Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].CSC[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].[C:20](#N)C>O>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([S:3]([CH3:20])(=[O:5])=[O:2])=[C:11]([N+:17]([O-:19])=[O:18])[CH:12]=1
Reactant: CC#N
Reactant: CSCc1ccc(Br)cc1[N+](=O)[O-]
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
A suspension of oxone (7.94 g) in water (16 ml) was added to a solution of (4-bromo-2-nitrophenyl)methyl methyl sulfide (Intermediate 72) (0.52 g) in acetonitrile (20 ml). The mixture was stirred for 5 h filtered and the residue was washed with ethyl acetate. The biphasic filtrate was separated, the aqueous layer was re-extracted with ethyl acetate (2×50 ml) and the combined organic extracts were washed with aqueous sodium metabisulphite (5%, 100 ml) water and brine. The solution was dried using a hydrophobic filter tube then concentrated under vacuum to give the title compound (0.35 g).
Reaction SMILES: COC(=O)/C=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:7]=1.[BH4-].[Na+].C([OH:24])C>>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][OH:24])=[CH:7][CH:8]=2)[CH:14]=1
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ccc(Cc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.41 g of the aldehyde (prepared as described in Reference Example 1), 8 ml of ethanol and 78 mg of sodium borohydride was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, and a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a 4% V/V solution of ethanol in chloroform as eluent to give 0.33 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH:1]([CH:3]1[CH2:5][C:4]1([C:11]([O:13][CH2:14]C)=[O:12])[C:6]([O:8][CH2:9]C)=[O:7])=[O:2].C(C=C)=O.COC(=O)C(Br)C(OC)=O.CO>C(O)C>[CH:1]([CH:3]1[CH2:5][C:4]1([C:6]([O:8][CH3:9])=[O:7])[C:11]([O:13][CH3:14])=[O:12])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1C=O
Agent: C=CC=O
Agent: COC(=O)C(Br)C(=O)OC
Solvent: CO
Solvent: CCO
Product: COC(=O)C1(C(=O)OC)CC1C=O

Procedure:
By following the procedure of D. T. Warner, cited above, used for preparing diethyl 2-formylcyclopropane-1,1-dicarboxylate from acrolein but using equivalent amount of dimethylbromomalonate and methanol instead of diethylbromomalonate and ethanol, respectively, the title compound, nmr (CDCl3) δ 1.98 (m,2H), 2.80 (m,1H), 3.79 (s,6H), 8.82 (d, J=4 cps, 1H), is obtained.
Reaction SMILES: [F:1][C@@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][OH:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[F:1][C@@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][O:4][S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CCCCCC[C@H](F)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC[C@H](F)COS(=O)(=O)c1ccc(C)cc1
Yield: 98 %

Procedure:
Three grams of the obtained (S)-2-fluorooctane-1-ol, 4.5 g of p-toluenesulfonyl chloride and 50 ml of pyridine were stirred at room temperature. 100 ml of water and 200 ml of toluene were added to the solution. The organic layer was separated and washed with an acid solution, with an alkali solution and with water, dried over magnesium sulfate, and concentrated. 6.0 g of (S)-2-fluoro-1-p-toluenesulfonyloxyoctane was obtained.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:32]=[C:31]([O:33][Si](C(C)(C)C)(C)C)[CH:30]=[CH:29][C:28]=1[CH:41]1[CH2:46][CH2:45][CH:44]([C:47]([OH:49])=[O:48])[CH2:43][CH2:42]1)(C(C)(C)C)(C)C>O1CCCC1>[OH:26][C:27]1[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=1[C@H:41]1[CH2:42][CH2:43][C@H:44]([C:47]([OH:49])=[O:48])[CH2:45][CH2:46]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(C(=O)O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Reaction time: 24 h

