Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[CH:32]=3)[C:27]([CH3:43])([CH3:42])[CH2:26]2)=[O:24])[CH2:10][C@H:9]1[CH3:44])=O)(C)(C)C.[ClH:45]>CCOC(C)=O.O1CCOCC1>[ClH:45].[ClH:45].[F:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C:31]2[CH:32]=[C:33]3[N:25]([C:23](=[O:24])[CH2:22][N:11]4[CH2:10][C@@H:9]([CH3:44])[NH:8][CH2:13][C@@H:12]4[CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@H:16]4[CH3:21])[CH2:26][C:27]([CH3:43])([CH3:42])[C:28]3=[N:29][CH:30]=2)=[CH:36][CH:37]=1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccc(F)cc4)cc32)[C@@H](CN2CCOC[C@H]2C)CN1

Procedure:
(2R,5S)-4-{2-[6-(4-Fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.9 g, 3.29 mmol) was dissolved in EtOAc (48 mL) and 4 M HCl in dioxane (82 mL) and stirred at room temperature for 18 h. The solvent was removed in vacuo and resulting solid triturated with diethyl ether and dried in a vacuum oven at 40° C., to give the title compound (1.36 g). 1H NMR (DMSO-d6): 11.71-10.46 (1H, m), 10.14 (1H, s), 9.52 (1H, s), 8.31 (1H, s), 8.25 (1H, s), 7.32 (2H, dd), 7.15 (2H, t), 4.12-4.01 (4H, m), 4.01-3.56 (7H, m), 3.45 (4H, s), 3.22 (2H, d), 3.17 (2H, s), 3.09 (1H, d), 2.89 (1H, d), 1.41 (6H, s), 1.24 (6H, m). MS: [M+H]+=510.
Reaction SMILES: O=[C:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].Cl.[CH3:18][O:19][NH2:20].[OH-].[Na+].C(=O)([O-])O.[Na+]>CO>[CH3:18][O:19][N:20]=[C:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CON
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CON=C(C)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
1.08 g (5.00 mmol) of N-(3-oxobutyl)phthalimide was dissolved in 10 ml of methanol and to the solution was added 0.835 g (10.0 mmol) of O-methylhydroxylamine hydrochloride. To this suspension was added 2 ml of 5N aqueous sodium hydroxide solution, followed by being stirred at room temperature for 16 hours. The reaction mixture was poured into 100 ml of saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform (30 ml×3), and the combined organic layer was dried over magnesium sulfate. Chloroform was distilled off and the residual solids were washed with hexane to give 1.23 g (yield 100%) of the titled compound as white crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]#[N:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16](=[N:20][OH:21])[NH2:17])=[N:13][C:12]=1[CH3:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1nc(C#N)sc1C(=O)NCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(C(N)=NO)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of N-benzyl-2-cyano-4-methylthiazole-5-carboxamide (0.15 g, 0.58 mmol) and hydroxylamine hydrochloride (0.09 g, 1.28 mmol) in ethanol (7 mL) was added triethylamine (0.2 mL, 1.43 mmol). The reaction mixture was heated to reflux for 3 hour, cooled to ambient temperature and concentrated in vacuo. The solid was washed with water and dried to afford the title compound in 70% yield (0.12 g): 1H NMR (300 MHz, CDCl3) δ 7.43-7.18 (m, 5H), 6.42 (br s, 1H), 5.74 (br s, 2H), 4.54 (d, J=5.3 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 291.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[S:6][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[NH:20][C:19](=[O:21])[O:18][N:17]=2)=[C:12]([O:22][CH3:23])[CH:11]=1.ClCCl>CN(C)C=O.[O-2].[O-2].[Mn+4]>[CH3:23][O:22][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[C:16]1[NH:20][C:19](=[O:21])[O:18][N:17]=1)[O:9][CH2:8][C:7]1[S:6][C:5]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[N:4][C:3]=1[CH:2]=[O:1]
Reactant: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)ccc1-c1noc(=O)[nH]1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C=O)ccc1-c1noc(=O)[nH]1
Temperature: 60 °C
Yield: 60.3 %

