Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1.[CH3:16][N:17]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[N:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>COCCOC.O.CO.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:16][N:17]1[C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([N:8]=[CH:9][C:10]=3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=2)=[CH:20][CH:19]=[N:18]1
Reactant: CCOC(=O)c1cnn2cc(Br)ccc12
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnn2cc(-c3ccnn3C)ccc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture comprising ethyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (1.5 g, 5.57 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.218 g, 5.85 mmol), cesium carbonate (7.26 g, 22.30 mmol) and PdCl2(dppf).CH2Cl2 adduct (91 mg, 0.111 mmol) in DME (10 ml) and water (4.00 ml) was heated using microwave radiation at 70° C. for 1 hr. Further PdCl2(dppf).CH2Cl2 adduct (91 mg, 0.111 mmol) was added and the mixture was heated at 80° C. for 1 hr. 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.218 g, 5.85 mmol) and PdCl2(dppf).CH2Cl2 adduct (91 mg, 0.111 mmol) were added and heating continued at 100° C. for 3 hrs. The mixture was diluted with 10% MeOH in EtOAc (200 ml) and washed with sat. NaHCO3. The organic solvent was removed under vacuum and azeotroped with toluene. The resulting solid was loaded onto silica and purified by chromatography eluting with 0-100% EtOAc in iso-hexane to afford the title compound;
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][C@@H:25]([OH:33])[C@@H:24]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[O:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][C:25](=[O:33])[CH:24]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O[C@@H]1Cc2ccccc2O[C@H]1c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: O=C1Cc2ccccc2OC1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 125.9 %

Procedure:
To a hazy suspension of Dess Martin periodinane (1 g, 2.295 mmol) in dry methylene chloride (10 mL) was added a solution of trans 3-flavanol 6 (0.8 g, 1.53 mmol) in methylene chloride (10 mL) at room temperature. The resulting purple solution was stirred at room temperature for 4 h, after which it was poured into a saturated solution of sodium bicarbonate (60 mL) containing 7 equivalents of sodium thiosulfate (16.06 mmol, 3.98 g) and stirred for 10 minutes. The resulting brown solution was extracted with methylene chloride and the organic layer washed with water and brine, and dried (MgSO4). The filtered solution was then evaporated to afford the crude 3-flavanone 7, which was purified by flash chromatography, using hexanes: ethyl acetate (95:5 to 8:2) to afford 0.432 g (53%) of pure product as a thick, colorless oil. TLC: hexanes: methylene chloride: ethyl acetate (3:1:1): Rf=0.39; 1H NMR (300 MHz, CDCl3): δ 3.60 (dd, 2H, 4-Hα and β), 3.79 (s, 6H, OCH3), 3.82 (s, 3H, OCH3), 5.02 (s, 2H, OCH2Ph), 5.04 (s, 2H, OCH2Ph), 5.29 (s, 1H, 2-H), 6.32 and 6.41 (2d, 2H, 6, 8-Ar—H), 6.58 (s, 2H, 2′,6′-Ar—H), 7.37–7.40 (m, 10H, Ar—H).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[N:13][C:12](Cl)=[N:11][C:10]=2[C:9]([CH2:24][NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[N:8]1.[NH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>CS(C)=O>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:1][C:2]([F:32])([F:31])[CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:15]2[C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)=[N:13][C:12]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[N:11][C:10]=2[C:9]([CH2:24][NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[N:8]1
Reactant: C1CNCCN1
Reactant: FC(F)(F)CNCc1nn(CCOCC(F)(F)F)c2c(Nc3ccncn3)nc(Cl)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: FC(F)(F)CNCc1nn(CCOCC(F)(F)F)c2c(Nc3ccncn3)nc(N3CCNCC3)nc12
Temperature: 120 °C