Procedure:
Tetrabutylammonium fluoride (0.12 ml) was added to a stirred solution of 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanecarboxylic acid (22 mg) in tetrahydrofuran (1 ml) at room temperature under argon. After 24 hr, the reaction mixture was partitioned between ethyl acetate (30 ml) and water (30 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 7:1 v/v, <1% acetic acid) to give the title compound as an orange solid (10 mg, 89%). δH(CD3OD) 1.40-1.65 (4H, m), 1.88-1.95 (2H, m), 2.06-2.14 (2H, m), 2.35 (1H, tt), 2.82 (1H, it), 6.25-6.30 (2H, m), 6.90 (1H, d); m/z (ES−) 235 (M−H)−.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[C:1]([C:3](=[CH:15][N:16]([CH3:18])[CH3:17])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])#[N:2]
Reactant: N#CCC(=O)Nc1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)Nc1ccccc1

Procedure:
A 10.0 g. amount of 2-cyanoacetanilide in 25 ml. of N,N-dimethylformamide dimethylacetal is heated on a steam bath for 2-6 hours. The reaction mixture volatiles are removed in vacuo and the resultant solid is dissolved in dichloromethane. The solution is passed through a short column of hydrous magnesium silicate, then n-hexane is added to the effluent until crystallization is noted. After cooling, the product is collected by filtration to give 2-cyano-3-dimethylamino-acrylanilide as colorless plates, m.p. 162.5°-164° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]1([CH3:19])[O:16][C:15](=[O:17])[CH2:14][C:13](=[O:18])[O:12]1>O>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:14]2[C:15](=[O:17])[O:16][C:11]([CH3:19])([CH3:10])[O:12][C:13]2=[O:18])[CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cccc(O)c1
Solvent: O
Product: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Temperature: 85 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To 3-hydroxybenzaldehyde (available from Aldrich) (24.4 g, 200 mmol) in water (1000 mL) at 85° C., was added 2,2-dimethyl-1,3-dioxane-4,6-dione (available from Aldrich) (28.8 g, 200 mmol). The resulting mixture was then stirred at 85° C. for 2 hours. The reaction was allowed to cool and then filtered to provide 8.1 (41.3508 g, 83.3% yield) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:21]=[CH2:22])=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[C:15](=[CH:14][C:13]([C:17]([F:20])([F:18])[F:19])=[C:12]([CH2:21][CH3:22])[CH:11]=2)[CH2:16]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2
Agent: [Pd]
Solvent: CO
Product: CCc1cc2c(cc1C(F)(F)F)CN(C(=O)OC(C)(C)C)C2
Reaction time: 72 h
Yield: 20 %

Procedure:
To a stirred solution 0.54 mmol 5-trifluoromethyl-6-vinyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 50 ml methanol was added 50 mg 10% palladium on charcoal and the mixture was stirred under an atmosphere of hydrogen (0.6 bar positive pressure) for 72 h. The reaction mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (20% yield). MS (m/e): 260.0 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH:15]=[N:16][C:12]([CH3:11])=[N:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1nc[nH]n1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ncn(-c2ccc(Cl)cc2C=O)n1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
In a 25 ml RBF, a mixture of 5-chloro-2-fluorobenzaldehyde (505 mg, 3.09 mmol), 3-methyl-1H-1,2,4-triazole (270 mg, 3.09 mmol), Cs2CO3 (1007 mg, 3.09 mmol) in DMSO (6179 μl) was heated at 45° C. for 4 hrs and stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water. The combined organic phase was washed with brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography to yield 74A as white solid product (140 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.95 (s, 1H), 9.02 (s, 1H), 7.96-7.88 (m, 2H), 7.80 (d, J=8.4 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1.[C:24]([C:26]1[O:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1)#[N:25].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CO.ClCCl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:31]([C:29]3[O:30][C:26]([C:24]#[N:25])=[CH:27][CH:28]=3)=[O:32])=[C:10]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)ccc2[N+](=O)[O-])CC1
Reactant: N#Cc1ccc(C(=O)O)o1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: CC1CCN(c2cc(N3CCN(C)CC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 54 %