Procedure:
50 mg of 3-{4-[4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-methoxy-phenyl}-4H-[1,2,4]oxadiazol-5-one were dissolved in 2 mL of dimethylformamide by heating to 60° C. and 2 mL of dichloromethane was added. To the resulting solution was added 90 mg of manganese dioxide. The reaction mixture was heated to 60° C. overnight. 5 mL of dimethylformamide was added. The hot mixture was filtered through celite and washed with dichloromethane/methanol. The filtrate was concentrated under reduced pressure to give 30 mg of 5-[3-methoxy-4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenoxymethyl]-2-(4-trifluoromethyl-phenyl)-thiazole-4-carbaldehyde which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.Br[CH:42]1[CH2:44][CH2:43]1.CCN(C(C)C)C(C)C>CC#N>[CH:42]1([N:32]2[CH2:31][CH2:30][CH:29]([N:22]3[CH2:21][C:20]4[CH:19]=[C:18]5[C:26]([NH:27][C:16]([C:10]6[C:11](=[O:15])[NH:12][CH:13]=[CH:14][C:9]=6[NH:8][CH2:7][CH:6]([OH:35])[CH2:5][O:4][C:3]6[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:2]=6[CH3:1])=[N:17]5)=[CH:25][C:24]=4[C:23]3=[O:28])[CH2:34][CH2:33]2)[CH2:44][CH2:43]1
Reactant: BrC1CC1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C3CC3)CC2)C4)c(C)c1
Temperature: 25 °C
Reaction time: 112 h
Yield: 5.6 %

Procedure:
To a solution of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (54.3 mg, 0.1 mmol) and bromocyclopropane (121 mg, 1.0 mmol) in CH3CN (8 mL) was added DIEA (129.3 mg, 1.0 mmol) and the resulting reaction mixture was stirred at the room temperature for 112 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (490:10:1) afforded the title compound (3.27 mg, 5.6%). 1H NMR (DMSO-d6) δ 1.70 (m, 2H), 1.80 (m, 2H), 2.04 (m, 2H), 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.90-3.00 (4H), 3.45 (m, 1H), 3.70 (m, 1H), 3.95-4.06 (3H), 4.11 (m, 1H), 4.42 (s, 1H), 4.47 (s, 1H), 5.10-5.22 (2H), 5.47 (d, J=3 Hz, 0.5H, NH), 5.52 (d, J=3 Hz, 0.5H, NH), 5.81 (m, 1H), 6.22 (m, 1H), 6.81 (m, 1H), 6.89-6.99 (2H), 7.32-7.38 (1.5H), 7.68 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.15 (d, J=6 Hz, 1H, NH), 11.21 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 583.7 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:4]([NH:22][CH:19]2[CH2:21][CH2:20]2)[N:3]=1
Reactant: NC1CC1
Reactant: Nc1nc(Cl)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 25 °C
Yield: 80 %

Procedure:
(1S,4R)-4-(2-Amino6-chloro-9-H-purin-9-yl)-2-cyclopentene-1-methanol (U.S. Pat. No. 5,206,435) or the hydrochloride salt thereof (Example 8) was refluxed in ethanol with 10 molar equivalents of cyclopropylamine for 2 hours. The resulting solution was cooled to ambient temperature and 1 N sodium hydroxide (1 or 2 molar equivalents, depending on whether the staring material was VIIa or the hydrochloride salt of VIIa) was added. The volatiles were evaporated in vacuo. (1S,4R)[2-Amino-6-(cyclopropylamino)-9H-purin-9-yl]-2yclopentene-1-methanol (IXa) was washed from a silica gel pad eluted with 5% methanol-chloroform or 10% methanol-ethyl acetate and isolated as a white solid foam (80%); spectra identical to those of the product of Example 9.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][CH2:35][NH2:36])=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[C:25](=[O:27])[NH:36][CH2:35][CH2:34][C:33]1[CH:37]=[CH:38][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: COc1ccc(CCN)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
18.9 g of N-(Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride are added to a cooled solution of 20.04 g of (S)-Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester, 14.9 g of 4-methoxyphenethylamine, 16.9 ml of diisopropylethylamine and 13.2 g of 1-hydroxy-benzotriazole in 250 ml of CH2Cl2. The reaction mixture obtained is stirred at rt for 16 hours, the reaction is quenched with aq. 2N HCl solution and the aq. phase obtained is extracted with CH2Cl2. The combined organic phases obtained are washed with aq. 2N HCl solution, brine and aq. saturated NaHCO3 solution, dried and solvent is evaporated. The residue obtained is purified by recrystallisation with EtOAc/hexane (1/3) to afford the title compound.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH:16][NH2:17]>C(O)C>[CH3:15][N:16]1[C:10](=[O:12])[CH2:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:17]1
Reactant: CNN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CCO
Product: CN1N=C(c2ccccc2)CC1=O
Yield: 72.7 %

