Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:15][CH3:16])[CH:8]=2)[C:3]=1[O:17][CH2:18][O:19][CH3:20].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:13][CH:12]([C:11]1[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:3]([O:17][CH2:18][O:19][CH3:20])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([O:15][CH3:16])=[CH:6][CH:5]=2)[CH3:14]
Reactant: OB(O)c1ccccc1
Reactant: COCOc1c(Br)c(C(C)C)cc2cc(OC)ccc12
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: COCCOC
Product: COCOc1c(-c2ccccc2)c(C(C)C)cc2cc(OC)ccc12
Temperature: 160 °C
Yield: 96.3 %

Procedure:
A sealed tube containing 2-bromo-3-(1-methylethyl)-6-(methyloxy)-1-{[(methyloxy)methyl]oxy}naphthalene (70) (0.24 g, 0.71 mmol), phenyl boronic acid (0.18 g, 1.41 mmol), Pd(PPh3)4 (82 mg, 0.07 mmol), 2 M Na2CO3 (5 mL) and DME (5 mL) was heated at 160° C. for 20 min. Cooled to room temperature, the mixture was extracted with ether (2×50 mL). The organic extracts were combined and washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a yellow oil. The crude product was purified by flash chromatography over SiO2 with hexanes:EtOAc (25:1) to give 0.23 g (97%) of compound 71 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.16 (d, J=6.8 Hz, 6H), 2.92 (sept, J=6.8 Hz, 1H), 3.06 (s, 3H), 3.93 (s, 3H), 4.71 (s, 2H), 7.08-7.15 (m, 2H), 7.30-7.40 (m, 3H), 7.40-7.46 (m, 2H), 7.52 (s, 1H), 8.01 (d, J=9.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[CH:12]1[O:17][CH2:16][C:15]([CH3:19])([CH3:18])[CH2:14][O:13]1.[CH:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:18][C:15]1([CH3:19])[CH2:16][O:17][CH:12](/[CH:11]=[CH:10]/[C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[OH:27])[O:13][CH2:14]1
Reactant: O=Cc1ccccc1
Reactant: Cc1cc(C)c(/C=C/C2OCC(C)(C)CO2)c(Br)c1
Product: Cc1cc(C)c(/C=C/C2OCC(C)(C)CO2)c(C(O)c2ccccc2)c1
Yield: 81 %

Procedure:
In the manner described in Example 1, (E)-2-[2-(2-bromo-4,6-dimethylphenyl)ethenyl]-5,5-dimethyl-1,3-dioxane was reacted with benzaldehyde to obtain (E)-2-[2-(5,5-dimethyl-1,3-dioxan-2-yl)ethenyl]3,5-dimethyl-α-phenylbenzenemethanol as a clear foam (271 mg, 81%): IR (film) 3420, 2940, 2840, 1660 and 1605 cm-1 ; NMR (DMSO-d6) δ 0.72 (3H, s), 1.14 (3H, s), 2.20 (3H, s), 2.24 (3H, s), 3.56 (2H, d, J=12 Hz), 3.64 (2H, d, J=12 Hz), 5.08 (1H, d, J=5 Hz), 5.64 (1H, dd, J=5, 15 Hz), 5.74 (1H, d, J=3 Hz, exchangeable), 5.90 (1H, d, J=3 Hz), 6.76 (1H, d, J=15 Hz), 6.96 (1H, s), 7.14 (1H, s), 7.16-7.36 (5H, m).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:4].[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(NC(=O)CN)c2ccccc2)cc1
Reactant: O=C(O)c1ccc(F)cc1
Product: Cc1ccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2ccccc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-(phenyl-p-tolyl-methyl)-acetamide (Example 3.3) and 4-fluorobenzoic acid.
Reaction SMILES: [OH:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1>>[OH:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:3]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:33]=[CH:34][C:35]=2[CH3:36])[CH2:26][CH2:25]1)=[O:4]
Reactant: Cc1ccc(C(O)(C(=O)O)c2ccc(C)cc2)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(C(O)(C(=O)NCCCN2CCC(c3cc(NC(=O)C(C)C)ccc3C)CC2)c2ccc(C)cc2)cc1