Procedure:
The procedure of Example 4, step (c) was followed using 50.2 mg (0.158 mmol) of 1-methyl-4-[3-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-piperazine (as prepared in the previous step), 20 mg of 10% palladium on carbon (50% by weight water), 22.8 mg (0.166 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 29.0 μL (0.332 mmol) of oxalyl chloride, and 57.8 μL (0.332 mmol) of DIEA. Chromatography on a 5-g silica SPE column with 0.5-3% MeOH-dichloromethane afforded 34.8 mg (54%) of the title compound as a light yellow solid: 1H-NMR (CDCl3; 400 MHz): o 9.59 (br s, 1H), 8.33 (d, 1H, J=8.9 Hz), 7.21, 7.25 (AB q, 2H, J=3.7 Hz, partially obscured by CHCl3 peak), 6.78 (d, 1H, J=2.7 Hz), 6.74 (dd, 1H, J=8.9, 2.7 Hz), 3.35-3.55 (m, 4H), 2.95-3.05 (m, 4H), 2.72-2.75 (m, 4H), 2.67 (br s, 3H), 1.83-1.87 (m, 2H), 1.45-1.65 (br m, 1H), 1.43-1.53 (m, 2H) and 1.07 (d, 3H, J=6.2 Hz), Mass spectrum (ESI, m/z): Calcd. for C23H29N5O2, 408.2 (M+H), found 408.3.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=1[O:31][CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[CH:1]([O:4][C:5](=[O:21])[NH:6][C@@H:7]1[CH2:20][C:10]2[N:11]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=3[O:31][CH3:32])[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2]
Reactant: COc1c(F)cccc1CCl
Reactant: CC(C)OC(=O)N[C@@H]1Cc2[nH]c3ccc(C#N)cc3c2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(F)cccc1Cn1c2c(c3cc(C#N)ccc31)C[C@H](NC(=O)OC(C)C)C2
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of (S)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester (1.50 g, 5.29 mmol) and 1-(chloromethyl)-3-fluoro-2-methoxybenzene (1.11 g, 6.35 mmol) in N,N-dimethylformamide (10 mL) is treated with cesium carbonate (2.59 g, 7.94 mmol) at room temperature and stirred overnight under nitrogen. The reaction mixture is diluted with water and ether/hexanes. The white solids that crash out of solution are filtered, rinsed with water, ether, hexanes, and dried under vacuum at 50° C. for 48 h to obtain the title compound as a white solid (2.18 g, 98%). LC-ES/MS m/z 422.2 [M+H]+, TR=4.57 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[N:3]1.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:13][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: BrP(Br)Br
Reactant: Cn1nc([N+](=O)[O-])cc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cn1nc([N+](=O)[O-])cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of (1-methyl-3-nitro-1H-pyrazol-5-yl)methanol (496 mg, 3.16 mmol) in chloroform (10 mL) at 0° C. was added phosphorus tribromide (854 mg, 0.30 mL, 3.16 mmol) drop wise via syringe. The resulting solution was warmed to room temperature and stirred for 1 h. The resulting solution was cooled to 0° C. and diluted with dichloromethane (50 ml). The resulting solution was made basic (pH 8.5) with saturated aqueous sodium bicarbonate (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo and the residue purified by flash chromatography (silica gel, 40 g, 20% to 40% ethyl acetate in hexanes) to give 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 63%) as a white solid.
Reaction SMILES: C([C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:10]=1[C:11]#[N:12])(=O)C1C=CC=CC=1.FC(F)(F)C(O)=[O:21]>C(Cl)Cl>[C:11]([C:10]1[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:9]=1[OH:21])#[N:12]
Reactant: N#Cc1c(Cl)cccc1C(=O)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(O)cccc1Cl
Yield: 67 %

Procedure:
2-Benzoyl-6-chlorobenzonitrile (10.0 g, 41 mmol) was dissolved in methylene chloride(40 ml) and trifluoroacetic acid(40 ml) and stirred at room temperature for 24 hrs. The reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CHCl2) gave the desired product(4.2 g, 67%). 1H NMR (CD3COCD3): δ10.31 (s,1H), 7.51 (t, 1H), 7.11 (d, 1H) 7.05 (d, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([C:11]([F:14])([F:13])[F:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:28]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C:2]([F:15])([F:1])[C:11]([F:13])([F:12])[F:14])=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(CC(F)(F)C(F)(F)F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)C(F)(F)Cc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
To a solution of 4-(2,2,3,3,3-pentafluoropropyl)toluene (9.97 g, 39.4 mmol) in carbon tetrachloride (300 ml) were added 2,2′-azobisisobutyronitrile (0.33 g, 197 mmol) and N-bromosuccinimide (8.50 g, 47.3 mmol) and the mixture was heated under reflux overnight. After cooling to room temperature, insoluble material was filtered off, and the filtrated was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0, 50:1, 20:1) to give 1-(bromomethyl)-4-(2,2,3,3,3-pentafluoropropyl)benzene (3.66 g, 31% (yield by two steps)) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:24][CH2:25]3)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reactant: c1ccc(CN2CCNCC2)cc1
Solvent: O
Solvent: ClCCl
Product: O=C(N1CCN(Cc2ccccc2)CC1)N1CC(Oc2ccc(F)cc2)C1
Reaction time: 18 h
Yield: 108.3 %

