Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH2:33](I)[CH2:34][CH2:35][CH2:36][CH3:37]>C(OCC)(=O)C>[CH2:33]([O:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6](=[O:19])[C:7](=[CH:9][C:10]3[CH:18]=[CH:17][C:16]4[O:15][CH2:14][O:13][C:12]=4[CH:11]=3)[O:8][C:4]=2[CH:3]=1)[CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C1C(=Cc2ccc3c(c2)OCO3)Oc2cc(O)ccc21
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCOc1ccc2c(c1)OC(=Cc1ccc3c(c1)OCO3)C2=O
Temperature: 25 °C

Procedure:
After 6-hydroxy-2-piperonylidene-3(2H)-benzofuranone 1 g and potassium carbonate 1.95 g were added to dimethylformamide 10 ml, n-pentyl iodide 0.79 ml was added, and the mixture was reacted at a temperature of 100° C. for two hours. After the solution was cooled to room temperature, ethyl acetate 200 ml was added. The ethyl acetate solution was washed with water 100 ml twice and a saturated sodium chloride solution 50 ml twice. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, and concentrated to 15 ml under reduced pressure. The precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.97 g.
Reaction SMILES: I[CH2:2][CH:3]1[S:7][CH2:6][CH:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1.[N-:12]=[N+:13]=[N-:14].C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[N:12]([CH2:2][CH:3]1[S:7][CH2:6][CH:5]([S:8][C:9](=[O:11])[CH3:10])[CH2:4]1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)SC1CSC(CI)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(=O)SC1CSC(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A solution, under argon, of 0.183 g of product from Example 140 in 1.0 ml of dry methylene chloride is treated with 0.689 g of tetra-n-butyl-ammonium azide. The reaction mixture is stirred vigorously overnight at room temperature. The reaction is concentrated in vacuo and the residue purified by chromatography (silica gel: 0-10% diethyl ether/hexane) to give 0.061 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH2:17][CH2:18][CH2:19][CH2:20]Cl)[CH:3]=1.[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24]>C(Cl)Cl>[CH2:22]([N:25]([CH2:20][CH2:19][CH2:18][CH2:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24]
Reactant: CCCNCCC
Reactant: ClCCCCc1cc(Cl)ccc1OCCc1ccccc1
Solvent: ClCCl
Product: CCCN(CCC)CCCCc1cc(Cl)ccc1OCCc1ccccc1
Temperature: 120 °C
Reaction time: 38 h

Procedure:
To 0.91 g of the crude 4-chloro-2-(4-chlorobutyl)-1-(2-phenylethoxy)benzene, was added 10 ml of di-n-propylamine and the resulting mixture was stirred at 120° C. for 38 hours. After diluting with methylene chloride, the mixture was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the obtained residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate:n-hexane =1:6) to give 1.07 g of N,N-di-n-propyl-4-[5-chloro-2-(2-phenylethoxy)phenyl]butylamine. To a solution of 1.07 g of N,N-di-n-propyl-4-[5-chloro-2-(2-phenylethoxy)phenyl]butylamine in 10 ml of ethanol, was added a solution of 123 mg of oxalic acid in 5 ml of ethanol. After evaporation of the solvent under reduced pressure, the obtained crystals were recrystallized from ethyl acetate to give 421 mg of N,N-di-n-propyl-4-[5-chloro-2-(2-phenylethoxy)phenyl]butylamine oxalate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]=O)=[O:4].[OH2:14].[OH-].[K+]>CO>[OH:4][C:3]1[C:2]([OH:14])=[CH:12][C:7]2[C:6](=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1
Reactant: O=Cc1ccccc1NC(=O)CCl
Reactant: O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Oc1cc2ccccc2nc1O
Temperature: 25 °C
Yield: 26 %