Procedure:
According to General Procedure A; ethyl benzoylacetate (18.4 mL, 95.5 mmol, 1.1 equ.) in ethanol (180 mL) was treated at 0° C. with methylhydrazine (4.57 mL, 86.8 mmol, 1.0 equ.) to give 1-methyl-3-phenyl-1H-pyrazol-5(4H)-one (11.0 g 63.1 mmol, 73%) after purification by crystallization (ethanol) as a light yellow solid. 1H-NMR (400 MHz) CDCl3: 7.67-7.65 (m, 2H), 7.42-7.41 (m, 3H), 3.60 (s, 2H), 3.41 (s, 3H), 13C-NMR (100 MHz) CDCl3: 171.8, 154.2, 131.0, 130.3, 128.8, 125.6, 37.9, 31.4. LC/MS-MS: 175.0→77.2 m/z; GS1 and GS2 at 30, DP=66, CE=43, CXP=4, tR=3.45 min.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[C:4]2[C:12](=[C:13]([O:15][CH3:16])[CH:14]=1)[C:11]1[C:6](=[CH:7][C:8]([F:17])=[CH:9][CH:10]=1)[CH:5]=2.[CH2:19]([NH-:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]2[C:11]3[C:6](=[CH:7][C:8]([F:17])=[CH:9][CH:10]=3)[C:5](=[N:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:4]=2[CH:3]=1
Reactant: [NH-]Cc1ccccc1
Reactant: COC1=C2C(=Cc3cc(F)ccc32)C(=O)C(F)=C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(F)cc2c1-c1ccc(F)cc1C2=NCc1ccccc1
Temperature: 24 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Titanium tetrachloride (0.127 mol, 127 mL of a 1.0 M methylene chloride solution) was added dropwise over a 15 minute to a mechanically stirred suspension of 2,7-difluoro-4-methoxyfluorenone (I) (50.0 g, 0.203 mol) and benzylamide (81 g, 0.76 mol) in methylene chloride (1 L) under nitrogen, keeping the temperature below 15° C. The mixture was stirred for 30 min while warming to 24° C., and then filtered through a pad of Florisil, washing with diethyl ether (4 L). The filtrate was concentrated to 500 mL and diluted with hexane (500 mL). The precipitated yellow imine was collected by filtration and combined with second and third crops obtained by concentration of the mother liquor to provide a total of 64 g (94%) of (II) as mixture of geometric isomers: IR (KBr) 1648, 1617, 1603, 1592, 1469, 1452, 1321, 1294 cm-1 ; 1H NMR (CDCl3, 200 MHz)δ7.95-6.40 (m, 10 H), 5.26 and 5.27 (singlets, total 2 H), 3.94 and 3.96 (singlets, total 6 H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:26]([CH:23]5[CH2:25][CH2:24]5)=[O:27])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: Nc1ccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)cc1
Reactant: O=C(Cl)C1CC1
Product: O=C(Nc1ccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)cc1)C1CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 170, starting from 4-[6-(4-cyclopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenylamine and cyclopropanecarbonyl chloride. 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.93 (d, 2H), 7.86 (d, 1H), 7.67 (d, 2H), 7.30 (d, 1H), 3.57-3.54 (m, 4H), 2.64-2.62 (m, 4H), 1.79-1.74 (m, 1H), 1.65-1.62 (m, 1H), 0.78 (d, 4H), 0.43-0.41 (m, 2H), 0.35-0.30 (m, 2H).
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[Cl:21][C:22]1[C:27]([C:28](O)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:21][C:22]1[C:27]([C:28]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[N:12]=[CH:11][N:10]=[C:9]3[NH:8][CH:5]2[CH2:6][CH2:7][C:2]([F:1])([F:20])[CH2:3][CH2:4]2)=[O:29])=[C:26]([F:31])[C:25]([CH2:32][NH:33][C:34](=[O:39])[C:35]([CH3:37])([CH3:36])[CH3:38])=[CH:24][CH:23]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(NC4CCC(F)(F)CC4)ncnc23)c1F
Yield: 28.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(4,4-difluorocyclohexyl)quinazoline-4,8-diamine (Intermediate-9, 75 mg, 0.27 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 116 mg, 0.41 mmol), oxalyl chloride (78 mg, 0.62 mmol), DMF (1 drop) and DIPEA (105 mg, 0.81 mmol) in CH2Cl2 (5 mL) to afford 42 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.40 (s, 1H), 8.69-8.66 (d, J=7.8 Hz, 1H), 8.49 (s, 1H), 8.12-8.09 (m, 2H), 7.53 (t, 1H), 7.40-7.32 (m, 2H), 4.28 (m, 3H), 2.09-1.98 (m, 6H), 1.73 (m, 2H), 1.12 (s, 9H); MS [M]+: 548.33.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:30]([C:32](=[O:43])[CH2:33][C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH:35]=2)[CH3:31])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([O:22][Si](C(C)(C)C)(C)C)[CH2:18]2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:44])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]([N:30]([C:32](=[O:43])[CH2:33][C:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[O:36][CH:35]=2)[CH3:31])[CH2:16][N:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)Cc1coc2ccccc12)C(CN1CCC(O[Si](C)(C)C(C)(C)C)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)Cc1coc2ccccc12)C(CN1CCC(O)C1)c1cccc(OCC(=O)OC(C)(C)C)c1
Reaction time: 2 h