Procedure:
1-(2-(2,2,2-trifluoroethoxy)ethyl)-3-((2,2,2-trifluoroethylamino)methyl)-5-chloro-N-(pyrimidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7-amine (213 mg, 0.41 mmol) prepared in Step 1 and piperazine (152 mg, 1.8 mmol) were mixed in dimethyl sulfoxide (3.0 ml) in a reaction vial. The reaction mixture was heated at 120° C. for 10 hours. The reaction was cooled to room temperature and brought to acidic condition by adding trifluoroacetic acid. The crude reaction mixture was purified by reverse phase HPLC (5-95% acetonitrile in water with 0.05% trifluoroacetic acid) and lyophilized to give the title compound as a dark yellow solid (70 mg).
Reaction SMILES: [BH4-].[Na+].C(O)C.[CH3:6][N:7]([CH3:20])[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13](OC)=[O:14])=[O:9]>O>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([CH:19]=[CH:18][CH:17]=1)[C:8]([N:7]([CH3:20])[CH3:6])=[O:9]
Reactant: COC(=O)c1cccc(C(=O)N(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Under ice cooling, sodium borohydride (264 mg, 6.97 mmol) was added to an ethanol (15 ml) solution of methyl 3-(N,N-dimethylcarbamoyl)benzoate (289 mg, 1.39 mmol). The temperature of the resulting mixture was allowed to rise back to room temperature and then, stirring was conducted at 50° C. for 14 hours. After the reaction mixture was cooled back to room temperature, it was ice cooled. Sodium borohydride (264 mg, 6.97 mmol) was added and the mixture was stirred at 50° C. for 6 hours. The reaction mixture was ice cooled, and then added with water, followed by concentration under reduced pressure. The residue thus obtained was added with water, followed by extraction with methylene chloride. The extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and the fraction obtained from the methanol:methylene chloride (=1:30) eluate was concentrated under reduced pressure, whereby the title compound (196 mg, 79%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:2]1[O:4][CH2:3]1.[CH3:16][C:17]([NH2:28])([CH3:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>>[OH:4][CH:2]([CH2:1][O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][NH:28][C:17]([CH3:27])([CH3:16])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: CCCCCCCCCCOCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: CCCCCCCCCCOCC(O)CNC(C)(C)Cc1ccc(OC)cc1
Yield: 44.5 %

Procedure:
Using the method of Example 5, supra, 1-decyl glycidyl ether (235 mg, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 175 mg of the title compound as a clear, colorless oil: GC/EI-MS, m/z (rel. int.) 394 (M+1, 1), 378 (6), 273 (97), 272 (100), 222 (9), 163 (37), 121 (61); 1H-NMR (CDCl3) δ 7.49 (2H, d, J=8.5), 6.82 (2H, d, J=8.5 Hz), 3.78 (3H, s), 3.75 (1H, m), 3.45 (4H, m), 2.80 (1H, dd, J=11.7 and 4.0), 2.77 (1H, broad s), 2.64 (4H, m), 1.56 (2H, m), 1.26 (16 H, m), 1.06 (3H, s), 1.05 (3H, s), 0.88 (3H, t, J=6.1); 13C-NMR (CDCl3) δ 158.1, 131.3, 130.0, 113.4, 73.5, 71.7, 69.1, 55.1, 53.3, 46.4, 44.6, 31.8, 29.6, 29.5, 29.4, 29.3, 26.7, 26.6, 26.1, 22.6, 14.1; FT-IR (film) cm−1 3115 (broad s), 1612, 1512, 1245, 1121, 824.
Reaction SMILES: C(=O)([O-])O.[K+].C(OC(=O)C)(=O)C.[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:21]=1)[CH:19]=O.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>O>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N+:22]([O-:24])=[O:23])=[C:18]([CH:19]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[CH:21]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)C(=Cc1cc(Cl)ccc1[N+](=O)[O-])C(=O)OCC
Temperature: 110 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
Potassium hydrogen carbonate (8.12 g) was added to an acetic acid anhydride (18 ml) solution of 5-chloro-2-nitrobenzaldehyde (9.99 g) and diethyl malonate (8.64 g), which was stirred at 110° C. for 2 hours. The reaction mixture was added to iced-water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/10) to obtain the entitled compound (15.10 g). 1H-NMR δ: 1.10(3H, t), 1.36(3H, t), 4.15(2H, q), 4.44(2H, q), 7.42(1H, d), 7.52(1H, dd), 8.11(1H, s), 8.18(1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[O:11][C:12](=[O:19])[C:13]([CH:16]([CH3:18])[CH3:17])([CH3:15])[N:14]=2)[CH3:9])=[CH:4][CH:3]=1.C[Li].[CH3:22]COCC.C(OCC)(=O)C.O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[C:10]([NH:14][C:13]([CH3:15])([CH:16]([CH3:18])[CH3:17])[C:12](=[O:19])[CH3:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)C(C)(NC(=O)C(C)c1ccc(Cl)cc1)C(C)C
Yield: 55.6 %

