16 mL, 2.5 M in hexanes) at −78° C. slowly. The resulting solution was stirred at −78° C. for about one hour. Then a freshly distilled trimethyl borate (B(OCH3)3) (5.6 mL) was added. The solution turned to yellow immediately, and was stirred at RT for about 2 hours. After addition of 1N HCl solution (150 mL), the whole was stirred at RT for about 18 hours and concentrated. The resulting solid was filtered and washed with diethyl ether to give a light yellow solid (Compound 26) (5.8 g, in 56% yield).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][N:31]1[C:36](=[O:37])[CH2:35][O:34][C:33]2[CH:38]=[CH:39][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:41][C:32]1=2.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:40]2[CH:39]=[CH:38][C:33]3[O:34][CH2:35][C:36](=[O:37])[N:31]([CH3:30])[C:32]=3[CH:41]=2)=[CH:7][CH:6]=1
Reactant: CN1C(=O)COc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1C(=O)COc2ccc(-c3ccc(C[C@H](NC(=O)C4(NC(=O)OC(C)(C)C)CCOCC4)C(N)=O)cc3)cc21
Temperature: 85 °C
Reaction time: 25 h
Yield: 52.7 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 276 mg) in acetonitrile (7 mL) under nitrogen was treated with 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (Example 10, step (ii), 154 mg) followed by sodium carbonate (0.533 mL). Nitrogen was bubbled through the mixture and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The mixture was stirred at 85° C. for 25 h and then allowed to cool. The solution was absorbed onto silica and purified by chromatography on silica using ethyl acetate 50-100% in isohexane as eluent to afford the sub-titled compound (155 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C1CCc2cc(OC)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(OC)cc2CCC1C(=O)OC
Yield: 67.3 %

Procedure:
To a solution of 69.3 g (0,313 mol) of (±)-6-methoxy-2-methoxycarbonyl-1,2,3,4-tetrahydroquinoline and 39 ml (0.407 mol) of ethyl chloroformate in 1400 ml of dichloromethane are added 85 g (0.63 mol) of potassium carbonate, and the mixture is heated at reflux for 18 h. The mixture is filtered, the filtrate is concentrated under reduced pressure and the residue is chromatographed on a column of silica, with a 3/7 mixture of ethyl acetate and cyclohexane. 80.4 g of product are obtained in the form of an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Br>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)cc1
Yield: 94.7 %