Procedure:
To a solution of Example 26 (1.20 g, 1.93 mmol) in THF (15 mL) at room temperature was added TBAF (2 mL of a 1 M solution in THF, 2 mmol). The reaction was stirred for 2 hours, then diluted with water (20 mL) and saturated brine (80 mL), and extracted with dichloromethane (4×120 mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo. Purification by column chromatography in ethyl acetate:methanol (9:1) gave the product as an oil. Yield=0.797 g, 81%.
Reaction SMILES: [Br-].[CH2:2]([S:18][CH2:19][CH:20]([O:28][CH3:29])[CH2:21][N+:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][OH:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH2:30](SCC(OCC)C[Br:50])CCCCCCCCCCCCCCC.CN(CCO)C>>[Br-:50].[CH2:2]([S:18][CH2:19][CH:20]([O:28][CH2:29][CH3:30])[CH2:21][N+:22]([CH3:26])([CH3:27])[CH2:23][CH2:24][OH:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCSCC(CBr)OCC
Reactant: CCCCCCCCCCCCCCCCSCC(C[N+](C)(C)CCO)OC
Agent: CN(C)CCO
Agent: [Br-]
Product: CCCCCCCCCCCCCCCCSCC(C[N+](C)(C)CCO)OCC
Yield: 30 %

Procedure:
This product was prepared in an analogous manner to that of (±)-3-hexadecylthio-2-methoxy-N, N-dimethyl-N-β-hydroxyethyl-1-propyl ammonium bromide from 2.2 grams (0.005 mole) of (±)-1-hexadecylthio-2-ethoxy-3-bromopropane and 0.15 milliliter (0.006 mole) of N,N-dimethylaminoethanol to give 0.775 milligram (30%) of product, (mp 112°-113° Centigrade). 1H-NMR (CDCl3): delta, 0.87(t, 3H, terminal methyl), 1.2-1.6[m, 31H, (CH2)14, CH3 --CH2 --O], 2.58(m, 2H, S--CH2), 2.7-2.9(m, 2H, CH2 --S), 3.48[s, 6H, N(CH3)2 ], 3.9-4.3(m, 9H, CH, CH2 --N--CH2 --CH2 --OH, CH3 --CH2 --O). Anal. (C25H54NO2SBr) C,H,N.
Reaction SMILES: I(O)(=O)(=O)=O.CC1(C)[O:11][C@H:10]([C@H:12]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:14](=[O:24])[C@H:13]2[NH:25][C:26](=[O:34])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)CO1>O1CCCC1.O>[CH:10]([C@H:12]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:14](=[O:24])[C@H:13]1[NH:25][C:26](=[O:34])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:11]
Reactant: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[C@@H]2COC(C)(C)O2)cc1
Agent: [O-][I+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2C=O)cc1