Procedure:
A stirred solution of 6.9 g (0.03 mole) of 3-(4-fluorophenoxy)-1-azetidinecarbonyl chloride in 60 ml of methylene chloride was treated with 10.8 g (0.06 mole) of 1-benzylpiperazine, added dropwise. After stirring for 18 hr, the reaction mixture was diluted with 200 ml of water and stirred for an additional 1 hr. The methylene chloride portion was separated and the aqueous portion was extracted with 2×25 ml of methylene chloride. The methylene chloride portions were combined, dried and concentrated in vacuo, yielding 12 g of oil residue. This oil solidified when triturated with ligroin and was recrystallized from benzene/ligroin to yield 10.1 (91%) of tan crystals. A 500 mg portion was recrystallized from benzene/ligroin to yield 250 mg of fine white crystals, m.p. 109°-111° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH2:16])[CH3:12].C(=O)([O-])[O-:20].[Na+].[Na+].[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27]>C(#N)C.CO>[OH2:20].[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27].[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH:16][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:12]
Reactant: BrCCCc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: CCN(CC)CCN
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CCN(CC)CCNCCCc1ccccc1
Product: O
Yield: 71.6 %

Procedure:
A mixture of 71.5 g (0.359 mole) of 3-bromo-1-phenylpropane, 82.0 g (0.707 mole) of N,N-diethylethylenediamine and excess sodium carbonate in 1 liter of acetonitrile was refluxed for 16 hr. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and diluted sodium hydroxide solution. The methylene chloride solution was dried over sodium sulfate, and the solvent was removed in vacuo to give an oil. This was dissolved in 1.5 liters of methanol, and a solution of 67.5 g (0.75 mole of oxalic acid in methanol was added. A white solid precipitated at room temperature to give 108.88 g (71.6%) of title compound, a white crystalline solid, mp 209°-211° C. with decomposition.
Reaction SMILES: [OH2:1].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]([CH:18]=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20][C:21]([NH2:34])([CH3:33])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1>CS(C)=O>[CH3:33][C:21]([N:34]=[C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:16][CH:18]=1)=[O:1])([CH3:20])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1
Reactant: O=CC(=O)c1ccccc1OCc1ccccc1
Reactant: COc1ccc(CC(C)(C)N)cc1OC
Reactant: O
Solvent: CS(C)=O
Product: COc1ccc(CC(C)(C)N=C(OCc2ccccc2)C(=O)c2ccccc2)cc1OC
Temperature: 20 °C
Reaction time: 2 h

