Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12].C([Li])CCC.CCCCCC.CN(C)[CH:28]=[O:29].Cl>O1CCCC1>[OH:4][C:5]1[C:6]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:8]=[CH:9][C:10]=1[CH:28]=[O:29]
Reactant: COCOc1ccccc1C(F)(F)F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cccc(C(F)(F)F)c1O
Reaction time: 1 h

Procedure:
1-methoxymethoxy-2-trifluoromethylbenzene (64.13 g) was dissolved in tetrahydrofuran (500 mL), and a 2.77M n-butyllithium-n-hexane solution (123 mL) was added to the solution over 45 minutes under an argon gas flow at −70° C., and then the mixture was stirred for 1 hour. N,N-dimethylformamide (28.5 mL) was added, followed by stirring at room temperature for 30 minutes. 4N hydrochloric acid (310 mL) was added, followed by stirring at 60° C. for 19 hours. The organic solvent was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (59.16 g) as a yellow crystal.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:26])=[CH:18][C:17]=3[F:36])[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:26])=[CH:18][C:17]=2[F:36])[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nccc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)n1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
A mixture of N1-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (Example 14, 25 mg, 0.048 mmol), anisole (52 mg, 0.48 mmol) in TFA (1 mL) was heated at 85° C. for 6 h. The TFA was removed under vacuum and the residue partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on SiO2 using EtOAc then 1-2% MeOH in CH2Cl2 as eluents gave the title compound (12 mg, 63%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.51 (s, 1H), 8.02 (s, 1H), 7.66 (dd, 1H, J=12.6, 2.0 Hz), 7.42-7.31 (m, 2H), 7.32-7.27 (m, 1H), 7.23 (t, 2H, J=8.6 Hz), 7.16 (t, 2H, J=9.1 Hz), 6.91 (s, 2H), 3.73 (s, 2H); MS(ESI+) m/z 400.11 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[N:8][C:7]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:6]2.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(N3CCOCC3)cc2c1
Product: COc1ccc2c(Cl)nc(N3CCOCC3)cc2c1
Yield: 95.8 %

Procedure:
A solution of 6-methoxy-3-morpholinoisoquinolin-1-ol (315 mg, 1.210 mmol) in POCl3 (1692 μl, 18.15 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in Hexanes as eluent. The product fractions were collected and the solvent removed under vacuum to give 4-(1-chloro-6-methoxyisoquinolin-3-yl)morpholine (323 mg, 95% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.01 (d, J=9.3 Hz, 1H), 6.97 (dd, J=9.3, 2.5 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 6.59 (s, 1H), 3.92 (s, 3H), 3.90-3.85 (m, 4H), 3.56-3.50 (m, 4H); MS: MS m/z 279.1 (M++1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][N:51]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=2)[C:35]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([N+:56]([O-:58])=[O:57])=[CH:52][N:51]=2)=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc([N+](=O)[O-])cn1)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
A solution of triphenylphosphine (393 mg, 1.5 mmol) in methylene chloride (10.0 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (303 mg, 1.7 mmol). After stirring at 0° C. for 10 min, the reaction mixture was treated with 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87, 304 mg, 1.0 mmol). The reaction mixture was stirred at 0° C. for 20 min and at 25° C. for 30 min. At this time, the reaction mixture was treated with 2-amino-5-nitropyridine (290 mg, 1.5 mmol) and pyridine (0.14 mL, 1.8 mmol). The resulting reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 200-400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-N-(5-nitro-pyridin-2-yl)-propionamide (425 mg, 60%) as a white solid: mp 121-122° C.; EI-HRMS m/e calcd for C20H19F4N3O3 (M+) 425.1363, found 425.1363.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([Br:9])[CH:5]=[C:4]([F:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20](Br)=[O:21].O>CN(C)C=O>[Br:9][C:6]1[CH:5]=[C:4]([F:10])[C:3]2[O:11][CH2:19][C:20](=[O:21])[NH:1][C:2]=2[C:7]=1[CH3:8]
Reactant: Cc1c(Br)cc(F)c(O)c1N
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cc(F)c2c1NC(=O)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
An ice cold suspension of 2-amino-4-bromo-6-fluoro-3-methylphenol (647 mg) and potassium carbonate (1.526 g, 11.04 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was treated by dropwise addition of 2-bromoacetyl bromide (0.320 mL, 3.67 mmol). The mixture was stirred at ambient temperature for 2 hours. The mixture was treated slowly with water (10 mL+10 mL), then poured into water (50 mL) and stirred to form a suspension which was passed through a fine glass frit and dried in vacuo to give the crude product as a yellow solid. The solid was washed with cold isopropanol and dried in vacuo to provide 6-bromo-8-fluoro-5-methyl-2H-benzo[b][1,4]oxazin-3(4 H)-one (510 mg) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) d=7.83 (br. s., 1 H), 7.10 (d, J=9.6 Hz, 1 H), 4.65 (s, 2 H), 2.30 (s, 3 H). LC/MS (m/z) ES+=259.99 (M+1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12](Br)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[S:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22].C(N(CC)CC)C>C(O)C.[Pd](Cl)Cl.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>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[F:19])[C:12]([C:26]3[S:27][C:23]([CH:21]=[O:22])=[CH:24][CH:25]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cccc(F)c21
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cn(S(=O)(=O)c3ccccc3)c3c(F)cccc23)s1
Yield: 77.3 %