Procedure:
Periodic acid (18.7 g, 45.6 mmol) was added to a suspension of (3S,4S)-4-[(R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-(4-methoxyphenyl)-3-phenylacetamidoazetidin-2-one (15.1 g, 36.8mmol) in tetrahydrofuran (210 ml) and water (210 ml). The reaction mixture was heated under reflux for 1.5 h and then cooled in ice. The precipitated product was collected by filtration, washed with water and dried over phosphorus pentoxide to yield the title compound as a mixture of aldehyde and the corresponding hydrate (10.18 g, 82%); νmax (KBr) 1713, 1638, 1552 and 1514 cm-1 ; aldehyde δH (d6 -DMSO) 3.43 and 3.50 (2H, ABq, J 14.4 Hz), 3.73 (3H, s), 4.95 (1H, dd, J 6.1, 1.2 Hz), 5.19 (1H, m), 6.95 (2H, d, J 9.0 Hz), 7.18-7.35 (7H, m), 9.09 (1H, d, J 7.3 Hz) and 9.52 (1H, d, J 1.2 Hz); hydrate δH (d6 -DMSO) 3.50 (2H, s), 3.72 (3H, s), 4.16 (1H, t, J 5.6 Hz), 5.07 (1H, q, J 5.8 Hz), 5.29 (1H, dd, J 9.4, 5.6 Hz), 6.28 (2H, t, J 6.7 Hz, exch.), 6.9 (2H, d, J 9.1 Hz), 7.19-7.35 (5H, m), 7.52 (2H, J 9.1 Hz) and 8.52 (1H, d, J 9.4 Hz); m/z (EI) 338 (10); (CI, +ve ion, ammonia) 339 (MH+), 356 (MNH4+).
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Cl:9][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=1[C:12](C#N)=[O:13].C(N(CC)CC)C.Cl>C(Cl)Cl.CCOCC.[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:9][C:10]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:11]=1[C:12]([CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8])=[O:13]
Reactant: O=C1CCCC(=O)C1
Reactant: N#CC(=O)c1ccc(Cl)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C1CCCC(=O)C1C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.7 %

Procedure:
1,3-Cyclohexanedione [11.2 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 g (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was dissolved in ether and stirred with 250 ml of 5% copper (II) acetate. The resulting copper salt was filtered, washed with ether and stirred with 6N hydrochloric acid to destroy the salt. The extract was washed with ether to yield 22.15 grams of the desired product m.p. 138°-140° C. (77.7% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1C>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([CH3:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: Cc1ccc(Nc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A mixture of 4-methyl-2-nitroaniline (1.006 g, 6.612 mmol), 4-benzyloxybromobenzene (5.794 g, 22.02 mmol), cuprous iodide (62.9 mg, 0.3306 mmol), potassium carbonate (0.914 g, 6.612 mmol) and anhydrous o-xylene (18 mL) was heated at 150° for 24 hours. Added additional cuprous iodide (30 mg) and heated an additional 6 hours at 160°. The reaction was cooled to room temperature and the solvent removed by rotary evaporation under vacuum. The residue was purified by silica gel flash chromatography using 1:1 methylene chloride/hexanes as eluent to afford the title compound as a red oil which slowly crystallized (1.23 g, 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]([CH:12]=O)=[CH:10][S:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[NH2:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:23][C:16]1[NH:15][C:16]([CH3:23])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]([C:11]2[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][C:8]=3[S:9][CH:10]=2)[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: O=Cc1csc2cc([N+](=O)[O-])ccc12
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1csc2cc([N+](=O)[O-])ccc12
Yield: 38.5 %

Procedure:
Following the procedure of Example 16C, 0.5 g of 6-nitrobenzo[b]thiophene-3-carboxaldehyde and 0.7 g of ethyl 3-aminocrotonate were reacted to provide 0.4 g of the desired title product, m.p. 191°-194° C.