Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].C(N(CC)CC)C.[CH3:10][C:11]([CH3:15])=[CH:12][CH:13]=[O:14].Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>C(#N)C.CCCCC>[CH3:18][Si:17]([CH3:20])([CH3:19])[O:14][CH:13]=[CH:12][C:11]([CH3:15])=[CH2:10]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)=CC=O
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: C=C(C)C=CO[Si](C)(C)C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
To a suspension of 180 g of anhydrous sodium iodide in 300 ml of dry acetonitrile is added a solution of 112 g of triethylamine and 84 g of 3-methyl-2-butenal in 400 ml of pentane at room temperature. Added dropwise to the above solution is 109 g of chlorotrimethylsilane at 35°-38° C. and the mixture stirred for 4 hours at 40°-45° C. The resulting solid is filtered, washed with 400 ml of pentane and the solvent evaporated to a residue. The residue is distilled to afford 112 g of the desired product, B.P. 56°-60° C./35 mm, nD20 1.4496.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](=[O:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1>O1CCCC1>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)([OH:24])[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1
Reactant: Br[Mg]C1CCCC1
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2cc(Cl)ccc2C1(O)C1CCCC1
Temperature: 25 °C

Procedure:
A solution of cyclopentyl magnesium bromide in ether (2.0 M, 12.5 mL, 25 mmol) (Aldrich) was added dropwise to a suspension of 6-chloroisatin (1.82 g, 10 mmol) (prepared according to the procedure of Kraynack, E. A. et al., supra) in tetrahydrofuran (40 mL) under argon with cooling in a −25° C. bath and magnetic stirring at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 1 hour, 15% aqueous ammonium chloride solution (50 mL) was added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 30 minutes and filtered to give crude rac-6-chloro-3-cyclopentyl-3-hydroxy-1,3-dihydro-indol-2-one as a white powder. (Yield 0.62 g, 24.6%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[C:5]([NH2:24])=[C:4]([NH2:25])[N:3]=1.[O:26]=[C:27]1O[C@H]([C@H](CO)O)[C:30]([O-])=[C:28]1O.[Na+].C1OC(O)(CO)COC1(O)CO>CC(N(C)C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])=[CH:14][CH:15]=2)[C:5]2[C:4](=[N:25][CH:30]=[C:28]([CH2:27][OH:26])[N:24]=2)[N:3]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: Nc1nc(N)c(N)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: OCC1(O)COC(O)(CO)CO1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c2nc(CO)cnc2n1
Temperature: 40 °C

Procedure:
Pyrimidine 61 (Example 43, 5.0 g, 14.1 mmol) is dissolved in dimethylacetamide/water (1:1) with sodium ascorbate (2.85 g, 14.4 mmol). Dihydroxyacetone dimer (2.57 g, 14.3 mmol) is added and the reaction mixture is heated to 40° C. while air is bubbled into the reaction mixture. After 4 h the reaction mixture is poured into 250 mL of H2O, and the formed solid collected by filtration. This solid is redissolved in CH2Cl2/MeOH (3:1, 500 mL), and dried over MgSO4. The crude product is adsorbed on SiO2 and purified by flash column chromatography using CH2Cl2/MeOH (20:1).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:21])[CH2:5]1.[C:22]1([CH2:28][CH2:29]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.CC(=O)OCC>[O:3]=[C:4]1[N:10]([CH2:29][CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6](=[O:21])[CH2:5]1
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1CCc1ccccc1
Reaction time: 0.33 h

Procedure:
Sodium hydride 80% dispersion in oil (0.13 g) was added portionwise to a solution of the 2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine (compound a) (1 g) in DMF (18 ml) previously cooled at 0°. The reaction was stirred for 20 min at 0°, then a solution of 2-phenylethyl bromide (0.85 ml) in DMF (2 ml) was added dropwise, the mixture was stirred at 23° for 15 h, then diluted with EA (80 ml) and washed with brine (3×100 ml), dried and concentrated "in vacuo". The crude product was purified by flash chromatography (eluting with CH-EA 1:1) to give the title compound as a white powder (0.85 g). T.l.c. CH-EA (1:1), Rf =0.27.
Reaction SMILES: [C:1]([N:4]([CH2:13][CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[C:1]([N:4]([CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1ccc(Cl)cc1)CC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(Cc1ccc(Cl)cc1)CC1CCNCC1

