Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14](=[O:15])[C:13]([O:16][CH3:17])=[CH:12][N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=1)(=[O:8])[CH3:1]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cccc(C(F)(F)F)c2)nc(C(C)=O)c1=O
Reaction time: 1 h
Yield: 78.8 %

Procedure:
MeMgBr (3 M solution in diethyl ether, 4 mL, 12 mmol) was added dropwise at −78° C. to a solution of N,5-dimethoxy-N-methyl-4-oxo-1-[3-(trifluoromethyl)phenyl]-1,4-dihydropyridazine-3-carboxamide (2.09 g, 5.85 mmol) in THF (50 mL). After stirring for 1 h, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with AcOEt three times. The combined extracts were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with AcOEt/MeOH (1/0-10/1) and recrystallized from hexane/AcOEt to give the title compound (1.44 g, 79% yield) as off-white crystals: mp 155-156° C.; 1H NMR (300 MHz, CDCl3): δ ppm 2.71 (3H, s), 3.98 (3H, s), 7.68-7.76 (2H, m), 7.83-7.88 (2H, m), 7.94 (1H, s). Anal. Calcd for C14H11F3N2O3: C, 53.85; H, 3.55; N, 8.97. Found: C, 53.79; H, 3.59; N, 9.02.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]#[N:9].[K].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14]>C(#N)C>[O:14]=[C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)[CH2:12][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]#[N:9]
Reactant: N#CN=C1CCCCN1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: [K]
Solvent: CC#N
Product: Cc1ccc(C(=O)CN2CCCCC2=NC#N)cc1
Yield: 59.5 %

Procedure:
A suspension of N-(piperidin-2-ylidene)cyanamide (1.23 g; 10 mmol) in acetonitrile (20 mL) was heated gently until dissolution and then potassium hydrogenocarbonate (1.66 g; 12 mmol) and 2-bromo-1-p-tolylethanone (2.98 g; 14 mmol) were added. The well stirred mixture was heated at reflux for 21 h and an extra amount of 2-bromo-1-p-tolylethanone (0.426 g; 2 mmol) was then added. The reaction mixture was heated for 6 additional hours. After cooling, the precipitate was filtered, washed with dichloromethane and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash-chromatography on silica gel using a gradient of ethyl acetate (1-20%) in dichloromethane to furnish 1.52 g (59%) of N-(1-(2-oxo-2-p-tolylethyl)piperidin-2-ylidene)cyanamide as an orange solid. ESI/APCI(+): 256 (M+H). 1H NMR (CDI3) δ 7.83 (d, J=8.22 Hz, 2H, Harom.); 7.29 (d, J=8.04 Hz, 2H, Harom.); 4.89 (s, 2H, COCH2); 3.43 (m, 2H, CH2); 2.89 (m, 2H, CH2); 2.43 (s, 3H, CH3); 1.92 (m, 4H, 2×CH2).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][O:1][C:2]2[CH:15]=[CH:14][C:5]3[C:6]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:7][O:8][C:4]=3[CH:3]=2)=[CH:19][CH:20]=1)[CH3:26]
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: CCOc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(COc2ccc3c(CC(=O)OC)coc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of methyl (6-hydroxy-1-benzofuran-3-yl)acetate (10.0 g, 48.5 mmol) in DMF (100 mL) were added 1-(chloromethyl)-4-ethoxybenzene (12.4 g, 72.7 mmol) and potassium carbonate (13.5 g, 97.0 mmol), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed twice with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with diethyl ether and hexane to give the title compound (15.8 g, yield 96%) as a white solid.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][NH:10][CH2:9][CH2:8]2.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1cccc2c1CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCc2cccc(O)c2C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To an-ice cooled suspension of 8-hydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (746 mg, 5.0 mmol, 1.0 eq.) and triethylamine (2.13 mL, 15.0 mmol, 3.0 eq.) in DCM (25 mL), benzyl chloroformate (0.83 mL, 5.5 mmol, 1.1 eq.) was added dropwise. The solution was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (50 mL). The layers were separated. The aq. phase was extracted with DCM (3×50 mL). The comb. org. phases were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (20 mL) and 1M aq. NaOH soln. (6 mL) was added. The mixture was stirred at r.t. for 68 hours. The org. solvent was removed in vacuo. The resulting aq. layer was acidified with 2N aq. HCl soln. and extracted with DCM (3×25 ml). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by CC (SiO2, Hept/AcOEt 8:2 to 7:3) to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:26])([CH3:25])[C:20](OCC)=[O:21].O>CS(C)=O>[CH3:25][C:19]1([CH3:26])[C:20](=[O:21])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2NC1=O
Temperature: 30 °C
Yield: 120.9 %