Procedure:
4.8 g (18 mmol) of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one was dissolved in 40 ml of tetrahydrofuran. Thereto was dropwise added, at 5° C., a solution obtained by diluting 20.4 ml of a 1.14 M/liter methyllithium ether solution (23.3 mmol) with 50 ml of tetrahydrofuran. The mixture was kept at 10° C. or below and subjected to a reaction for 1 hour. After the completion of the reaction, ethyl acetate and water were added for phase separation. The separated organic layer was concentrated. The resulting concentrate was subjected to column chromatography to obtain 2.9 g (0.01 mol) (yield=55%) of 2-(4-chlorophenyl)-N-[1-methyl-1-isopropyl-2-oxopropyl]propanamide.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[CH2:10][CH2:9]1.[CH:36](=O)[CH:37]([CH3:39])[CH3:38].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:36]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH2:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)[N:21]=[CH:20]3)[CH2:12][CH2:13]1)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)C=O
Reactant: NS(=O)(=O)c1ccc(Nc2ncc3cccc(OC4CCNCC4)c3n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN1CCC(Oc2cccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc23)CC1
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a solution of the TFA salt of 4-(8-(piperidin-4-yloxy)quinazolin-2-ylamino)benzenesulfonamide in DCM was added isobutyraldehyde (2 eq) and a few drops of acetic acid. The mixture was stirred for 10 mins and to it was added sodiumtriacetoxyborohydride (1.5 eq) and the mixture was stirred for 1 h. The reductive amination went to completion, by LC/MS. The crude mixture was concentrated and purified on prep HPLC to give the product 4-(8-(1-isobutylpiperidine-4-yloxy)quinazolin-2-ylamino)benzenesulfonamide in 80% yield. ES/MS m/z 456.2 (MH+).
Reaction SMILES: OC[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[OH-].[K+].ClCC(O)CO>CO>[O:19]1[CH2:20][CH2:3][CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1=[O:18]
Reactant: COC(=O)CCCCCCCCC/C=C\CCCCO
Agent: O=C1CCCCCCCCC/C=C\CCCCO1
Agent: OCC(O)CCl
Agent: [K+]
Solvent: CO
Product: O=C1CCCCCCCCCC=CCCCCO1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
240 g (0.84 mol) of methyl Z-16-hydroxyhexadec-11-enoate and 50 g of potassium hydroxide were dissolved in 500 ml of methanol in a 3 liter flask. The mixture was heated to reflux temperature for 2 hours. Then, the methanol was distilled off and 800 ml of glycerol were added to the residue. 250 ml of glycerol were distilled off (150° C., 3 mmHg). 160 g (1.45 mol) of 3-chloropropane-1,2-diol were added slowly at 150° C. and the mixture was stirred at this temperature for 1 hour. Then, 200 ml of a mixture of 3-chloropropane-1,2-diol and glycerol were distilled off (120-148° C. 3 mmHg, internal temperature 160-170° C.). The mixture was cooled to 60° C. and treated at this temperature with 25 ml of 5.4M ethanolic sodium methanolate solution. The mixture was distilled further (3 mmHg, 180-200° C.) and glycerol was replaced continuously. After 950 ml of a two-phase mixture had been distilled off the residue was extracted with hexane. After distillation there were obtained 167 g (78%) of 12Z-oxacycloheptadec-12-en-2-one, were obtained having the following characteristics: Z/E=91/9;
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:12][N:11]=1>C1C=CC=CC=1>[C:20]1([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=3)=[N:11][N:12]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: c1ccccc1
Product: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A pressure bottle was charged with 4-aminophenol (0.453 g, 0.416 mmol), 1-chloro-4-phenylphthalazine (1.00 g, 0.416 mmol) and 16.8 mL of benzene. The bottle was sealed and heated to 100° C. for 25 h. The reaction mixture was concentrated. The crude material was dissolved in methanol and was purified by Gilson reverse phase liquid chromatography, 5-75% ACN/H2O/0.1% TFA over 14 min. The product-containing fractions were combined, brought to basic pH by addition of 1M NaHCO3, and extracted with dichloromethane. The organic portion was dried with MgSO4, filtered and concentrated to provide 4-(4-phenylphthalazin-1-ylamino)phenol as a yellow solid. MS m/z=314 [M+H]+. Calc'd for C20H15N3O: 313.35.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:15][CH:16]([OH:23])[C:17]#[C:18][Si](C)(C)C)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH:2]=[CH2:3].[CH2:24]([OH:27])[CH2:25][OH:26].O1CCCC1.C(=O)([O-])O.[Na+]>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Hg+2]>[CH2:1]([O:4][C:5]([N:7]([CH2:15][CH:16]([C:17]1([CH3:18])[O:27][CH2:24][CH2:25][O:26]1)[OH:23])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N(Cc1ccccc1)CC(O)C#C[Si](C)(C)C
Reactant: OCCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Product: C=CCOC(=O)N(Cc1ccccc1)CC(O)C1(C)OCCO1
Reaction time: 35 h