Procedure:
To a solution of 4-(N-acetyl-N-(4-chlorobenzyl)aminomethyl)-1-t-butoxycarbonylpiperidine (280 mg, 0.73 mmol) in dichloromethane (20 mL) stirring at room temperature, was added trifluoroacetic acid (5 mL). After 16 h the solvent was evaporated under vacuum, then toluene was added and evaporated (5 mL twice), followed by diethyl ether (10 mL twice) to obtain 4-(N-acetyl-N-(4-chlorobenzyl)aminomethyl)piperidine trifluoroacetic acid salt (298 mg, quantitative yield) as a tan solid.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:8])[CH:6]=[CH2:7])[CH2:2]C.[CH:9](N1CCCC1=O)=[CH2:10]>>[CH2:1]([N:4]([CH2:9][CH3:10])[C:5](=[O:8])[CH:6]=[CH2:7])[CH3:2]
Reactant: C=CN1CCCC1=O
Reactant: C=CC(=O)NCCC
Product: C=CC(=O)N(CC)CC

Procedure:
N-n-propylacrylamide (NnPAM) and vinylpyrrolidone were purchased from a commercial vendor and used as received. Anhydrous methanol was degassed by vigorously bubbling dry nitrogen through it.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19](O)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1.[CH3:27][S:28]([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:40]=1[NH:39][CH:38]=[CH:37]2)(=[O:30])=[O:29]>ClCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:37]2[C:36]3[C:40](=[C:32]([CH2:31][S:28]([CH3:27])(=[O:30])=[O:29])[CH:33]=[CH:34][CH:35]=3)[NH:39][CH:38]=2)[CH:20]2[CH2:22][CH:21]2[C:23]#[N:24])=[C:15]([F:26])[CH:14]=1
Reactant: N#CC1CC1C(O)c1ccc(Cl)cc1F
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3F)C3CC3C#N)c[nH]c12

Procedure:
1.76 g (7.98 mmol) of indium(III) chloride and 0.92 ml (12.0 mmol) of trifluoroacetic acid were added to 1.50 g (6.65 mmol) of the compound from Example 165A and 1.67 g (7.98 mmol) of the compound from Example 86A under argon in 69 ml of dichloromethane, and the mixture was heated under reflux for three days. It was concentrated and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) and another isocratic RP18 separation with acetonitrile/water 1:1 to result in 283 mg (10% of theory) of diastereomer 1 and 145 mg (5% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:33][C:34](O)=O.C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:33][CH3:34])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione (30 mg, 0.06 mmol) in THF and AcOH (4.8 mg, 0.08 mmol) was added acetaldehyde (2.0 mL, 0.2 mmol) and sodium triacetoxy borohydride (85.0 mg, 0.4 mmol). The mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-ethylpiperidin-4-ylamino) pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione. LCMS (M+1=481)
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]>CS(C)=O>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]2[CH3:1])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1cc(CCl)ccc1Cl
Solvent: CS(C)=O
Product: Cc1nc2ccccc2n1Cc1ccc(Cl)c([N+](=O)[O-])c1