Procedure:
To a solution of 2-amino-5-nitrophenol (200 g) in dimethylsulfoxide (1000 mL) was added anhydrous potassium carbonate (269 g) under stirring at 30° C. or lower, then to the mixture was added ethyl 2-bromo-2-methylpropionate (278.4 g) at 30° C. or lower, and the mixture was stirred at 26° C. for 24 hours. To the reaction mixture was added water (2000 mL) at 40° C. or lower, and then stirred at room temperature for 3 hours. The reaction product was collected by filtration, and successively washed with dimethylsulfoxide/water (2:1, 800 mL) and water (3200 mL) to obtain the title compound (348.6 g) as a yellow solid (wet material) (yield: 121%, purity: 96%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH3:21])[CH3:20])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([NH:18][CH:19]([CH3:20])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:30])=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3ccccc3c2n1NC(C)C
Solvent: ClCCl
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NC(C)C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
A solution of N-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (0.98 g, 3.45 mmol) in 35 mL of CH2Cl2 was treated with MCPBA (77% max., 1.10 g, 4.48 mmol). After stirring for 3 h, the reaction was quenched with 2% Na2CO3 solution and extracted into CH2Cl2. The organic portion was washed with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)isopropylamine (0.93 g) as a light-orange solid.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:6]([O-:8])=[O:7])[CH3:2].[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:17])[S:12][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCON=C(C(=O)[O-])c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 87.3 %

Procedure:
2-Ethoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate acid (syn isomer) (100 g.), formic acid (85.5 g.) and acetic anhydride (190.1 g.) were treated according to a similar manner to that of Example 7(a) (5) to give 2-ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (99.1 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24](I)=[C:23]([F:28])[CH:22]=2)=[N:16]1.[CH3:29][C:30]([CH3:34])([CH3:33])[C:31]#[CH:32].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>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.CS(C)=O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[NH:18][C:17]([C:21]2[CH:26]=[CH:25][C:24]([C:32]#[C:31][C:30]([CH3:34])([CH3:33])[CH3:29])=[C:23]([F:28])[CH:22]=2)=[N:16]1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(I)c(F)c3)[nH]c2=O)c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: CC(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C#CC(C)(C)C)c(F)c3)[nH]c2=O)c1
Yield: 12.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-111 by using N-(4-chloro-3-(3-(3-fluoro-4-iodophenyl)-4,5-dihydro-5-oxo-1,2,4-triazol-1-yl)benzyl)isobutyramide (0.080 g, 0.155 mmol), 3,3-dimethylbut-1-yne (0.019 g, 0.233 mmol), TBAF (0.121 g, 0.466 mmol), bis(triphenylphosphine)palladium(II) chloride (0.004 g, 0.006 mmol) and DMSO (3.0 mL) to afford 0.009 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.02 (d, J=6.9 Hz, 6H), 1.31 (s, 9H), 2.39-2.42 (m, 1H), 4.29 (d, J=5.7 Hz, 2H), 7.35 (d, J=7.5 Hz, 1H), 7.43 (s, 1H), 7.57-7.67 (m, 4H), 8.37 (m, 1H), 13.0 (br s, 1H); MS (m/z): 469.31 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[S:22][CH:23]=[CH:24][N:25]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:26])=[CH:4][N:3]=1.CCO.[N:30]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:30]1([CH2:35][C:36]2[CH:43]=[CH:42][C:39]([C:40]3[NH:1][C:2]4=[N:3][CH:4]=[C:5]([Cl:26])[C:6]([N:11]5[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]6[S:22][CH:23]=[CH:24][N:25]=6)=[O:19])[CH2:13][CH2:12]5)=[C:7]4[N:8]=3)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[N:31]1
Reactant: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: O=C(CN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(Cn5cccn5)cc4)nc23)CC1)Nc1nccs1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (0.028 g, 0.07 mmol) and EtOH (3.0 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.017 g, 0.09 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.30 ml, 0.30 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 5%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a pale yellow solid. The title compound was obtained as a white solid after trituration with diethyl ether (0.006 g, 16%); 1H-NMR (500 MHz, DMSO-d6) 2.77 (br s, 4H, piperazine N(CH2)2), 3.40 (s, 2H, NCH2CON), 3.73 (br s, 4H, piperazine N(CH2)2), 5.41 (s, 2H, C6H4CH2N), 6.30 (t, J=1.9 Hz, 1H, pyrazole 4-H), 7.23 (d, J=3.5 Hz, 1H, thiazole H), 7.35 (d, J=7.6 Hz, 2H) and 8.14 (d, J=8.3 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.49 (d, 2H, thiazole-H, and pyrazole-H), 7.86 (d, J=1.84 Hz, 1H, pyrazole-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.89 (s, 1H, CONH), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): Rt=3.89 min—534, 536 [(M+H)+, Cl isotopic pattern]. ESI-HRMS: Found: 534.1595, calculated for C25H25ClN9OS (M+H)+: 534.1591.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][S:5]1(=[O:16])=[O:15])[CH3:3].CC(C)([O-])C.[K+].[Cl:23][CH2:24][C:25](Cl)=[O:26]>C(#N)C>[Cl:23][CH2:24][C:25]([N:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9](=[O:10])[N:4]([CH:2]([CH3:1])[CH3:3])[S:5]1(=[O:16])=[O:15])=[O:26]
Reactant: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Reactant: O=C(Cl)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1C(=O)c2ccccc2N(C(=O)CCl)S1(=O)=O