Procedure:
570 mg of 2-benzyloxyphenylglyoxal hydrate are dissolved in 0.5 ml of dimethylsulfoxide, and a solution of 450 mg of α,α-dimethyl-3,4-dimethoxyphenethylamine in 0.7 ml of dimethylsufoxide is added thereto. The mixture is stirred at 20° C. for 2 hours, whereby a solution of α-(α,α-dimethyl-3,4-dimethoxyphenethylimino)-2-benzyloxyacetophenone in dimethylsufoxide is obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:8][CH:9]([CH3:25])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:14]=1)=[O:11]>>[OH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:22]1[CH2:23][CH2:24][CH:19]([C:15]2[CH:14]=[C:13]([NH:12][C:10](=[O:11])[CH:9]([CH3:8])[CH3:25])[CH:18]=[CH:17][CH:16]=2)[CH2:20][CH2:21]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: OCCCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCO)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 5-chloro-1-pentanol and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 333.3 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][C:20](Cl)=[O:21]>>[Br:18][CH2:19][C:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:21]
Reactant: O=C(Cl)CBr
Reactant: O=[N+]([O-])c1ccc(NCc2ccccc2)cc1
Product: O=C(CBr)N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-benzylamino-nitrobenzene and bromoacetyl chloride
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:20](=[O:28])[N:21]=[C:22]3[NH:27][CH:26]=[CH:25][N:23]3[CH:24]=2)=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:45]>>[ClH:45].[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:20](=[O:28])[N:21]=[C:22]3[NH:27][CH:26]=[CH:25][N:23]3[CH:24]=2)=[CH:17][CH:18]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1ccc(-c2cn3cc[nH]c3nc2=O)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCCNCc1ccc(-c2cn3cc[nH]c3nc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
{(3-{tert-Butoxycarbonyl-[4-(7-oxo-1,7-dihydro-imidazo[1,2-a]pyrimidin-6-yl)-benzyl]-amino}-propyl)-carbamic acid tert-butyl ester (48 mg, 0.097 mmol) was dissolved in CH2Cl2 (5 mL), TFA (1 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated and 3 mL of 0.6 N HCl and 2 mL of acetonitrile were added and stirred for 0.5 h, concentrated to a ca. 3 mL and lyophilized to give the title compound (35 mg, 100%). 1NMR (300 MHz, CD3OD): δ 8.90 (s, 1H), 7.79 (s, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.70 (d, J=8.2 Hz, 2H), 7.67 (s, 1H), 4.33 (s, 2H), 3.23 (t, J=8.1 Hz, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.15 (m, 2H). LCMS (EI) m/z: 297.1 (M+H+).
Reaction SMILES: C(O[C@H:5]1[C@H:10]2[C@H:8]([C:9]2([CH3:12])[CH3:11])[C:7](=[O:13])[O:6]1)(=O)C.Cl.[CH3:15][O:16][NH2:17].[OH-].[Na+].Cl>C(O)C>[CH3:12][C:9]1([CH3:11])[C@@H:10]([CH:5]=[N:17][O:16][CH3:15])[C@H:8]1[C:7]([OH:6])=[O:13]
Reactant: CON
Reactant: CC(=O)O[C@@H]1OC(=O)[C@@H]2[C@H]1C2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C[C@H]1[C@@H](C(=O)O)C1(C)C
Reaction time: 4 h

Procedure:
A 184 mg sample of (1R,4R,5S)-4-acetoxy-6,6-dimethyl-3-oxabicyclo[3.1.0]hexane-2-one in 2.5 ml of 60% aqueous ethanol was treated with 835 mg of methoxyamine hydrochloride and 40 mg of sodium hydroxide at room temperature. After 4 hours, the resulting mixture was acidified to pH 2 with dilute hydrochloric acid, and extracted with methylene chloride. The organic phase was dried (MgSO4) and stripped to yield 148 mg of the desired (1R,cis)-2,2-dimethyl-3-((methoxyimino)methyl)cyclopropanecarboxylic acid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([CH3:8])[CH:7]=1.[CH3:9][C:10]1[N:15]=[C:14]([SH:16])[N:13]=[C:12]([OH:17])[CH:11]=1>>[CH3:9][C:10]1[N:15]=[C:14]([S:16][CH2:2][C:3]2[N:4]=[CH:5][N:6]([CH3:8])[CH:7]=2)[N:13]=[C:12]([OH:17])[CH:11]=1
Reactant: Cn1cnc(CCl)c1
Reactant: Cc1cc(O)nc(S)n1
Product: Cc1cc(O)nc(SCc2cn(C)cn2)n1
Yield: 60 %

Procedure:
This example was synthesized from 4-(chloromethyl)-1-methyl-1H-imidazole and 6-methyl-2-sulfanylpyrimidin-4-ol following the general procedure as shown in the last step of Example 109. This provided the title compound as a white solid (260 mg, 60% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 3.60 (s, 3H), 4.24 (s, 2H), 5.97 (bs, 1H), 7.06 (s, 1H), 7.52 (s, 1H); M+237.