Procedure:
Prepared analogously to Example 9a from 2-methyl-benzimidazole and 4-chloro-3-nitrobenzyl chloride in dimethylsulphoxide.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[CH:9][CH2:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl-].[NH4+].[OH-].[Na+].Br.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>CN(C=O)C.O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]2[N:8]([CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=[CH:10][O:11][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: BrCc1cccnc1
Reactant: O=[N+]([O-])c1ccc2c(c1)OCC=N2
Agent: Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)OC=CN2Cc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
To a dry reaction flask equipped with a reflux condenser, a magnetic stirring bar and a rubber septum with a N2 inlet was placed 7-nitrobenz[1,4]oxazine (1.0 g, 5.55 mmol), tertabutyl ammonium chloride (56 mg), powdered NaOH (0.58 g) in dry DMF (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. 3-(Bromomethyl)-pyridine hydrobromide (1.40 g, 5.55 mmol) was added. The reaction mixture was heated at 80° C. for over night, cooled to room temperature, poured in water (200 mL), left aside for 2 h, added ethyl acetate (200 mL). The organic layer was washed with water (2×200 mL), brine (200 mL), dried (Na2SO4) and concentrated. The solid was purified by silica gel column, eluted with EtOAc to give 0.67 g (44%) of the desired 7-nitro-4-(3-pyridylmethyl)benz[1,4]oxazine. 1H NMR (CDCl3, 300 MHz): δ 8.56 (d, 1H, J=4.8 Hz), 8.53 (s, 1H), 7.72 (m, 2H), 7.53 (m, 1H), 7.28 (dd, 1H, J=5.1 and 7.8 Hz), 6.57 (d, 1H, J=9.0 Hz), 4.61 (s, 2H), 4.29 (t, 2H, J=4.2 Hz), 3.59 (t, 2H, J=4.5 Hz); LCMS (m/z): 272 (MH+).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[N:5]1)(=O)C.C[O-].[Na+].C(=O)(O)[O-].[Na+]>CO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[NH:4][N:5]=3)[CH2:19][CH2:18]2)=[CH:25][CH:24]=1
Reactant: CC(=O)n1nc(CN2CCN(c3ccc(F)cc3)CC2)c2ccccc21
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(N2CCN(Cc3n[nH]c4ccccc34)CC2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
1-Acetyl-3-[4-(4-fluorophenyl)piperazin-1-ylmethyl]-1H-indazole (112 mg, 0.32 mmol) in MeOH (3 mL) was treated with sodium methoxide (50 mg) and stirred for 1 h at 20° C. The mixture was poured into saturated aqueous sodium bicarbonate solution (5 mL) and extracted with CH2 Cl2 (3×5 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (10→100% EtOAc in hexane) to give the title compound as a white solid (52 mg, 52%); mp 191°-192 ° C. (from CH2Cl2 /hexane); 1H NMR (360 MHz, d6 -DMSO) δ12.85 (bs, 1H, NH), 7.88 (d, J=8.9 Hz, 1H, indazole), 7.49 (d, J=8.9 Hz, 1H, indazole), 7.33 (t, J=8.9 Hz, 1H, indazole), 7.09 (t, J=8.9 Hz, 1H, indazole), 7.00 (m, 2 H, Ph), 6.92 (m, 2H, Ph), 3.89 (s, 2H, Ar--CH2N), 3.06 (m, 4H, piperazine), 2.58 (m, 4H, piperazine); MS (CI+) m/e 311 M+H+); Anal. calcd for C18H19N4F.1/4 H2O: C, 68.66; H, 6.24; N, 17.79. Found: C, 68.75; H, 6.13; N, 17.74.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[C:5]([F:15])[CH:4]=1.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.C1C(=O)[N-]C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd+]>[F:15][C:5]1[CH:4]=[C:3]([CH2:2][C:17]2[S:16][CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:7][C:6]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: COC(=O)C(C)c1ccc(CBr)cc1F
Reactant: OB(O)c1cccs1
Agent: Br[Pd+]
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)[N-]1
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(Cc2cccs2)cc1F
Yield: 74.7 %

Procedure:
Compound 20 (0.98 g, 3.8 mmol) and 2-thiopheneboronic acid (0.73 g, 5.7 mmol) were dissolved in tetrahydrofuran (12 mL) and a 2 M-aqueous solution (4.8 mL) of sodium carbonate. To this solution, trans-bromo(N-succinimidyl)bis(triphenylphosphine)palladium(II) [trans-PdBr(N-Succ) (PPh3)2] (30.8 mg, 1.0 mol %) was added and treated in the same manner as in Example 11. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (20:1) solution followed by conventional hydrolysis with potassium hydroxide to give 0.75 g (76%) of compound (21b) of interest as white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])(=[O:4])=[O:3].[C:13]([N:15]=[C:16]([NH2:18])[NH2:17])#[N:14].[OH-].[K+]>COCCO.O>[NH2:14][C:13]1[N:15]=[C:16]([NH2:18])[N:17]=[C:8]([C:7]2[CH:10]=[CH:11][CH:12]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[N:9]=1
Reactant: N#CN=C(N)N
Reactant: CS(=O)(=O)c1cccc(C#N)c1
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2nc(N)nc(N)n2)c1