Procedure:
2-Chloro-N-(2-formyl-phenyl)-acetamide (960 mg) was dissolved in a mixed solvent composed of water (60 ml) and methanol (24 ml) at 100° C. A 10% aqueous potassium hydroxide solution (12 ml) was added dropwise to the solution and was then heated under reflux for one hr. The reaction solution was cooled to room temperature, methanol was then removed under the reduced pressure, and the residue was neutralized with a 1 N aqueous hydrochloric acid solution. The precipitate was collected by filtration, was washed with ethyl acetate, and was dried under the reduced pressure to give 2,3-dihydroxyquinoline (450 mg, yield 26%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:3]=1[Cl:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Cl:20][C:3]1[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5][C:6]2[C:11]([C:2]=1[C:25]1[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=1)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2
Reactant: Oc1ccc(-c2nc3ccc(O)cc3c(Br)c2Cl)cc1
Reactant: OB(O)c1ccc(F)cc1
Product: Oc1ccc(-c2nc3ccc(O)cc3c(-c3ccc(F)cc3)c2Cl)cc1
Yield: 95 %

Procedure:
This compound was prepared from 35a and 4-fluorophenylboronic acid according to method P. White solid; Yield: 95%; mp 295–296° C.; 1H-NMR (300 MHz, DMSO-d6) δ 6.55 (d, J=2.6 Hz, 1H), 6.87 (d, J=8.6 Hz, 2H), 7.31 (dd, J=9.1, 2.6 Hz, 1H), 7.45 (m, 4H), 7.57 (d, J=8.6 Hz, 2H), 7.92 (d, J=9.1 Hz, 1H), 9.73 (s, 1H), 10.07 (s, 1H); MS (ESI) m/z 364/366 ([M−H]−), 366/368 ([M+H]+); Anal. Calcd for C21H13ClFNO2: C: 68.96, H: 3.58, N: 3.83. Found: C: 68.19, H: 3.56, N: 3.74.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:22])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:22][C:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:37])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2ncccn2)CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g (0.66 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(pyrimidin-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.18 mL (1.32 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.11 g (0.73 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for one hour at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.21 g (68%) as a white solid; mp=121-123° C.; MS (+) ESI m/z=414 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:37])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:41](OC(=O)C)(=[O:43])[CH3:42]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:37][C:41](=[O:43])[CH3:42])[CH2:16][N:17]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2([CH3:29])[CH2:26][C:25]3[C:20](=[CH:21][C:22]([CH3:28])=[C:23]([CH3:27])[CH:24]=3)[CH2:19]2)=[CH:11][C:10]=1[N+:38]([O-:40])=[O:39])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(cc1C)CC(C)(N(Cc1ccccc1)C[C@H](O)c1ccc(OCc3ccccc3)c([N+](=O)[O-])c1)C2
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CN(Cc1ccccc1)C1(C)Cc2cc(C)c(C)cc2C1)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
To a solution of (R)-1-(4-Benzyloxy-3-nitro-phenyl)-2-[benzyl-(2,5,6-trimethyl-indan-2-yl)-amino]-ethanol in pyridine is added acetic anhydride and the mixture stirred for 18 hours. The reaction mixture is quenched with water and after addition of ethyl acetate washed twice with aqueous KHSO4 solution, twice with aqueous NaHCO3 and once with brine. The product is purified by chromatoghaphy (silica, ethyl acetate/hexane 1:4). ES+ MS m/e 579 (MH+)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](Cl)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-].[CH:16]#[CH:17]>[N+](C)([O-])=O>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:8])[C:16]#[CH:17]
Reactant: C#C
Reactant: O=C(Cl)CCCCC(F)(F)F
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Product: C#CC(=O)CCCCC(F)(F)F

