Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][CH2:11][CH2:12][C@H:13]1[NH:16][C:15](=[O:17])[C@@H:14]1[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].CO[C:31](OC)([CH3:33])[CH3:32].[Cl-].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:32][C:31]1([CH3:33])[O:10][CH2:11][CH2:12][C@H:13]2[N:16]1[C:15](=[O:17])[C@@H:14]2[N:18]1[C:19](=[O:28])[C:20]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:21]2[C:22]1=[O:23]
Reactant: COC(C)(C)OC
Reactant: O=C1N[C@H](CCO)[C@H]1N1C(=O)c2ccccc2C1=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC1(C)OCC[C@@H]2[C@@H](N3C(=O)c4ccccc4C3=O)C(=O)N21
Reaction time: 2 h

Procedure:
Boron trifluoride etherate (5 μl) was added to a suspension of (3R,4R)-4-(2-hydroxyethyl)-3-phthalimidoazetidin-2-one (126 mg) and 2,2-dimethoxypropane (74 μl) in dichloromethane (3 ml) at ambient temperature. The mixture was stirred for two hours. Additional dimethoxypropane (50 μl) was added and the mixture was stirred for an additional 1.5 hours. The resulting solution was poured into a saturated aqueous solution of sodium chloride and sodium bicarbonate and extracted twice with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to give a crystalline solid. Chromatography on silica gel (4 g; eluting with 3% acetone in dichloromethane) and washing the crystals with ether afforded 100 mg of (6R,7R)-2,2-dimethyl-7-phthalimido-1-aza-3-oxabicyclo[4.2.0]octan-8-one: IR (CH2Cl2): 1770 and 1720 cm-1 ; NMR (CDCl3) δ: 1.56 (s, 3H), 1.81 (s, 3H), 1.7-2.0 (m, 2H), 3.7-4.1 (m, 3H), 5.01 (d, J=2 Hz, 1H), and 7.5-7.9 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1>C1COCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: Fc1ccc(CBr)cc1
Solvent: C1CCOC1
Product: Fc1ccc(CNCc2ccc(F)cc2)cc1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To 4-flourobenzylamine (1.17 g, 9.4 mmol) dissolved in 5 mL of THF was added 4-fluorobenzyl-bromide (0.88 g, 4.7 mmol) dropwise. The reaction was stirred overnight resulting in the formation of a white solid. After filtering off the solid solvent was removed to yield 1.08 g crude di-(4-fluorobenzyl) amine. To this was added 19 mL of CH2Cl2 and 19 mL of saturated (aq.) NaHCO3. Acetyl chloride (0.67 mL, 9.4 mmol) was added to the rapidly stirring mixture and the reaction allowed to proceed overnight. The mixture was diluted with CH2Cl2, transferred to a separatory funnel. The organic layer was separated, washed with satd (aq.) NaCl, dried over Na2SO4 and the solvent removed to yield 1.01 g oil. The product was purified by column chromatography (4×7 cm SiO2, 20-40% EtOAc/Hexanes) to yield 603 mg (55% yield) oil. LC/MS (M+H) calcd for C14H14NF2: 276.12, found: 276.13. HRMS (M+H) calcd for C14H14NF2: 276.1200, found: 276.1192. Anal calcd for C16H15F2NO: C, 69.80; H, 5.49; N, 5.08; found: C, 59.53; H, 5.41; N, 5.06. 1H NMR (500 MHz, DMSO) δ: 2.10 (s, 3), 4.45 (s, 2), 4.49 (s, 2), 7.18-7.27 (m, 8). 13C NMR (125 MHz, DMSO) δ; 21.34, 47.04, 50.04, 114.90, 115.07, 115.27, 115.45, 128.51, 128.58, 129.57, 129.64, 133.32, 133.34, 133.86, 133.89, 160.25, 160.33, 162.17, 162.27, 170.22.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12].[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-]>CN(C)C(=O)C.C(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][NH:6][C:5]2=[O:12]
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Reactant: O=c1[nH]cnc2ccc(Br)cc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-c2ccc3nc[nH]c(=O)c3c2)c(C)c1
Yield: 37.9 %

Procedure:
To a solution of 6-bromo-3H-quinazolin-4-one (43.1 mg, 0.1915 mmol) dissolved in 2 ml N,N-dimethylacetamide in a 20 ml vial, 2,4,6-trimethylphenylboronic acid (114.9 mg, 0.76 mmol) dissolved in 1 ml ethanol and potassium carbonate (26.7 mg, 0.193 mmol) dissolved in 1 ml water were added. Triphenylphosphine (5 mg, 0.019 mmol) and tris(dibenzylideneacetone)dipalladium (0) (3.5 mg, 3.8 umol) were added to the mixture which refluxed overnight. The crude product was poured into 50 ml saturated bicarbonate solution and methylene chloride was used to extract the product. Solvent in the organic phase was removed under vacuum. The resulted residue was purified by preparative HPLC. 19.2 mg product was obtained. Yield: 40%; 1H NMR (500 MHz, DMSO-d6): δ 1.96741(s, 6H), 7.114769–7.16307(d, J=7.69 Hz, 2H), 7.19260–7.22248(dd, J1=8.62 Hz, J2=6.31 Hz 1H), 7.60434–7.62503(dd, J1=8.335 Hz, J2=1.97 Hz, 1H), 7.75179–7.76829(d, J=8.25 Hz, 1H), 7.81882–7.82258(d, J=1.88 Hz, 1H), 8.17882 (s, 1H); ESI-MS: m/z 265 (M++1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].C([N-]C(C)C)(C)C.[Li+].CN([CH:21]=[O:22])C.Cl>O1CCCC1.O>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([F:8])=[C:6]([CH:7]=1)[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: Cc1cc(F)ccc1Br