Procedure:
5.0 g of m-methylsulfonylbenzonitrile (101°-103° C.), 2.8 g of dicyanodiamide and 2.0 g of caustic potash are refluxed in 20 ml of methyl cellosolve for 3 hours. After cooling, the mixture is diluted with water, and the separated crystals are recrystallized from ethanol. Melting point: 228°-289° C.; yield: 4.8 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:26]=[CH:25][N:24]([Si](C(C)C)(C(C)C)C(C)C)[CH:23]=2)[C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[C:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:6]=2[CH:21]=1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:22]2[CH:26]=[CH:25][NH:24][CH:23]=2)[C:5]2[O:9][C:8]([C:10](=[O:12])[CH3:11])=[C:7]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)[C:6]=2[CH:21]=1
Reactant: CC(=O)c1oc2c(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)cc(F)cc2c1Cc1cccc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1oc2c(-c3cc[nH]c3)cc(F)cc2c1Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
1-[5-Fluoro-3-(3-fluoro-benzyl)-7-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-benzofuran-2-yl]-ethanone (0.38 gm, 0.748 mmol) and tetrabutylammonium fluoride hydrate (0.28 gm, 0.89 mmol) were added to tetrahydrofuran (10 ml) and stirred at room temperature for four hours. The solution was concentrated under reduced pressure and purified by column chromatography to give 1-[5-fluoro-3-(3-fluoro-benzyl)-7-(1H-pyrrol-3-yl)-benzofuran-2-yl]-ethanone (0.205 gm, 79% yield).
Reaction SMILES: [OH:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][N:4]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([O:1][CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][CH2:5][N:4]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH2:3]2)=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCc3ccccc3C(O)C2)cc1
Reactant: COc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COc1ccc(OC2CN(S(=O)(=O)c3ccc(C)cc3)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.1 %

Procedure:
To a solution of 1-hydroxy-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine (15 g, 47 mmole), p-methoxyphenol (7 g, 57 mmole) and triphenylphosphine (57 mmole) in 300 ml benzene, cooled with an ice bath, was slowly dropped a solution of diethyl azodicarboxylate (10 g, 57 mmole) in 100 ml benzene. After stirring two hours at ambient temperature, the reaction mixture was filtered to remove sym-dicarbethoxyhydrazine (8 g, 96%, m.p. 130°-132° C.), then evaporated to an oil which was purified by column chromatography (silica gel, dichloromethane) to give an oil. This oil was crystallized from hexane-ether to give 6 g (30%) of 1-(p-methoxyphenoxy)-2,3,4,5-tetrahydro-3-(p-toluenesulfonyl)-3-benzazepine, m.p. 84°-85° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N:15]=[CH:16][N:17]([CH2:19][CH3:20])[CH3:18])=[C:10]([CH3:21])[CH:9]=2)=[N:4][C:3]=1[CH:22]=O.Cl.[NH2:25][O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CO>O>[C:27]([O:26][N:25]=[CH:22][C:3]1[N:4]=[C:5]([O:7][C:8]2[C:13]([CH3:14])=[CH:12][C:11]([N:15]=[CH:16][N:17]([CH2:19][CH3:20])[CH3:18])=[C:10]([CH3:21])[CH:9]=2)[S:6][C:2]=1[Cl:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)ON
Reactant: CCN(C)C=Nc1cc(C)c(Oc2nc(C=O)c(Cl)s2)cc1C
Agent: Cl
Solvent: CO
Solvent: O
Product: CCN(C)C=Nc1cc(C)c(Oc2nc(C=NOC(C)(C)C)c(Cl)s2)cc1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 74 %