Procedure:
Example 157 was prepared from hydroxy[bis(4-methylphenyl)]acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 12: 1H NMR (400 MHz, CDCl3) δ 8.80–8.59 (s, br, 1 H), 7.91 (s, 1 H), 7.42 (d, 4 H, J=8.4 Hz), 7.15 (s, 1 H), 7.09 (d, 4 H, J=8.0 Hz), 7.04 (d, 1 H, J=8.0 Hz), 6.96–6.78 (br, 1 H), 5.30–5.05 (br, 1 H), 3.55–3.41 (m, 2 H), 3.15–3.00 (m, 2 H), 2.82–2.64 (m, 1 H), 2.59–2.46 (m, 2 H), 2.40–2.27 (m, 1 H), 2.30 (s, 6 H), 2.28 (s, 3 H), 2.17–1.95 (m, 4 H), 1.83–1.56 (m, 4 H), 1.02 (d, 6 H, J=6.8 Hz); ESMS m/e: 556.4 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][CH:13]=[CH2:14])[CH:10]=1)[CH:2]=[CH2:3].[C:20](O)(=[O:22])[CH3:21].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[C:20]([C:8]1[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][C:7]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:22])[CH3:21]
Reactant: C=CCOc1cc(CC(=O)OC)cc(OCC=C)c1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: C=CCOc1cc(CC(=O)OC)c(C(C)=O)c(OCC=C)c1
Temperature: 4 °C
Reaction time: 3.5 h
Yield: 70.4 %

Procedure:
Methyl 3,5-diallyloxyphenylacetate (40 g, 0.14 mol) obtained in Example 5, Step 1 was dissolved in trifluoroacetic acid (0.15 L). After the solution was cooled to 4° C., acetic acid (9.5 mL, 0.17 mol) and trifluoroacetic anhydride (40 mL, 0.28 mol) were added thereto, followed by stirring at 4° C. for 3.5 hours. The reaction mixture was gradually added to a saturated aqueous solution of sodium hydrogencarbonate for neutralization, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/20-1/6) to obtain methyl 2-acetyl-3,5-diallyloxyphenylacetate (30 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:45][CH2:44][CH2:43][C:42]1=[O:46]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH2:40][N:41]4[CH2:45][CH2:44][CH2:43][C:42]4=[O:46])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NCCCN1CCCC1=O
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCCCN3CCCC3=O)c(O)c3ncc(Cc4ccc(F)cc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-{[4-(methylsulfonyl)phenyl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(3-aminopropyl)-2-pyrrolidinone employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.25 (t, J=5.3 Hz, 1 H), 8.57 (s, 1 H), 7.84 (d, J=8.2 Hz, 2 H), 7.20 (d, J=8.1 Hz, 2 H), 7.02-6.97 (m, 5 H), 5.45 (br, 2 H), 4.02 (s, 2 H), 3.50-3.38 (m, 6 H), 3.03 (s, 3 H), 2.39 (t, J=7.9 Hz, 2 H), 2.04 (m, 2 H), 1.88 (m, 2 H); HRMS C31H31FN4O6S (M+H)+ calcd 607.1948, found 607.2043.
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.Br[CH2:38][C:39]1[CH:40]=[CH:41][C:42]2[S:46][C:45]([CH3:47])=[N:44][C:43]=2[CH:48]=1>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][CH2:38][C:39]5[CH:40]=[CH:41][C:42]6[S:46][C:45]([CH3:47])=[N:44][C:43]=6[CH:48]=5)[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: Cc1nc2cc(CBr)ccc2s1
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: Cc1nc2cc(COC(C)c3ccc([C@H]4C[C@@]5(C)[C@@H](CC[C@@]5(O)C(F)(F)C(F)(F)F)[C@@H]5CCC6=CC(=O)CCC6=C54)cc3)ccc2s1
Yield: 24 %