Procedure:
The acetylenic ketones HC≡CCOCR2R3 (CH2)pQ can be prepared by several alternate routes analogous to those described for preparation of the corresponding vinyl ketones. For example (Method 1) propiolaldehyde is treated with the ##STR236## Grignard reagent derived from Q(CH2)pCR2R3X where X is halogen, preferably chlorine, affording an acetylenic carbinol which in turn is oxidized with chromic acid to the acetylenic ketone. Care must be taken that the aldehyde be added very slowly to cold Grignard reagent lest the aldehyde undergo extremely vigorous decomposition or polymerization. Method (2) involves addition of excess acetylene to an acyl chloride in the presence of a Friedel-Crafts catalyst such as aluminum chloride. Finally, in Method (3) sodium acetylide is allowed to react with a suitable aldehyde to afford an acetylenic carbinol, which in turn is oxidized by chromic acid to give the acetylenic ketone. Of these three methods (2) and (3) are usually the most satisfactory. Thus 6,6,6 trifluorohexanoic acid chloride (prepared via adipic acid monomethyl ester and SF4) reacts smoothly as its complex with aluminum chloride in nitromethane with excess acetylene (Method 2) to give a good yield of 8,8,8-trifluoro-1-octyn-3-one. Likewise, the acid chloride of 4 (p-chlorophenyl)butyric acid gives 6-(p-chlorophenyl)-1-hexyn-3-one. Hexaldehyde readily reacts with acetylene in glyme in the presence of powdered KOH to give an acetylenic carbinol which in turn is oxidized by a solution of CrO3 in water and sulfuric acid to 1-octyn-3-one (Method 3).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:17][CH3:18])=[O:10])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(O)cc1

Procedure:
4-Hydroxyphenylacetic acid (50.0 g) is dissolved in ethanol (400 ml) and thereto is added conc. sulfuric acid (0.5 ml). The mixture is refluxed with stirring, and ethanol is distilled off to give ethyl 4-hydroxyphenylacetate (60 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].[CH2:12]([NH:14][CH2:15][C:16](O)=[O:17])[CH3:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:16](=[O:17])[CH2:15][N:14]([CH2:12][CH3:13])[C:10]1=[S:11]
Reactant: CCNCC(=O)O
Reactant: S=C=Nc1c(Cl)cccc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2c(Cl)cccc2Cl)C1=S
Yield: 45 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 10.2 g of 2,6-dichlorophenyl-isothiocyanate, 7.4 g of N-ethyl glycine, 10 g of triethyl amine, and 250 mL of chloroform. Purification was achieved through crystallization from ethanol. The title compound (6.5 g) was obtained as a tan solid, m.p. 170°-172° C. Anal. Calcd. for. C11H10C12N2O S: C, 45.69; H, 3.48; N, 9.69. Found: C, 45.53; H, 3.19; N, 9.62. Mass spectrum (El, M.+) m/z 288/290/292.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[P:12](Cl)([Cl:14])[Cl:13].P(Cl)(Cl)(Cl)=O>>[Cl:13][P:12]([Cl:14])[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1
Reactant: Clc1ccccc1
Reactant: ClP(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(P(Cl)Cl)cc1