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(F)c(C=O)cc1Br
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-5-fluorotoluene (20 g) in dry tetrahydrofuran (200 ml) was added dropwise lithium diisopropylamide (2.0 M, heptan-tetrohydrofuran-ethylbenzene solution, 52.9 ml) under argon atmosphere at −78° C. After stirring as such for 2 hours, a solution of DMF (41 ml) in dry tetrahydrofuran (50 ml) was added dropwise. The mixture was returned to room temperature and stirred for 1 hour. Then, water was added and the mixture was neutralized with 1N hydrochloric acid. After extraction with ethyl acetate, the extract was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=24:1) and re-crystallized from hexane-ethyl acetate to give 5-bromo-2-fluoro-4-methylbenzaldehyde (9.39 g).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.[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>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[CH:13][C:14]([C:6]2[CH:2]=[C:3]([CH:7]=[O:8])[S:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: O=Cc1sccc1Br
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of 3-bromothiophene-2-carboxaldehyde (2.0 g) and 3-trifluoromethylbenzene boronic acid (2.19 g) in ethylene glycol dimethyl ether (100 ml) was added sodium carbonate (2.9 g), tetrakis(triphenylphosphine) palladium (0) (0.12 g) and water (50 ml). The mixture was heated to 90° C. under nitrogen. After 18 hours the reaction was allowed to cool and was concentrated. The residue was partitioned between water and ethyl acetate; the organic solution was taken and was washed with brine and then dried (MgSO4) and concentrated. The crude material was purified by SPE (Si); the product eluted with neat chloroform to furnish the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([O:12][CH:13]([CH3:18])[C:14]([CH3:17])(O)[CH3:15])[CH:7]=1)[C:2]#[C:3][CH3:4].N1C=CC=CC=1.S(Cl)(Cl)=O.O>C(Cl)(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([O:12][CH:13]([CH3:18])[C:14]([CH3:17])=[CH2:15])[N:9]=[CH:10][N:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1cc(OC(C)C(C)(C)O)ncn1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: C=C(C)C(C)Oc1cc(OCC#CC)ncn1
Reaction time: 2 h
Yield: 59 %

Procedure:
In 3 ml of chloroform was dissolved 0.42 g of 3-[6-(2-butynyloxy)pyrimidin-4-yloxy]-2-methyl-2-butanol, to which 0.2 g of pyridine was added and 0.15 ml of thionyl chloride was added dropwise at −13° C., followed by stirring 2 hours. The reaction mixture was then poured into water, which was extracted three times with chloroform. The combined organic layers were washed with a saturated aqueous sodium hydrogencarbonate, a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.23 g of 4-(2-butynyloxy)-6-(1,2-dimethylallyloxy)pyrimidine.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([C@:27]1([CH3:33])[CH2:31][O:30][C:29](=[O:32])[NH:28]1)[CH:21]=[CH:20]2.N1C=CC=CC=1.C(Cl)Cl>>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C@:27]3([CH3:33])[CH2:31][O:30][C:29](=[O:32])[NH:28]3)[CH:23]=2)[CH:18]=1)(=[O:5])=[O:4]
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@]1(c2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)COC(=O)N1
Reaction time: 8 h
Yield: 88.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.144 mL, 0.000859 mol) was slowly added to a solution containing (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (190 mg, 0.00078 mol), pyridine (2 mL, 0.02 mol), and methylene chloride (2 mL, 0.03 mol) at 0° C. After stirring overnight TLC showed complete reaction. After concentration, the crude was purified by chromatography using a 0-100% EtOAc/hexane gradient to give (R)-6-(4-methyl-2-oxooxazolidin-4-yl)naphthalen-2-yl trifluoromethanesulfonate as a yellow gel (259 mg, 88%). 1H NMR (400 MHz, CDCl3-d) δ=7.95 (s, 1H), 7.94-7.89 (m, 2H), 7.77 (d, J=1.9 Hz, 1H), 7.59 (dd, J=1.6, 8.6 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 4.48 (d, J=8.4 Hz, 1H), 4.43 (d, J=8.4 Hz, 1H), 1.88 (s, 3H).