Procedure:
A solution of 1-benzenesulfonyl-3-bromo-7-fluoroindole (0.5 g, 1.41 mmol), 5-formyl-2-thiophene boronic acid (0.24 g, 1.55 mmol), bis(triphenylphosphine) palladium (II) dichloride (0.06 g, 0.08 mmol) and triethylamine (0.39 ml, 2.82 mmol) in ethanol (4 ml) was subjected to microwave irradiation at 150° C. for 420 s. The resulting suspension was concentrated under reduced pressure and the residue passed through a silica pad eluting with dichloromethane to afford crude 5-(1-benzenesulfonyl-7-fluoroindol-3-yl)-thiophene-2-carboxaldehyde as a brown solid (0.42 g) which was used in the next step with no further purification.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].Cl>C1COCC1>[Br:9][C:10]1[C:15]([CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[Cl:16])[OH:20])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Brc1ccccn1
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1cccnc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add LDA (400 mL, 0.8 mol) to 2-bromopyridine (105 g, 0.667 mol) in THF (3.2 L) at −78° C. and stir. After 2 hours, add 2-chlorobenzaldehyde (103 g, 0.733 mol) in THF (300 mL) and allow the reaction mixture to gradually warm to ambient temperature. Treat the reaction mixture with 1 M HCl (1.7 L) and extract with diethyl ether. Combine the organic layers and wash with water and brine. Dry over sodium sulfate, filter, and concentrate under reduced pressure. Purification by flash chromatography, eluting with hexane:ethyl acetate (10:1 to 1:1) gives the title compound: 1H NMR (300 MHz, CDCl3), δ8.28(dd, 1H, J=1.83, 4.73), 7.67 (dd, 1H, J=1.83, 7.63), 7.48-7.19 (m, 5H), 6.41 (s, 1H), 3.10 (bs, 1H); MS (IS) m/z 298.0 (M+1), 300.0 (M+1); Analysis for C12H9BrClNO: calcd: C, 48.27; H, 3.04; N, 4.69; found: C, 49.06; H, 3.18; N, 4.64. Rf=0.29 heptane: ethyl acetate, 2:1).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[O:8][C:7]3[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:24]>O>[Br:24][CH2:3][CH2:2][CH:1]=[C:4]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[O:8][C:7]2[CH:15]=[CH:16][CH:17]=[CH:18][C:6]=2[CH2:5]1
Reactant: OC1(C2CC2)Cc2ccccc2Oc2ncccc21
Reactant: Br
Solvent: CC(=O)O
Solvent: O
Product: BrCCC=C1Cc2ccccc2Oc2ncccc21
Temperature: 60 °C