Procedure:
Mercury(II) sulfate (3.55 g) was added to a solution of 1-(N-allyloxycarbonyl-N-benzylamino)-4-trimethylsilyl-3-butyn-2-ol (19.75 g) in a mixture of sulfuric acid (0.15 ml), ethylene glycol (60 ml), and tetrahydrofuran (120 ml). The mixture was stirred at 30°~40° C. for 35 hours. Sodium hydrogen carbonate (1 g) was added to the mixture and the mixture was stirred at 30°~40° C. for one hour. An insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. A solution of the syrup in ethyl acetate (250 ml) was washed with water (150 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give an oil. The oil was subjected to a column chromatography on silica gel (400 g) and eluted with a mixture of hexane and ethyl acetate (5:5, V/V) to give 2-[2-(N-allyloxycarbonyl-N-benzylamino)-1-hydroxyethyl]-2-methyl-1,3-dioxolane (11.6 g) as a syrup.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[OH:14][C:15]1[CH:39]=[CH:38][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC.O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[N:4][C:3]=1[CH2:2][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][O:20]/[N:21]=[C:22](/[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)\[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:38][CH:39]=1
Reactant: CCOC(=O)CCCC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Reactant: Cc1oc(-c2cccs2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCC/C(=N\OCc1ccc(OCc2nc(-c3cccs3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole (397 g), ethyl E-6-(4-hydroxybenzyloxyimino)-6-phenylhexanoate (600 mg), potassium carbonate (467 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl E-6-[4-[5-methyl-2-(2-thienyl)-4-oxazolylmethoxy]benzyloxyimino]-6-phenylhexanoate (856 mg, yield 95%) as a colorless oil from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:12]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CC(C)(C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Cc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.5 %

Procedure:
A mixture of 3-bromo-phenyl acetic acid (5.00 g, 23.24 mmol), tert-butanol (1.89 g, 25.57 mmol), DMAP (3.12 g, 25.57 mmol), and DCC (5.27 g, 25.57 mmol) in CH2Cl2 (150 mL) was stirred for 24 h at room temperature. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the mixture was filtered. The organic solution was washed consecutively with 5.5% HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to provide the title compound (5.64 g).
Reaction SMILES: [F-].[K+].I[CH3:4].[Si]([O:12][C:13]1[C:14]([F:22])=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=1)[CH:16]=[O:17])(C(C)(C)C)(C)C.O>CN(C=O)C>[F:22][C:14]1[C:13]([O:12][CH3:4])=[CH:20][C:19]([F:21])=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(F)cc(C=O)c1F
Reaction time: 5 h
Yield: 74.4 %