Procedure:
To 100 ml of acetonitrile was added 10.0 g of 3-(1-methylethyl)-1H-2,1,3-benzothiadiazin-4(3H)-one- -2,2-dioxide and 4.9 g of potassium t-butoxide. The mixture was stirred vigorously and 3.3 ml of chloroacetyl chloride in 50 ml acetanitrile was added dropwise over a 0.5 hour period. The resultant mixture as stirred overnight, filtered and the solvent removed from the filtrate in vacuo. The residue was washed with carbon tetrachloride and filtered. The tan granular precipitate was dissolved in 50 ml of methylene chloride and 50 ml of carbon tetrachloride was added. The methylene chloride was removed under a nitrogen atmosphere and the resultant mixture was filtered. The precipitate was washed 5% aqueous potassium carbonate, filtered and the white flocculent precipitate air dried to afford 2.23 g of 1-(2-chloroacetyl)-3-(1-methylethyl)- -1H-2,1,3-benzothiadiazin-4 (3H)-one-2,2-dioxide, m.p. 133°-135° C.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][CH2:5][N:6]([CH2:10][CH2:11][CH3:12])[CH2:7][CH2:8][CH3:9].[NH2:13][C:14]([NH2:16])=[S:15].C(OCC)(=O)C>C(O)C>[ClH:2].[ClH:1].[CH2:7]([N:6]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:4][CH2:3][S:15][C:14](=[NH:13])[NH2:16])[CH2:8][CH3:9]
Reactant: NC(N)=S
Reactant: CCCN(CCC)CCCCl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCN(CCC)CCCSC(=N)N
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A stirred mixture of 1-chloro-3-(dipropylamino)-propane hydrochloride (42 g), thiourea (15.5 g) and ethanol (250 ml) was heated under reflux for 24 hours then allowed to cool to ambient temperature. Ethyl acetate was added until a faint opalescence was observed, then the mixture was stored at 4° C. for 24 hours. After this time it had deposited an oil which was isolated by decantation of the bulk of the solvent followed by removal of residual solvent in vacuo. The oil was triturated with ethanol, the solvent was removed by decantation, and the residue was dried in vacuo at ambient temperature for 24 hours to give a pale brown solid. The ethanol solution decanted from the oil was concentrated in vacuo, and the residue was triturated with ethanol as described above to give a second crop of pale brown solid. The ethanol solution remaining after isolation of the second crop was concentrated in vacuo and the residue was triturated with propan-2-ol to give a third crop of solid. The three crops were combined to give S-[3-(dipropylamino)propyl]isothiourea dihydrochloride as a pale brown solid (51 g), m.p 143°-145° C.
Reaction SMILES: [C:1]1([CH2:6]Br)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C.Cl>O1CCCC1.[Zn]>[CH3:8][C:9]1[O:14][CH2:13][N:12]([C:15]([CH3:18])([CH3:19])[CH:16]([CH:2]2[CH2:3][CH2:4][CH2:5][C:1]2=[CH2:6])[OH:17])[C:11](=[O:20])[C:10]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C=O)CO1
Reactant: BrCC1=CCCC1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C1CCCC1C(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 53 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of (cyclopent-1-enyl)methylbromide (3.8 g) in tetrahydrofuran was added to a stirred mixture of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropionaldehyde (3.5 g) and zinc powder(1.6 g) in tetrahydrofuran at 20° C. under an inert atmosphere. The temperature increased to 53° C. slowly and after 2 hours, ethyl acetate and hydrochloric acid (1N) were added and the organic phase washed with brine, dried (magnesium sulphate), evaporated and purified by silica gel column chromatography, eluting with n-hexane/ethyl acetate (2:1) to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methyl-1-(2-methylenecyclopentyl)propan-1-ol (3.66 g), NMR: 1.46(s,3H), 1.61(s,3H), 1.88(s,3H), 1.5-1.9(4H), 2.24(2H), 2.50(1H), 3.24(d,1H), 3.80(s,1H), 4.93(s,1H), 5.06(s,1H), 5.19(d,1H), 5.26(d,1H), 7.22-7.38(5H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][C@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@@H:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14]1.C(OCC)C>C(Cl)Cl>[O:12]=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:15]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14]1
Reactant: CCOC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 69 %