Procedure:
To a suspension of 53.3 g (0.4 mol) of aluminium chloride in 40 ml (0.39 mol) of chlorobenzene, 104.8 ml (1.2 mol) of phosphorus trichloride are added dropwise at ambient temperature. The reaction mixture is refluxed for three hours. Then within 30 minutes 37.2 ml (0.4 mol) of phosphorus oxychloride are added dropwise at 83° C. After 12 hours at ambient temperature the residue is stirred with petroleum ether and decanted off. The combined organic extracts are distilled under high vacuum at 57-61° C. and 0.048-0.035 mbar.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([Cl:18])=[C:5]([CH2:9][N:10]2[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[CH2:12][O:11]2)[CH:6]=[CH:7][CH:8]=1.N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>O>[N:2]([C:3]1[C:4]([Cl:18])=[C:5]([CH2:9][N:10]2[C:14](=[O:15])[C:13]([CH3:16])([CH3:17])[CH2:12][O:11]2)[CH:6]=[CH:7][CH:8]=1)=[N+:23]=[N-:24]
Reactant: CC1(C)CON(Cc2cccc(N)c2Cl)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CON(Cc2cccc(N=[N+]=[N-])c2Cl)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
Concentrated hydrochloric acid (25 ml) was added dropwise to a stirred mixture of 2-[(3-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone (6.45 g, 0.025 mole) and water (75 ml). The reaction mixture was cooled to 0° C., and a solution of sodium nitrite (2.0 g, 0.03 moles) in water (25 ml) was added dropwise. Upon completion of addition, the reaction mixture was stirred at 0° C. for 30 minutes. An insoluble material was removed by filtration. The filtrate was cooled to 0° C., and sodium azide (1.6 g, 0.025 mole) was added portionwise. Upon completion of addition, the reaction mixture was stirred for 15 minutes. The reaction mixture was diluted with water (500 ml) and extracted with methylene chloride (3×100 ml). The dried (sodium sulfate) methylene chloride extract was concentrated under reduced pressure to yield 5.3 g of 2-[(3-azido-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone as a brown oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:12](Cl)([Cl:14])=[O:13].C(N(CC)C1C=CC=CC=1)C>C(OCC)(=O)C>[C:12]([Cl:14])(=[O:13])[O:11][C:8]1[CH:9]=[CH:10][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: CC(=O)Nc1ccc(O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CC(=O)Nc1ccc(OC(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 4-acetominophenol (75.0 g), phosgene solution (450 mL, 20% in toluene), and ethyl acetate (1875 mL) was cooled to 0° C. N,N-Diethylaniline (94.7 mL) was added dropwise and the reaction was stirred at 0° C. for two hours. The reaction was then allowed to warm to room temperature. An aliquot for NMR analysis was taken four hours post addition. The reaction remained incomplete and was stirred at room temperature overnight. An-aliquot for NMR analysis after overnight stirring indicated no change had occurred in the reaction since the previous aliquot. The reaction was heated to 40° C. until phosgene gas evolution ceased (approximately 30 minutes). The reaction was cooled to room temperature and was then filtered. The filter cake was washed with ethyl acetate. NMR analysis of the filtered solid indicated it was N,N-diethylaniline related material. The filtrate was washed was washed with 0.1N HCl (375 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a pale yellow solid. The solid was triturated using ether (375 mL) for twenty minutes at room temperature. The solid was filtered and washed with ether. NMR analysis indicated product with residual ether remaining. The solid was dried overnight in a vacuum oven at ambient temperature to afford 77.55 g (73.3% yield). NMR and MS analysis indicated product. 1H NMR (300 MHz, CDCl3+DMSO-d6): δ 9.18 (s, 1H), 7.62 (d, 2H), 7.15 (d, 2H), 2.18 (s, 3H); MS m/z: 214 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]=O)[N:6]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH:11]=[N:2][OH:3])[N:6]=1
Reactant: O=Cc1nccc(Cl)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=Cc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Hydroxylamine hydrochloride (244 mg, 3.51 mmol), 4-chloropyrimidine-2-carboxaldehyde (500 mg, 3.51 mmol), and sodium acetate (288 mg, 3.51 mmol) were dissolved in dry ethanol (17.5 mL) and transferred to a flame-dried round bottom flask. The reaction was allowed to stir at room temperature for 20 minutes. It was then concentrated under reduced pressure, redissolved in ethyl acetate, and washed with water. The aqueous layer was extracted with ethyl acetate two times. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH:3]1[OH:8].[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](Cl)=[CH:12][C:11]=1[Cl:20].C(N(CC)CC)C>C(O)(C)(C)C>[Cl:9][C:10]1[C:11]([Cl:20])=[CH:12][C:13]([NH:1][CH:2]2[CH2:6][CH2:5][CH:4]([OH:7])[CH:3]2[OH:8])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: NC1CCC(O)C1O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NC1CCC(O)C1O

Procedure:
(±)-(1R*, 2S*, 3R*)-3-Amino-1,2-cyclopentanediol (7.10 g, 50.0 mmol), 1,2,4-trichloro-5-nitrobenzene (11.67 g, 50.0 mmol as 97%, Aldrich), triethylamine (10 mL) and t-butanol (50 mL) were refluxed under nitrogen for 7 hours. Volatiles were removed in vacuo and the black residue chromatographed on silica gel. Title compound was eluted with methanol:chloroform/1:24 as an orange solid (6.45 g, 42%). Crystallization of such a sample from ethanol-water gave title compound as yellow needles, m.p. 137°-140° C.; 1H-NMR (DMSO-d6)δ: 8.26 and 7.49 (both s, 1 each, 2 aromatic CH), 8.06 (d, J=7.0 Hz, 1, NH), 5.04 (d, J=6.1 Hz, 1, OH), 4.65 (d, J=4.1 Hz, 1, OH), 4.0-3.7 (m, 3, 2 OCH and NCH), 2.2-2.21, 2.0-1.8, 1.7 -1.3 (all m, 4, 4 CH).
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@@H:27]([CH3:29])[C@@H:25]([OH:26])[C@@H:23]([OH:24])[C@@H:21]1[OH:22])[CH2:2][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][CH2:17][CH3:18].[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>C(Cl)Cl.CO>[CH:20]1([N:19]([CH2:1][CH2:2][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][CH2:17][CH3:18])[C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:28][C@@H:27]([CH3:29])[C@@H:25]([OH:26])[C@@H:23]([OH:24])[C@@H:21]1[OH:22]
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCCCCCC)C1O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]1O