Procedure:
To a 2 L eggplant flask with a magnetic stirring bar was added 75.0 g. of 5-Cyclopropyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ol (0.30 mole) and 75 mL of acetic acid. The solution was cooled with water (ca. 10° C.), 120 ml of 47% aqueous hydrobromic acid was added over a period of 5 minutes. The reaction mixture was warmed to 60° C., stirred for an hour, and evaporated (aspirator vacuum, ca. 50° C.) to ca. 200 mL. The reaction mixture was poured to 1500 mL of saturated aqueous sodium bicarbonate, the mixture is extracted with two 800 mL portions of ethyl acetate, and the combined organic extracts are washed with 500 mL of saturated aqueous sodium chloride. The organic solution was dried with anhydrous magnesium sulfate, filtered, and evaporated (aspirator vacuum, ca. 30° C.). The oily residue was chromatographed on 500 g. of Silica gel 60 by eluting with 5:1-4:1 (v/v) hexane-ethyl acetate mixture. The elution was evaporated, giving the titled compound as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:16]C1CCCO1.C(Cl)(=O)C(Cl)=O.CO>C([O-])([O-])=O.[Na+].[Na+]>[OH:1][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: CC1CCCO1
Reactant: COc1cc([N+](=O)[O-])c(C(=O)O)cc1O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Temperature: 15 °C
Yield: 92 %

Procedure:
5-hydroxy-4-methoxy-2-nitrobenzoic acid (31.9 g, 0.15 mol, 1.0 eq) and 2-methyltetrahydrofuran (200 mL) are charged into a glass reactor under nitrogen. The solution is stirred and jacket temp is set to 20° C. Oxalyl chloride (24 g, 0.19 mol, 1.25 eq) is added at a rate that the internal temperature is below 25° C. The reaction mixture is stirred for 1-2 hour at 20° C., and cooled to 15° C. Then, anhydrous MeOH (60 ml, 1.5 mol, 10 eq) is added over 15 min, and the reaction temperature is maintained below 25° C. during addition. The reaction mixture is stirred for 2-4 hour at 20° C. until HPLC sample shows complete conversion. Na2CO3 aqueous solution (1 M, 100 ml) is added to the reaction mixture. Layers are separated. The upper organic layer is distilled under vacuum to minimum volume. The dark brown residue is stirred in 100 mL mixed solvent of toluene/hexane (v/v, 2:1) to give a suspension. The slurry is filtered. The solid is dried under vacuum to provide the desired product, methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (31.3 g, 92% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].[CH3:19][C:20]1([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH2:22][O:21]1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[N:6]([CH2:19][C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)([OH:21])[CH3:22])[C:5]=2[CH2:4][CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC1(c2cccnc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2cccnc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.3 %