Procedure:
A solution of 0.23 g (0.50 mmol) of N′-{4-[(5-chloro-4-formyl-1,3-thiazol-2-yl)oxy]-2,5-dimethylphenyl}-N-ethyl-N-methylimidoformamide and 63 mg (0.50 mmol) of 2-(aminooxy)-2-methylpropane hydrochloride in a solvent mixture of 10 ml of methanol and 3 ml of water was stirred at ambient temperature for 5 days. Evaporation of the solvents and column chromatography of the crude mixture (gradient cyclohexane->ethyl acetate) yielded 130 mg (0.37 mmol) 61% of N′-[4-({4-[(tert-butoxyimino)methyl]-5-chloro-1,3-thiazol-2-yl}oxy)-2,5-dimethylphenyl]-N-ethyl-N-methylimidoformamide. Log P (pH 2.3)=2.65
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:16]2[CH2:17][CH:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH:12]1[CH2:13][O:14][CH2:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:32])C=CC=CC=1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH:12]2[CH2:19][CH:18]([CH:20]([OH:32])[C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH:16]1[CH2:15][O:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1CC2COCC(C1)N2C(=O)OCc1ccccc1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(O)C1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 220.2 %

Procedure:
To a stirred solution of 7-methoxycarbonylmethyl-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound AI) (130 mg, 0.39 mmol) in anhydrous THF at −78° C. was added 1 M NaN(trimethylsilyl)2 in THF (0.43 mL, 0.43 mmol) during a period of 5 mins. Then the mixture was stirred for 20 mins at −78° C. To this solution was added a pre-cooled (−78° C.) solution of 2-(phenylsulfonyl)-3-phenyloxaziridine (153 mg, 0.585 mmol) in THF. The solution was stirred for 30 mins at −78° C. and then quenched by rapid addition of 6N HCl. The mixture was stirred at room temperature for 30 mins and then diluted with dichloromethane. The mixture was washed with water and 5% aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and then concentrated in vacuo. The residue was purified by flash column chromatography to afford 7-(hydroxy-methoxycarbonyl-methyl)-3-oxa-9-aza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (Compound AJ) (0.30 g, 85%). MS: calc'd (MH+) 350, measured (MH+) 350.
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH3:16][O:17][NH2:18].C(O)C>N1C=CC=CC=1>[CH3:16][O:17][N:18]=[C:4]1[C:3]2[C:8](=[C:9]([CH3:13])[CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1
Reactant: CON
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C1CCSc2c(C)cc(Br)c(C)c21
Yield: 94.4 %

Procedure:
3.2 Grams (12 mmol) of 5,8-dimethyl-6-bromothiochroman-4-one and 1.9 g (23 mmol) of O-methylhydroxylamine hydrochloride were refluxed in a solvent mixture of 10 ml of ethanol and 10 ml of pyridine under heat for 30 minutes. The solvent was distilled off under reduced pressure, and then 50 ml of 5% hydrochloric acid was added to form a solid. The solid was recovered by filtration, washed with water and dried to give 3.4 g of 4-methoxyimino-5,8-dimethyl-6-bromothiochroman (yield 93%).
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].[H][H]>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4]
Reactant: CC(C=O)=Cc1ccccc1
Reactant: [H][H]
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CC(CO)Cc1ccccc1

Procedure:
α-methylcinnamaldehyde was hydrogenated using copper chromite (2% by weight) as catalyst at a temperature of 150° C. and a pressure of 130° C. psig hydrogen. After the uptake of hydrogen ceased, the mixture was filtered and distilled to obtain the 2-methyl-3-phenylpropanol (b.pt 100° C./1 mm).
Reaction SMILES: [NH:1]1[C:9](=O)[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:9]1[N:1]=[CH:2][N:3]=[C:4]2[C:8]=1[NH:7][CH:6]=[N:5]2
Reactant: O=c1[nH]cnc2nc[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnc2nc[nH]c12

Procedure:
reacting hypoxanthine and phosphorus oxychloride in the presence of an organic base to form 6-chloropurine;
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20]CC)=[O:19])=[CH:8][N:9]2[C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=[CH:4][C:3]=1[F:24].Cl.O>C(O)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([OH:20])=[O:19])=[CH:8][N:9]2[C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=[CH:4][C:3]=1[F:24]
Reactant: CCOC(=O)c1cn(-c2nonc2C)c2nc(Cl)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1nonc1-n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
Compound No. 78 (30 mg) obtained in Example 39 was dissolved in acetic acid (2 ml ) and 6N-HCl (0.5 ml). The solution was stirred at 100° C. for 0.5 hour. After cooling and addition of water (10 ml), the precipitate was filtrated and washed with ethanol and ether. The title compound No. 79 was obtained as a colorless solid (5 mg).