Procedure:
A dry reaction flask was charged with 4-nitrophenol (3.858 g, 27.75 mmol), anhydrous K2CO3 (8.29 g, 60 mmol) and acetone (250 mL). To this heterogeneous mixture was added 2-pyridylmethylbromide hydrobromide (7.0 g, 27.75 mmol) and refluxed for 24 h. From the resulting reaction mixture, 200 mL of acetone was removed under reduced pressure. The resulting residue was then diluted with ice-water (1 liter), the solid crushed out was filtered, washed with water and dried well to give 2-[(4-nitrophenoxy)methyl]pyridine (6.05 g, 95% yield). 1H NMR (CDCl3): δ 8.61 (d, 1H, J=4.8 Hz), 8.19 (d, 2H, J=9.0 Hz), 7.72 (m, 2H), 7.46 (d, 1H, J=7.8 Hz), 7.25 (m, 1H), 7.05 (d, 2H, J=9.3 Hz), 5.28 (s, 2H); LCMS (m/z): 231 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22](=[O:23])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1[O:34][CH3:35])[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Product: CCOC(=O)COc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with ethyl bromoacetate
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:13]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH:28]=[CH:29][C:30](OCC)=[O:31].Cl>C1(C)C=CC=CC=1.ClCCl>[CH3:11][C:12]1[O:16][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[N:14][C:13]=1[CH2:23][O:24][C:25]1[CH:26]=[C:27](/[CH:28]=[CH:29]/[CH2:30][OH:31])[CH:35]=[CH:36][CH:37]=1
Reactant: CCOC(=O)C=Cc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/CO)c1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A solution of diisobutyl aluminum hydride in toluene (1.5M, 51 ml) was added dropwise to a solution of ethyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate (14.0 g) in dichloromethane (200 ml) at 0° C. After stirring for 30 minutes, 2N hydrochloric acid (150 ml) was added at 0° C., and the mixture was stirred for 1 hour. The dichloromethane layer was separated, washed with saturated brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave crystals of (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-propenol (11.5 g, 92%). The crystals were recrystallized from ethyl acetate. Colorless prisms, mp: 118-119° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]([CH3:17])[CH2:13][CH:12]=1.[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH2:29].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH:28]([C:2]1[CH:3]=[C:4]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)=[CH2:29]
Reactant: CN1C=CC(c2c[nH]c3c(Br)cc(OS(=O)(=O)c4ccccc4)cc23)=CC1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cc(OS(=O)(=O)c2ccccc2)cc2c(C3CCN(C)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of benzenesulfonic acid 7-bromo-3-(1-methylpyridin-4-yl)-1H-indol-5-yl ester and Pd (PPh3)4 (0.2 eq.) in dry toluene was degassed and then treated with vinyl tributyltin (1.1 eq.). Heat the reaction mixture to reflux. After 5 hours, cool to room temperature, pour into ethyl acetate, wash with brine, dry the organic layer over Na2SO4, and concentrate. Purify to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:8])[O:5][C:4](=[O:18])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:25]([C:29]1[CH:34]=[C:33]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[C:32]([CH3:47])=[CH:31][C:30]=1[S:48]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([C:29]1[C:30]([S:48][C:3]2[C:4](=[O:18])[O:5][C:6]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)([CH3:8])[CH2:7][C:2]=2[OH:1])=[CH:31][C:32]([CH3:47])=[C:33]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][C:42]([C:45]#[N:46])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:34]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(NS(=O)(=O)c3ccc(C#N)cc3)cc2C(C)(C)C)cc1
Reactant: CC1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(C)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1NS(=O)(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 from 4-hydroxy-6-[2-(4-hydroxy-phenyl)-ethyl]-6-methyl-5,6-dihydro-pyran-2-one (prepared in Example KK; 0.09 g, 0.37 mmol), DMF (6 mL), K2CO3 (0.11 g, 0.81 mmol), and toluene-4-thiosulfonic acid S-[2-tert-butyl-4-(4-cyano-benzenesulfonylamino)-5-methyl-phenyl] ester (prepared in Example JJJJ; 0.19 g, 0.37 mmol). The mixture was stirred at room temperature overnight. After the standard work-up, the resulting residue was flash chromatographed on silica gel, eluting with 2% EtOH:EtOAc, then triturated with EtOAc:CH2Cl2 :hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 1.24 (s, 9 H), 1.42 (s, 3 H), 1.87 (s, 3 H), 1.92 (m, 2 H), 2.52 (m, partially obscured by DMSO, 2 H), 2.75 (d of ABX q, 1 H), 2.95 (d of ABX q, 1 H), 6.46 (s, 1 H), 6.64 (d, 2 H), 6.70 (s, 1 H), 6.96 (d, 2 H), 7.77 (d, 2 H), 8.06 (d, 2 H), 9.15 (s, 1 H), 9.68 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:19]1[CH:20]=[C:21]([F:23])[CH:22]=[C:17]([F:16])[C:18]=1[N+:24]([O-:26])=[O:25])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3[N+](=O)[O-])cccc2[nH]1
Temperature: 25 °C

Procedure:
4-Hydroxy-1H-indole-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) and 2,4-Difluoro-1-nitro-benzene (0.534 ml, 4.87 mmol) are dissolved in 20 ml of dimethylformamide. After addition of potassium carbonate (1.3 g, 9.74 mmol) the mixture is stirred over night at room temperature. Then the reaction mixture is evaporated under reduced pressure, dissolved with ethyl acetate and washed with water. The organic layers are dried over sodium sulfate and evaporated. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:13]>C(OCC)(=O)C>[Br:13][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OCCCCc1ccccc1
Solvent: CCOC(C)=O
Product: BrCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 1.50 g of 4-phenylbutanol was added 385 μl of phosphorus tribromide with ice cooling, and the mixture was stirred at a room temperature for 5 minutes and then at 80° C. for one hour. To the reaction mixture were added 20 ml of ice water and 30 ml of ethyl acetate. The separated organic layer was, successively washed with water, 5% sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated under a reduced pressure to obtain an oily residue. The residue was applied to a silica gel column and eluted with hexane/benzene (6:1) to obtain 1.94 g of (4-bromobutyl)benzene as a colorless liquid.