Procedure:
2.9 g of the compound from Example 23 were acylated with oleoyl chloride as described in Example 6. Column chromatography with the eluting agent CH2Cl2 /CH3OH=15/1.
Reaction SMILES: [NH2:1][C:2]1([C:11]#[N:12])[CH2:7][CH2:6][C:5]([F:10])([CH2:8][OH:9])[CH2:4][CH2:3]1.C(Cl)Cl.[C:16](Cl)(=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[C:11]([C:2]1([NH:1][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3][CH2:4][C:5]([F:10])([CH2:8][OH:9])[CH2:6][CH2:7]1)#[N:12]
Reactant: N#CC1(N)CCC(F)(CO)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: N#CC1(NC(=O)OCc2ccccc2)CCC(F)(CO)CC1
Reaction time: 8 h
Yield: 60.4 %

Procedure:
A flask was charged with 1-amino-4-fluoro-4-(hydroxymethyl)cyclohexanecarbonitrile, Intermediate 32, (12.2 g, 70.8 mmol), CH2Cl2 (200 mL), water (80 mL) and benzyl chlorocarbonate (12.14 mL, 85 mmol) and the mixture stirred under nitrogen overnight. The CH2Cl2 portion of the reaction mixture was separated, washed with water then brine, dried (MgSO4) and concentrated to give a yellow oil. The oil was purified by column chromatography on silica gel, eluted with hexane/ethyl acetate (0 to 100%). The appropriate fractions were combined and the solvent evaporated to provide the title compound (13.1 g, 42.8 mmol, 60.4% yield)] as a colorless oil that crystallized upon standing.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O.COCCO.OO>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CC=O
Reactant: CC(C)=CCO
Agent: OO
Solvent: O
Solvent: COCCO
Product: CC(C)=CCCC(C)=CC=O
Yield: 88 %

Procedure:
A mixture of 100 parts of 3-methyl-2-buten-1-ol, 100 parts of 3,3-dimethylacrolein, 200 parts of ethylene glycol monomethyl ether and 3 parts of 30% aqueous hydrogen peroxide solution is heated under reflux for six hours while stirring and the water formed is removed continuously using pentane as entrainer. Fractional distillation of the reaction product gives 84.5 parts of citral, equivalent to a yield of 88% of theory, at a conversion of 53% (based on 3,3-dimethylacrolein).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([Br:41])[CH:35]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([Br:41])[CH:35]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccc(O)c(Br)c1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Br)c3)n2)c1)S(C)(=O)=O

Procedure:
Intermediate 4 was coupled to 4-(2-amino-ethyl)-2-bromo-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 634. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 8.1 (m, 1H) 8.0 (d, 1H) 7.5 (m, 3H) 7.4 (s, 1H) 7.1 (m, 2H) 6.9 (d, 1H) 4.9 (m, 1H) 4.5 (s, 2H) 3.8 (m, 2H) 2.9 (m, 5H) 1.6 (m, 2H) 1.4 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C#N)c2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C#N)c2)CC1

Procedure:
tert-Butyl 4-(3-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g, 3.52 mmol) was combined with 20% Pd(OH)2/C (1 g) in 25 mL of methanol. This mixture was stirred under a hydrogen atmosphere using a hydrogen filled balloon for 5 h. The reaction mixture was filtered through a celite plug and the filtrate was concentrated. Purification by MPLC (silica, 38% ethyl acetate/hexanes) gave tert-butyl 4-(3-cyanophenyl)piperidine-1-carboxylate. ESI-MS calc. for C17H22N2O2: 286; Found: 309 (M+Na+).