Procedure:
In analogy to Example 2, 500 mg (0.98 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-13-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using 5-bromomethyl-2-methylbenzothiazole and, after workup and purification, 157 mg (24%) of the title compound were isolated as a colourless foam.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[NH:8][CH2:7]2)[O:5][CH2:4]1.Br[CH2:20][CH2:21][Cl:22]>CN(C=O)C>[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[N:8]([CH2:20][CH2:21][Cl:22])[CH2:7]2)[O:5][CH2:4]1
Reactant: ClCCBr
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2C2(CN1CCCl)OCCO2
Reaction time: 1 h

Procedure:
To a suspension of 440 mg (11 mmol) of 60% sodium hydride in 20 ml of DMF, a solution of 2.41 g (10 mmol) of 3,4-dihydro-2H-1,2-benzothiazin-4-one 1,1-dioxide ethylene acetal in 10 ml of DMF was added under ice cooling and stirring. The reaction mixture was stirred for one hour at 0° C. and then for further one hour at room temperature. Under ice cooling, a solution of 2.86 g (20 mmol) of 1-bromo-2-chloroethane in 10 ml of DMF was added to the reaction mixture, followed by stirring for 16 hours at room temperature.
Reaction SMILES: Br[C:2]1[N:3]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Br-].[CH:24]1([Zn+])[CH2:26][CH2:25]1>O1CCCC1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:24]1([C:2]2[N:3]([CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:4]3[C:9]([C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:26][CH2:25]1
Reactant: [Zn+]C1CC1
Reactant: COC(=O)c1c(Br)n(C(C)c2ccccc2)c2ccccc12
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(C2CC2)n(C(C)c2ccccc2)c2ccccc12
Temperature: 25 °C
Yield: 82 %

Procedure:
To a solution of methyl 2-bromo-1-(1-phenylethyl)-1H-indole-3-carboxylate (0.30 g, 0.84 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.09 g, 0.08 mmol) in tetrahydrofuran (20 mL) was added cyclopropylzinc(II) bromide (6.0 mL, 0.5 mol/L in tetrahydrofuran). The reaction mixture was stirred at reflux for 12 hours. After the reaction, it was cooled to room temperature and diluted with water (100 mL). The product was extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (silica gel: ethyl acetate:petroleum ether=1:10) to give the crude product methyl 2-cyclopropyl-1-(1-phenylethyl)-1H-indole-3-carboxylate (0.22 g, 82%) as a yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:15])([F:14])[C:7]1[S:8][CH:9]=[C:10]([CH2:12]O)[N:11]=1>>[Cl:3][CH2:12][C:10]1[N:11]=[C:7]([C:6]([F:15])([F:14])[F:5])[S:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1csc(C(F)(F)F)n1
Product: FC(F)(F)c1nc(CCl)cs1
Reaction time: 3 h
Yield: 60.7 %

Procedure:
Thionyl chloride (4.89 g) was added to [2-(trifluoromethyl)thiazol-4-yl]methanol (512 mg) at room temperature, and the mixture was stirred for 3 hr. The reaction mixture was concentrated to give the title compound (342 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([CH3:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15](Cl)(=O)C(Cl)=O.CN(C=O)C>ClCCl>[Br:1][C:2]1[C:3]([C:13]#[N:14])=[C:4]([CH3:12])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(O)c(C(=O)O)cc(Br)c1C#N
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(C#N)c(C)c1O
Reaction time: 3 h
Yield: 53.8 %