Procedure:
To a 1 l. 138 round bottom flask was added 33.6 g (0.16 mol) of pyridinium chlorochromate, 35 g of powdered 4A molecular sieves and 200 ml of methylene chloride. After stirring the mixture at room temperature for sixty minutes, a solution of 21.3 g (0.078 mol) of ethyl cis-4-hydroxy-N-t-butoxycarbonyl-2-piperidinecarboxylate in 50 ml of methylene chloride was added. After stirring the mixture for sixty minutes at room temperature, 700 ml of diethyl ether was added. The mixture was filtered through three-fourths inch of Celite and three-fourths inch of silica gel (230-400 mesh) in a 650 ml medium porosity sintered glass funnel. The solids were washed with 1 1. of diethyl ether and the filtrate was concentrated under vacuum. To the residue was added 200 ml of diethyl ether and the mixture filtered through three-eighths inch of Celite and three-eighths inch of silica gel (230-400 mesh) in a 150 ml medium porosity sintered glass funnel. The solids were washed with 500 ml of diethyl ether and the filtrate was concentrated under vacuum. The residue was purified by high pressure liquid chromatography to provide 14.6 g of ethyl 4-oxo-N-t-butoxycarbonyl-2-piperidinecarboxylate as a colorless oil.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(CCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 80 h

Procedure:
To a solution of 1-(2-bromoethyl)-4-nitrobenzene (460 mg, 2.0 mmol) in acetone (15 mL) was added morpholine (610 mg, 7.0 mmol) and 680 mg of K2CO3. The mixture was stirred for 80 hours at ambient temperature, and then poured into water. The aqueous mixture was extracted with ether. The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo to give 456 mg (1.93 mmol; 97%) of the title compound, which was converted to the appropriate amine by the method disclosed in Preparation 16.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[N:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[O:16])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[Si:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:1][C:2]1[CH:3]=[C:4]([CH:9]=[N:10][N:11]2[CH2:15][CH2:14][N:13]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:12]2=[O:16])[CH:5]=[CH:6][C:7]=1[O:8][Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: C[Si](C)(C)Cl
Reactant: O=C1NCCN1N=Cc1ccc(O)c(O)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)Oc1ccc(C=NN2CCN([Si](C)(C)C)C2=O)cc1O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a mixture of 5.0 g (22.6 mmol) of 1-[[(3,4-dihydroxyphenyl)methylene]amino]-2-imidazolidinone and 8.1 g (74.6 mmol) of chlorotrimethylsilane in 200 ml of ethyl acetate was added 7.5 g (74.6 mmol) of triethylamine. After stirring overnight at ambient temperature, the precipitate was filtered off and the filtrate evaporated in vacuo to afford 8.8 g of 1-[[[3,4-bis[(trimethylsilyl)oxy]phenyl]methylene]amino]-3-(trimethylsilyl)-2-imidazolidinone.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8](OCC)=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2].C[Si](C)(C)[NH:21][Si](C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:8]([NH2:21])=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6](=[O:18])(=[O:17])[N:5]=1)[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)C1=C(OCC)C(OCC)=NS1(=O)=O
Solvent: ClCCl
Product: CCOC(=O)C1=C(N)C(OCC)=NS1(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Under a nitrogen atmosphere a solution of 1.41 g (5.3 mmol) of the Example 3 compound in 15 ml of methylene chloride is stirred in an ice bath while a solution of 1.2 g (7.9 mmol) hexamethyldisilazane in 10 ml methylene chloride is added dropwise. The solution is allowed to warm to room temperature at which temperature stirring is continued for 18 hours. The solution is then evaporated in vacuo to an oil which is redissolved in 20 ml of a mixture of methylene chloride (15)-ethanol (5). After stirring at room temperature for one hour, the solution is again concentrated in vacuo, leaving a solid, 1.1 g (85%), mp 163°-165°. Recrystallization from ethyl acetate provides analytically pure title compound, mp 172.5°-173°.
Reaction SMILES: I[CH:2]([CH3:6])[CH:3](I)[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].[CH2:13]([O:15][C:16](=[O:26])[CH2:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>CN(C)C=O>[C:18]([C:17]1([C:16]([O:15][CH2:13][CH3:14])=[O:26])[CH2:4][CH2:3][CH2:2][CH2:6]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CC(I)C(C)I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)c2ccccc2)CCCC1
Temperature: 57.5 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Diiodobutane (17.1 g, 55 mmol), sodium carbonate (35 g, 330 mmol), ethylbenzoylacetate (10.6 g, 55 mmol) and dimethylformamide (170 ml) were mixed and the mixture was stirred at 55 to 60° C. overnight. The mixture after completion of reaction was poured into ice water and the mixture was extracted twice with ethyl acetate (100 ml). The extract was dried over sodium sulfate, and after concentration, purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (7.9 g, 58%) as a colorless oil.