Reaction SMILES: [CH2:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])[CH:2]([CH3:4])[CH3:3].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].C(N(CC)CC)C.O1CCCC1>CCOCC>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CC(C)CS(=O)(=O)c1nc[nH]n1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)CC(C)C)n1

Procedure:
A mixture of 9.5 g. 3-isobutylsulphonyl-1,2,4-triazole, 8.2 g. dipropylcarbamoyl chloride, 7.5 ml. dry triethylamine and 100 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 11 hours. The reaction mixture was worked up as described in Example 1, using ether in place of methylene dichloride, to give 1-dipropylcarbamoyl-3-isobutylsulphonyl-1,2,4-triazole, m.p. 62° - 63.5° C. (from petroleum ether, b.p. 62° - 68° C.).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:10])[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-]>CCCCCC.C1COCC1.C(Cl)Cl>[O:15]=[C:14]1[CH2:13][C:12]([CH3:17])([CH3:11])[C:7]2[C:8](=[C:3]([CH3:10])[CH:4]=[CH:5][CH:6]=2)[O:9]1
Reactant: CC(C)=CC(=O)Cl
Reactant: Cc1ccccc1O
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc2c1OC(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml of round bottom flask, NaH (1.66 g, 60% suspension in oil, 0.046 mol) was washed with dry hexane. Then, dry THF (22 ml) was added followed by o-cresol (5 g, 0.046 mol) in 10 ml of dry THF. The reaction mixture was stirred at 0° C. for 30 min followed by addition of 3,3-dimethyl acryloyl chloride in 10 ml of THF. The resulting white slurry was stirred at room temperature for 12 h, then slowly quenched with water. The mixture was then extracted with ethyl acetate. The organic layer was washed with brine, water and dried over MGSO4. After filtration and removal of the solvent, a yellow oil was obtained (10.44 g). This oil was then dissolved in 50 ml of dry CH2Cl2, and was canulated into a solution of AlCl3 (10.8 g, 0.069 mmol) in 10 ml of CH2Cl2. The reaction mixture was stirred at room temperature for 12 h. Then ice-water was carefully added and the organic layer was separated, and washed with NaHCO3 (sat), brine, water and finally dried over MgSO4After removal of the drying agent and solvent, the residue was purified by column chromatography (silica gel, ethyl acetate/hexane 1/9) to yield the title compound (4.408 g) as an oil.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]([CH3:14])([CH3:13])[CH2:11]O>>[CH3:11][C:10]1([CH3:14])[CH2:13][O:8][C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9]1
Reactant: CCCCCC(=O)O
Reactant: CC(C)(N)CO
Product: CCCCCC1=NC(C)(C)CO1
Temperature: 185 °C
Yield: 81.2 %

Procedure:
Following the procedure under Example 8, 6.085 g (52.4 mmoles) of hexanoic acid and 10 ml (9.34 g, 104.8 mmoles) of 2-amino-2-methylpropanol were heated to 185° C. Work up and fractional distillation gave 7.2 g (81%) of product, b.p. 90°-92° C./25 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C:12]([CH3:14])([CH3:13])[O:11][C:10](=[O:15])[NH:9]2)=[CH:4][CH:3]=1.I[C:17]1[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:22])=[CH:19][CH:18]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C:12]([CH3:13])([CH3:14])[O:11][C:10](=[O:15])[N:9]2[C:17]2[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:33]=3[N:32]=[CH:31][CH:30]=[CH:29]4)=[O:22])=[CH:19][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C(Nc1cccc2cccnc12)c1ccc(I)cc1
Reactant: CC1(C)OC(=O)N[C@H]1c1ccc(F)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CC1(C)OC(=O)N(c2ccc(C(=O)Nc3cccc4cccnc34)cc2)[C@H]1c1ccc(F)cc1
Temperature: 140 °C
Yield: 89.1 %

Procedure:
A microwave vial was charged with (S)-4-(4-fluorophenyl)-5,5-dimethyloxazolidin-2-one (0.050 g, 0.239 mmol), 4-iodo-N-(quinolin-8-yl)benzamide (0.098 g, 0.263 mmol), tribasic potassium phosphate (0.254 g, 1.195 mmol) and dioxane (2.50 mL). The mixture was purged with argon and then copper (I) iodide (0.046 g, 0.239 mmol) and N,N′-dimethylethylenediamine (0.051 mL, 0.478 mmol) were added. The system was purged with argon, the tube was sealed, and the reaction mixture was heated at 140° C. for 2 hours in the microwave. The reaction mixture was filtered through Celite® brand filter aid, and the filtrate was concentrated to afford an orange brown solid. The residual material was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% EtOAc-hexane) to afford (S)-4-(4-(4-fluorophenyl)-5,5-dimethyl-2-oxooxazolidin-3-yl)-N-(quinolin-8-yl)benzamide (0.097 g, 0.213 mmol, 89% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (s, 3H) 1.66 (s, 3H) 5.60 (s, 1H) 7.16-7.29 (m, 2H) 7.36 (br. s., 2H) 7.58-7.81 (m, 5H) 7.97 (d, J=8.80 Hz, 2H) 8.45 (dd, J=8.31, 1.66 Hz, 1H) 8.67 (dd, J=7.68, 1.32 Hz, 1H) 8.95 (dd, J=4.21, 1.66 Hz, 1H) 10.55 (s, 1H). m/z (ESI) 456 (M+H)+.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][C:6]1[CH:7]=[C:8](Br)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)(C)C.[C:23]([C:25]1[CH:39]=[CH:38][C:28]([N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)#[CH:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[CH2:30]([N:29]([CH2:34][CH2:35][CH2:36][CH3:37])[C:28]1[CH:27]=[CH:26][C:25]([C:23]#[C:24][C:7]2[C:6]([OH:5])=[CH:15][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:39][CH:38]=1)[CH2:31][CH2:32][CH3:33]
Reactant: C#Cc1ccc(N(CCCC)CCCC)cc1
Reactant: CC(C)[Si](Oc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)c1ccc(C#Cc2cc3ccccc3cc2O)cc1
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
A solution of 3-triisopropylsilyoxy-1-bromonaphthalene (3.17 g, 8.4 mmol), 4-ethynyl-N,N-dibutylaniline (2.87 g, 12.5 mmol), Pd(PPh3)2Cl2 (176 mg, 3 mol %), PPh3 (329 mg, 15 mol %) and CuI (120 mg, 7.5 mol %) in Et3N (20 mL) under N2 was heated at reflux for 3 h. The resulting mixture was cooled, poured into water (200 mL), extracted with DCM (3×50 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using DCM (20% in hexanes) as eluent. The solvent was removed under reduced pressure and the residue dissolved in Et2O (30 mL). Tetrabutylammonium fluoride (3.8 mL, 1 M, 3.8 mmol) was added and stirring continued for 10 min. The solution was poured into water (100 mL), extracted with Et2O (3×40 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (15% in hexanes to 0% in EtOAc gradient) as eluent. The solvent was removed under reduced pressure to give the title compound (1.40 g, 21%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH:23][CH:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
3-chloro-4-nitro-benzoyl chloride (Intermediate 54; 2.2 g, 10.00 mmol) was dissolved in DCM (20 mL) and N,N-diisopropylethylamine (2.095 mL, 12.00 mmol) added. The mixture was cooled in an ice/water bath and 4-amino-1-methylpiperidine (Fluorochem; 1.14 g, 10.00 mmol) in DCM (10 mL) added dropwise. The mixture was allowed to warm to room temperature and stirred for 0.5 hr. A white precipitate resulted. The reaction mixture was washed with 2N NaOH, filtered and the filter cake washed with water and dried on a sinter over the weekend to give the title compound as a white solid (1.80 g, 60%) as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.Cl.[NH2:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.[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>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:21]3[CH:22]=[CH:23][C:18]([NH2:17])=[CH:19][CH:20]=3)=[CH:3][N:4]=[C:5]2[CH:10]=1
Reactant: Nc1ccc(B(O)O)cc1
Reactant: Brc1cnc2cc(-c3nccs3)ccn12
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(-c2cnc3cc(-c4nccs4)ccn23)cc1
Temperature: 95 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