Procedure:
To a solution of 5-bromo-4-cyano-2-hydroxy-3-methylbenzoic acid (7.40 g) in dichloromethane (70.0 mL) were added oxalyl chloride (3.91 g) and DMF (0.20 mL) under ice-cooling, and the mixture was stirred for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with THF. To this mixture was added dropwise a solution of triethylamine (5.66 g) in methanol (50.0 mL) under ice-cooling, and the mixture was stirred for 20 min. The reaction mixture was poured into 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.20 g).
Reaction SMILES: C([NH:4][C:5]1[CH:18]=[CH:17][C:8]([O:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)(=O)C>Cl.C(O)C>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(C)Oc1ccc(NC(C)=O)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(N)cc1
Yield: 95.6 %

Procedure:
Ethyl 2-(4- acetamidophenoxy)propanoate (5.0 g, 2.0 mmol) is hydrolyzed by refluxing for 6 hours at 80° C. with ethanol (10 mL) and 3 drops of concentrated hydrochloric acid. The reaction is concentrated under reduced pressure to obtain ethyl 2-(4-aminophenoxy)propanoate (0.4 g) (yield 95%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]O)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:23])[CH3:24]
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCCCCO
Product: CC(C)(C)[Si](C)(C)OCCCCCOc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Mitsunobu reaction of phenol 58 with 5-(tert-butyldimethylsilanyloxy)pentan-1-ol gave 2-(3-(3-(5-(tert-butyldimethylsilanyloxy)pentyloxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.725 g, 44%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.83 (m, 2H), 7.68-7.72 (m, 2H), 7.11-7.16 (m, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.73 (s, 1H), 6.65 (dd, J=8.4, 2.0 Hz, 1H), 3.92 (t, J=6.6 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 3.64 (t, J=6.2 Hz, 2H), 2.65 (t, J=7.8 Hz, 2H), 1.99-2.07 (m, 2H), 1.75-1.82 (m, 2H), 1.56-1.62 (m, 2H), 1.47-1.53 (m, 2H), 0.89 (s, 9H), 0.10 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][OH:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:22]([CH2:23][CH2:24][CH2:25][OH:26])[C:18]([CH3:19])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCO
Yield: 79.1 %

Procedure:
A solution of 1-(4-benzyloxyphenyl)pentan-1,4-dione (5.00 g, 17.7 mmol), 3-amino-1-propanol (1.33 g, 17.7 mmol) and p-toluenesulfonic acid monohydrate (253 mg, 1.33 mmol) in toluene (100 ml) was refluxed for 12 hours under heating using Dean-Stark's apparatus, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the object compound as a solid. 4.50 g (yield: 79.1%)
Reaction SMILES: C([Li])CCC.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[C:15]1([CH2:21][CH2:22][C:23](Cl)=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:23](=[O:24])[CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:8])[CH3:7]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: O=C(Cl)CCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCc1ccccc1
Reaction time: 0.5 h
Yield: 84.6 %

Procedure:
68.3 ml (0.11 mol) of butyllithium (as a 1.6M solution in hexane) were added dropwise, at -78° C. and under an atmosphere of nitrogen, to a solution of 11.75 g (91.0 mmole) of 4(S)-isopropyl-2-oxazolidinone in 200 ml of anhydrous tetrahydrofuran; the mixture was then stirred for 30 minutes, after which a solution of 18.41 g (0.11 mole) of phenylpropionyl chloride in 100 ml of anhydrous tetrahydrofuran was added to it over a period of 10 minutes. The mixture was then stirred for 1 hour, after which it was mixed with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then removed by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel (using a 1:3 by volume mixture of ethyl acetate and hexane as the eluent), followed by recrystallization from diisopropyl ether, to afford 20.12 g (yield 85%) of the title compound as white crystals, melting at 62°-63° C.
Reaction SMILES: [OH-:1].[Li+].[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]1[CH2:21][CH:20]([C:22]([O:24]C)=[O:23])[NH:19][C:18]1=[O:26].Cl>O.O1CCCC1>[CH:3]1[C:15]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][C:4]=1[O:16][CH:17]([C:18]([OH:26])=[O:1])[CH2:21][C@@H:20]([C:22]([OH:24])=[O:23])[NH2:19]
Reactant: [OH-]
Reactant: COC(=O)C1CC(Oc2ccc3c(c2)Cc2ccccc2-3)C(=O)N1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CC(Oc1ccc2c(c1)Cc1ccccc1-2)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 3.3 h