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1 g, 4.6 mmol) in DMF (10 mL) was stirred at RT for 5 min. NaH (60%, 933 mg, 23.33 mmol) was added and the reaction mixture was stirred at RT for 10 min. 3-(2-methyloxiran-2-yl)pyridine (1.26 g, 9.34 mmol) was added to the reaction mixture and the mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-water and extracted with EtOAc (200 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by column chromatography using silica gel: 100-200 mesh and 10% MeOH/DCM/1 mL NH4OH to obtain 600 mg of 1-(3,9-dimethyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(pyridin-3-yl)propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.74 (s, 1H), 8.54 (d, 1H), 7.71 (d, 1H), 7.26 (s, 1H), 7.27 (m, 1H),7.19 (d, 1H), 6.96 (d, 1H), 4.26 (dd, 2H), 2.91 (m, 2H), 2.9 (m, 4H), 2.74 (m, 2H), 2.44 (s, 6H), 1.63 (s, 3H). Separation by chiral HPLC provided enantiomers II-135a-b.
Reaction SMILES: [IH:1].N[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOCC>[I:1][C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: I
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: O=C(c1ccccc1)c1ccc(I)cc1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
A solution of 57% aqueous HI (3.29 ml, 25 mmol) dissolved in DMSO (25 ml) was added dropwise to a solution of 4-aminobenzophenone (0.986 g, 5 mmol) in a mixture of 25 ml of DMSO and KNO2 (0.851 g, 10 mmol) at 35° C. with agitation. The added mixture was stirred at 35° C. for 10 minutes and then was transferred to a solution containing K2CO3 (5 g) in 100 ml ice-water. The reaction mixture was then taken up in ether, and then the ethereal extracts were washed with water and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave the crude 4-iodobenzophenone. The crude product was further purified by column chromatography to obtain 4-iodobenzophenone. The yield determined by gas chromatography was 88% (based on decane as an internal standard).
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].[CH2:8]([O:15][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20](Br)[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C[O:26][B:27](OC)[O:28]C>C1COCC1>[CH2:8]([O:15][C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([B:27]([OH:28])[OH:26])[CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COB(OC)OC
Reactant: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1cc(B(O)O)cc(OCc2ccccc2)c1=O
Temperature: -10 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a solution of isopropylmagnesium chloride (2 M in THF, 2.04 mL) was added LiCl (173 mg, 4.08 mmol) and the resulting solution was stirred for 1 h. THF (3 mL) was added to this solution, cooled to −10° C. Solid 3-(benzyloxy)-5-bromo-1-methylpyridin-2(1H)-one (400 mg, 1.36 mmol) was added and stirred for 1 h. Trimethylborate (0.456 mL, 4.08 mmol) was added to the reaction mixture, stirred at −10° C. for 1 h and then quenched with cone HCl (0.6 mL). The cooling bath was removed, stirred at room temperature overnight and concentrated. Purification by preparative HPLC (5-95% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 276 mg [5-(benzyloxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl]boronic acid (78%) as a white solid. LC/MS (M+H)+260.2.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][NH:9]1)=[O:7])C.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1F)([O-:17])=[O:16]>O.C(O)C>[CH3:14][N:12]1[CH2:11][CH2:10][N:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:8]([C:6]([OH:5])=[O:7])[CH2:13]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)C1CN(C)CCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccccc2[N+](=O)[O-])C(C(=O)O)C1

Procedure:
A solution of 6.6 g. (0.164 mole) of sodium hydroxide, 28.2 g. (0.165 mole) of ethyl-4-methylpiperazine-2-carboxylate, 20 ml. of water and 200 ml. of ethanol is refluxed for 3 hours. This solution is then added under nitrogen to a hot stirred solution of o-nitrofluorobenzene in 300 ml. of ethanol and 30 ml. of water. The resultant solution is refluxed for 48 hours, cooled and filtered to give 12.8 g. of yellow product, m.p. 222°-225°. Concentration of the mother liquors to ~100 ml. and adjusting the pH to 6 yields an additional 6.6 g. of product. Further concentration of mother liquors gives yet another 3 g. of product. Total yield is 22.4 g., 51.5%. The analytical sample had m.p. 234° dec.
Reaction SMILES: S(O)(=O)(=O)C.[CH2:6]([C:8]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:9]=1[CH2:10][NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18](N)=[O:19])[CH:17]=1)[CH3:7].[OH-:31].[Na+]>C(O)C>[CH2:6]([C:8]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:9]=1[CH2:10][NH:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([OH:19])=[O:31])[CH:17]=1)[CH3:7]
Reactant: [OH-]
Reactant: CCc1cccc(C)c1CNc1cc(C(N)=O)cn2c(C)c(C)nc12
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCO
Product: CCc1cccc(C)c1CNc1cc(C(=O)O)cn2c(C)c(C)nc12
Yield: 90.1 %