Take up 3-bromo-7-thiazol-2-yl-imidazo[1,2-a]pyridine (1.07 g, 3.82 mmol) and 4-aminophenylboronic acid hydrochloride (793 mg, 4.58 mmol, 1.2 eq) in 15 mL of dioxane and 7 mL of 2 N aqueous sodium carbonate, then deoxygenate with vacuum/nitrogen bubbling as described above. Add tetrakis (triphenylphosphine) palladium (0) (221 mg, 0.19 1 mmol, 0.05 eq), fit the reaction flask with a reflux condenser and heat the mixture to 95° C. with stirring under nitrogen for approximately 16 hours. Cool the dark brown reaction mixture, dilute with ethyl acetate (˜40 mL) and partition the layers in a separatory funnel. Dry the organic layer over solid magnesium sulfate, filter, then apply to a 10 g SCX Mega Bond-Elut™ cartridge (Varian) prewashed with 100 mL 1:1 CH2Cl2:MeOH. After loading, wash the cartridge with another 200-250 mL of the CH2Cl2:MeOH solution, then elute the product with 100 mL of CH2Cl2:2 M NH3-MeOH, concentrate to a brown-orange oil, and purify via flash chromatography with a gradient of 0 to 5% methanol in dichloromethane. Pool the clean fractions and concentrate to provide 750 mg (67%) of the title compound as a yellow-brown solid after drying. MS (ES) m/z 293 (M+1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.Cl.[OH:15][C:16]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:17]=1/[CH:18]=[CH:19]/[C:20](O)=[O:21].C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O>[OH:7][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:1]=1)[NH:10][CH:9]=[C:8]2[CH2:11][CH2:12][NH:13][C:20](=[O:21])[CH:19]=[CH:18][C:17]1[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][C:16]=1[OH:15]
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: O=C(O)/C=C/c1ccc(O)cc1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: O=C(C=Cc1ccc(O)cc1O)NCCc1c[nH]c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 50.9 %

Procedure:
Serotonin hydrochloride (300 mg, 1.41 mmol) and trans-2,4-dihydroxycinnamic acid (253 mg, 1.41 mmol) were dissolved in a mixed solvent of dichloromethane (6 ml) and N,N-dimethylformamide (6 ml), and the solution was maintained at 0° C. To this solution were added triethylamine (216 μl, 1.55 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 237 mg, 1.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl, 297 mg, 1.55 mmol), and the mixture was gradually warmed to room temperature and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (10 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (10 ml). The ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (PTLC, eluent: ethyl acetate-n-hexane=2:1, 0.01% formic acid) to give N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-3-(2,4-dihydroxyphenyl)-2-propenamide (243 mg, yield 51.0%) as a viscous oil.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][CH:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[N:10]=1)=[O:8])[CH3:5].[OH-].[Na+].CN1CCC[C:31]1=[O:35]>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([C:7]2[O:8][C:5]([CH2:31][OH:35])=[C:4]([CH2:3][CH3:2])[N:6]=2)=[N:10]1
Reactant: CC(C=C(Cl)Cl)NC(=O)c1nn(Cc2ccccc2F)c2ccccc12
Reactant: CN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Product: CCc1nc(-c2nn(Cc3ccccc3F)c3ccccc23)oc1CO
Yield: 60 %

Procedure:
730 mg of 1,1-dichloro-3-[1-(2-fluorobenzyl)indazole-3-carboxamido]-but-1-ene (1.86 mmol) and 3.75 ml of NaOH, 1N (3.75 mmol) were stirred in 7.4 ml of N-methylpyrrolidone at 50° C. under argon overnight. After cooling, the mixture was poured onto ice-water and the product which had precipitated out was filtered off and dried. Finally, it was purified by column chromatography (SiO2, cyclohexane:ethyl acetate 2:1). 375 mg (60%) of 2-[1-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyl-4-ethyl-oxazole were obtained as white crystals.