Procedure:
A mixture of lithium hydroxide (0.117 g) in water (1.5 ml) and tetrahydrofuran (4.7 ml) was treated with methyl 3-(2-fluorenoxy)-2-pyrrolidone-5-carboxylate (0.526 g), and heated to 60° C. After about 3.3 hours, the reaction mixture was allowed to cool to room temperature. The reaction mixture was treated with 5N HCl (976 ml). The resulting colloidal suspension was sonicated for ten minutes. The insolubles were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (10 ml). The insolubles were dried overnight in at vacuum oven at 60° C. to afford the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[S:15][C:14]([C:16]3[N:20]([C:21]4[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=4)[N:19]=[C:18]([C:28]([F:31])([F:30])[F:29])[CH:17]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(Cl)Cl>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N:20]2[C:16]([C:14]3[S:15][C:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)=[CH:12][CH:13]=3)=[CH:17][C:18]([C:28]([F:31])([F:29])[F:30])=[N:19]2)[CH:22]=1
Reactant: CN(C)CCO
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3cccc(O)c3)s2)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCOc1cccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cccc(S(C)(=O)=O)c3)s2)c1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
3-(5-(5-(3-(methylsulfonyl)phenyl)thiophen-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (120 mg, 0.26 mmol), 2-(dimethylamino)ethanol (46 mg, 0.52 mmol) and triphenylphosphine (138 mg, 0.52 mmol) were dissolved in a mixture solvent of anhydrous THF (2.5 mL) and DCM (2.5 mL) and cooled off at 0° C. under nitrogen atmosphere. To this solution was added diisopropyl azodicarboxylate (111 mg, 0.52 mmol). The reaction mixture was stirred vigorously and warmed up to mom temperature overnight. The solvent was evaporated in vacuo and the residue was purified by HPLC, providing the product (61 mg, 44%). 1H-NMR (Acetone-d6): δ 8.13 (m, 1H), 7.93 (m, 1H), 7.90 (m, 1H), 7.71 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.17-7.09 (br, 5H), 4.12 (t, J=5.8 Hz, 2H), 3.18 (s, 3H), 2.65 (t, J=5.8 Hz, 2H), 2.21 (s, 6H). MS (ES): 536 [M+H]+.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>C1COCC1>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([OH:17])=[C:9]([C:18]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25]([O:27][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:8]1=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: OCc1ccccc1
Reactant: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)O)cc2)c(O)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCCn1c(=O)c(C(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)c(O)c2ccccc21
Reaction time: 8 h

Procedure:
A solution of 4-(1-hexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamido)benzoic acid (41 mg, 0.1 mmol) in THF is cooled to 0° C., and benzyl alcohol (21 mg, 20 μl, 0.2 mmol) is added, along with EDCI (19 mg, 0.1 mmol) and dimethylaminopyridine (3 mg, 0.02 mmol). The reaction mixture is left to stir overnight. The organic phase is washed with water and evaporated under reduced pressure. The crude product is purified by column chromatography, using 4:1 petroleum ether:ethyl acetate, with a yield of 30 mg (60%). 1H NMR (DMSO): δ 8.16 (d, J=8 Hz, 1H), 8.04 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 3H), 7.68 (d, J=8 Hz, 1H), 7.46-7.25 (m, 6H), 7.38 (m, 1H), 5.30 (s, 2H), 4.28 (bs, 2H), 1.59 (bs, 2H), 1.41-1.15 (m, 6H), 0.84 (bs, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18](O)[CH3:19]>N1CCCCC1>[CH3:4][C:8]1[CH:9]=[C:13]([CH3:14])[NH:12][C:18]=1[CH:19]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2cccc(Cl)c2)N1
Reactant: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(3-chloro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (60 mg, 68%).