Procedure:
8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxamide mesylate (11.0 g, 0.025 mol) and sodium hydroxide (7.0 g, 0.17 mol) were solved in ethanol(95%) (120 ml) and was refluxed for 20 h. The solvent was evaporated under reduced pressure and to the residue was added water (150 ml). The pH was adjusted to 5 by addition of conc HCl and acetic acid and the solid that precipitated was isolated by filtration, washed with water and acetone, and dried to give 7.6 g (88%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[OH:11][CH2:12][CH:13]([CH2:15]O)[OH:14]>COCCOC>[F:1][C:2]([F:10])([F:9])[C:3]1([C:5]([F:8])([F:7])[F:6])[O:14][CH:13]([CH2:12][OH:11])[CH2:15][O:4]1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: OCC(O)CO
Solvent: COCCOC
Product: OCC1COC(C(F)(F)F)(C(F)(F)F)O1

Procedure:
In a 4 L round bottom flask, hexafluoroacetone (99.7 g; 0.6 moles) was condensed at 0° C. into a well stirred solution of glycerol (55.3 g; 0.6 moles) in 500 mL of anhydrous ethylene glycol dimethyl ether. After the addition of hexafluoroacetone was complete, the solution was allowed to warmn to ambient temperature. Next, a solution of 1,3-dieyclohexylcarbodiimide (136.2 g; 0.66 moles) in 2 L of anhydrous ethylene glycol dimethyl ether was added slowly to the resulting hemiketal solution over a period of about one and a half hours. The combined solution was stirred for an additional hour and then the low boiling solvent was removed using a rotary evaporator. The remaining liquid was transferred to a 250 mL round bottom flask and the liquid heated with stirring at 100° C. for 1 hour. While continuing to heat the liquid, the product was isolated by vacuum distillation at 76° C. and 18 mm of Hg. The yield of product was 117 g which is 81% of the theoretical value.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[C:15]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)(=[O:17])[CH3:16]
Reactant: Cc1cccc(O)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(C)c1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of m-cresol (Aldrich) (80 g, 0.74 mol) in dry CH2Cl2 (300 mL) was added pyridine (71 mL, 0.89 mol) and at 0° C. was added dropwise acetyl chloride (58 mL, 0.81 mol). The reaction mixture was stirred for 1 h and then diluted with more CH2Cl2. The organic phase was washed successively with HCl 1N (3×), brine, dried over MgSO4 and evaporated. The residue was distilled under vacuum to give 108 g (97% ) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)=[O:5].S(Cl)([Cl:22])=O>>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:22])=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 10.3 g of 4-[(2-methylbenzoyl)amino] benzoic acid and 32 ml of thionyl chloride is refluxed for 1.5 hours. The solution is concentrated in vacuo. Toluene is added and the solvent removed in vacuo. Toluene is added and the mixture chilled and filtered to give the desired product as a yellow solid, 135°-141° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][OH:13].B(F)(F)F.CCOCC.[C:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=O)[CH2:24][CH3:25]>ClCCl>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][C:23]1([CH2:24][CH3:25])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:11][CH2:12][O:13]1)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=3)[CH3:32]
Reactant: CCOC(=O)CC(=O)CC
Reactant: Cc1ccc2[nH]cc(CCO)c2c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1ccc(C)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
To a solution of 2-(5-methyl-1H-indol-3-yl)-ethanol (0.48 g, 2.7 mmol) in dichloromethane (10 mL) was added boron trifluoride diethyl etherate (0.468 g, 3.3 mmol), followed by ethyl propionylacetate (0.649 g, 4.5 mmol). The mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness. Flash chromatography on silica gel provided 0.421 g (52%) of the title compound as an oil. 1H NMR (500 MHz, CDCl3) δ 8.90 (br, 1H), 7.28 (s, 1H), 7.24 (d, 1H), 6.99 (d, 1H), 4.16 (m, 2H), 4.03 (m, 1H), 3.94 (m, 1H), 2.98 (d, 1H), 2.88 (d, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 2.44 (s, 3H), 2.12 (m, 1H), 1.98 (m, 1H), 1.25 (t, 3H), 0.80 (t, 3H); ESI (−) MS m/e=300 (MH−).