Procedure:
Potassium fluoride (7.79 g, 134 mmol) and iodomethane (4.98 ml, 80 mmol) were added to a stirred solution of 3-tert-butyldimethylsilyloxy-2,5-difluorobenzaldehyde (19.45 g, 67 mmol) in DMF (100 ml) at room temperature. After 5 hr, the mixture was poured into water (100 ml) and extracted with ethyl acetate (200 ml). The extract was washed with water (100 ml), brine (100 ml), dried (magnesium sulfate) and evaporated. The residue was purified by column chromatography (silica gel) eluting with ethyl acetate/n-hexane (1/10) to give 8.58 g (74%) of the titled compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:6]1[CH2:11][NH:10][C:9](=O)[CH2:8][O:7]1.[N:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[C:13]1([C@H:5]([O:4][C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]=2[C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C@H:6]2[O:7][CH2:8][CH2:9][NH:10][CH2:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1COC(C(Oc2ccccc2Br)c2ccccc2)CN1
Product: c1ccc([C@H](Oc2ccccc2-c2cccnc2)[C@@H]2CNCCO2)cc1

Procedure:
(S)-2-[(S)-Phenyl-(2-pyridin-3-yl-phenoxy)-methyl]-morpholine was synthesized from 6-[(2-Bromo-phenoxy)-phenyl-methyl]-morpholin-3-one and 4-pyridineboronic acid according to general procedures A and B and was isolated as a gummy oil. MS (APCI): 347 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1.[OH-].[K+].O>CS(C)=O>[Cl:17][C:16]1[C:11]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)=[N:12][CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: COc1ccc(O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(Oc2ncc(Cl)cc2Cl)cn1
Yield: 88.2 %

Procedure:
A solution of 5-hydroxy-2-methoxypyridine (1.25 g, 10.0 mmol), 2,3,5-trichloropyridine (1.82 g, 10.0 mmol) and potassium hydroxide (85% pure, 1.08 g, 10.0 mmol) in dimethyl sulfoxide (25 mL) was heated at 90° C. for 1.5 hours. The solution was poured slowly into water (200 mL). The precipitate was collected by suction, washed thoroughly with water and dried in a vacuum oven at 45° C., yielding the title compound (2.39 g, 88% yield).
Reaction SMILES: [CH2:1](Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:10][CH:11]1[C:15]23[CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:22]=[CH:21][CH:20]=[C:16]2[N:17]=[CH:18][CH:19]=[C:14]3[S:13][CH2:12]1.Cl>C(O)(C)C.CO>[CH3:10][CH:11]1[C:15]23[CH:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:22]=[CH:21][CH:20]=[C:16]2[N:17]=[CH:18][CH:19]=[C:14]3[S:13][CH:12]1[CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCCc1ccccc1
Reactant: CC1CSC2=CC=NC3=CC=CC(c4ccccc4)C321
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: CC1C(CCc2ccccc2)SC2=CC=NC3=CC=CC(c4ccccc4)C321

Procedure:
Phenethyl bromide is condensed with 3-methyl-4-phenyl-1,2,3,4-tetrahydro-benzo(b)thieno[3,2-c]pyridine (Example 2) according to the procedure described in Example 6. Hydrochloride: white crytals, m.p. 210° C. (isopropanol-methanol); Yield : 72%.
Reaction SMILES: B(Br)(Br)Br.C[O:6][CH:7]1[CH2:12][N:11]2[CH:13]=[CH:14][N:15]=[C:10]2[CH2:9][CH2:8]1.O>ClCCl>[N:15]1[CH:14]=[CH:13][N:11]2[CH2:12][CH:7]([OH:6])[CH2:8][CH2:9][C:10]=12
Reactant: COC1CCc2nccn2C1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: OC1CCc2nccn2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Add boron tribromide (1.24 mL; 2.0 equiv; 13.14 mmoles) to a solution of 6-methoxy-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.0 g; 1.0 equiv; 6.57 mmoles) in dichloromethane (40 mL) dropwise and stir at ambient temperature for 4 hours. Add water (10 mL) and stir for 20 minutes, then concentrate the mixture. Add methanol (20 mL) and load the solution onto an scx ion-exchange column. Purify the product by eluting with methanol followed by 2M ammonia in methanol to give 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-ol (0.908 g; 80% yield), which crystallizes upon standing. MS (m/z): 139 (M+1).