Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:16].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([F:39])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:16]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
n-Butyl lithium (2.5M/Hexanes, 3.83 ml; 9.575 mmol) added dropwise to solution of diisopropylamine (1.36 ml; 9.62 mmol) at −78° C. Solution was allowed warm to room temperature and stirred for 30 minutes, then cooled to −78° C. A solution of Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2 g, 8.72 mmol) in THF (10 ml) was added dropwise, warmed to −40° C. for 1 hour, then cooled to −70° C. A solution of N-fluorobenzene-sulfonimide (3.02 g, 9.57 mmol) in THF (15 ml) was added dropwise, stirred at −78° C. for 1 hour, then stirred at room temperature overnight. Precipitated solid was filtered, washed with EtOAc (2×150 ml). Organic layer was washed with 1 N HCl (30 ml), brine (100 ml), dried (MgSO4), filtered and solvent evaporated. The residue was chromatographed on silica gel eluting with 10% v/v EtOAc/hexanes yielding product as colorless oil (1.38 g:64% yield). MS (ESMS, MH 249).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([O:13][CH2:14][CH2:15]Br)=[CH:11][CH:10]=1)C1C=CC=CC=1.[ClH:19].[F:20][C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=1[CH2:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:19].[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:27]2[CH2:28][CH2:29][CH:24]([CH2:23][C:22]3[CH:30]=[CH:31][CH:32]=[CH:33][C:21]=3[F:20])[CH2:25][CH2:26]2)=[CH:17][CH:18]=1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Reactant: Fc1ccccc1CC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Oc1ccc(OCCN2CCC(Cc3ccccc3F)CC2)cc1

Procedure:
The title compound was prepared from 2-(4-benzyloxyphenoxy)ethyl bromide (0.393 g, 1.28 mmol), 4-(2-fluorobenzyl)piperidine hydrochloride (0.294 g, 1.28 mmol) and potassium carbonate (0.442 g, 3.2 mmol) in two steps as an off white solid (0.237 g), mp 196-198° C. 1H NMR (CD3OD) 1.629 (m, 2 H), 1.900 (m, 3 H), 2.704 (m, 2 H), 3.052 (m, 2 H), 3.500 (m, 2 H), 3.612 (m, 2 H), 4.252 (m, 2 H), 6.703 (d, J=9. 0 Hz, 2 H), 6.825 (6, J=9.0 Hz, 2 H), 7.057-7.248 (m, 2 H), 7.248 (m, 2 H). Anal. Calcd for C20H25ClFNO2.1.2H2O: C, 61.70; H, 7.15; N, 3.60. Found: C, 61.45; H, 6.90; N, 3.53.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:14]=[C:13]([CH2:15][C:16]([O-:18])=O)[O:12][N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[C:1]([O:9][C:10]1[CH:14]=[C:13]([CH2:15][C:16]([Cl:23])=[O:18])[O:12][N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])Cc1cc(OC(=O)c2ccccc2)no1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1cc(OC(=O)c2ccccc2)no1
Reaction time: 0.5 h

Procedure:
0.59 g of sodium (3-benzoyloxyisoxazol-5-yl)acetate was suspended in 5 ml of methylene chloride, and 0.37 ml of oxalyl chloride were then added, with ice-cooling. After adding one drop of N,N-dimethylformamide, the mixture was stirred for 30 minutes. The solvent was then distilled off under reduced pressure to give (3-benzoyloxyisoxazol-5-yl)acetyl chloride, which was then dissolved in 5 ml of methylene chloride. This solution was added dropwise to a solution of 685 mg of benzhydryl 3-acetoxymethyl-7β-amino-7α-methoxy-3-cephem-4-carboxylate and 325 mg of N,N-diethylaniline in 5 ml of methylene chloride, maintaining the internal temperature at about -10° C. After stirring the mixture at a temperature between -10° C. and -5° C. for 45 minutes, the reaction mixture was evaporated to dryness under reduced pressure and the residue was adsorbed on a silica gel preparative thin layer chromatograph and developed by a 2:1 by volume mixture of benzene and ethyl acetate. The portion having an Rf value of 0.54 was extracted to give 660 mg (64.7%) of the benzhydryl ester of the desired Compound No. 4.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[Cu](C#N)[C:11]#[N:12].[C-]#N.[Na+]>CN(C)C=O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:11]#[N:12])=[N:3][CH:4]=1
Reactant: Cc1cc(Br)ncc1Br
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ncc1Br
Temperature: 158 °C
Yield: 73 %

Procedure:
2,5-Dibromo-4-methylpyridine (5.0 g, 19.9 mmol), copper cyanide (1.43 g, 15.9 mmol), sodium cyanide (0.801 g, 16.3 mmol) and dimethylformamide (30 mL) were combined in a sealed reaction vessel and heated at 158° C. for 3 h. The reaction mixture was purified by silica gel column chromatography (0-80% ethyl acetate in hexanes). The resulting material was subjected to a second silica gel column (0-20% methanol in dichloromethane). Clean fractions were combined and concentrated to afford the title compound as a white solid (2.30 g, 11.6 mmol, 58% yield). MS (ESI) m/z 198.0 [M+1]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]([C:15]2[CH:16]=[C:17]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)=[CH:12][CH2:13]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)Cl>[C:5]1([C:11]([C:15]2[CH:16]=[C:17]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=2)=[CH:12][CH2:13][Cl:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)c1cccc(C(=CCO)c2ccccc2)c1
Solvent: ClCCl
Product: CC(C(=O)O)c1cccc(C(=CCCl)c2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of 18.5 g of dry thionyl chloride in 30 mL methylene chloride was added, along 1 hour, to a solution of 41.7 g of 2-[3-(1-phenyl-3-hydroxy-1-propenyl)phenyl]propionic acid in 60 mL of the same solvent, kept at 5-10° C. After standing for 1 hour, volatile materials were removed under vacuum. The oily residue, mainly formed by the title compound, was used in subsequent reactions without further purification. IR Spectrum (film), cm-1 : 3400-2600, 1710, 1600, 1490, 1410, 1245, 1230, 1070, 790, 770, 700.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[CH2:5].I[CH3:16]>O1CCCC1.O>[CH2:3]([O:6][N:7]([CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCON(C)C(=O)OC(C)(C)C
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Sodium hydride (NaH, 60% dispersion in mineral oil; 390 mg, 9.7 mmol, 1.1 equiv) was added to a stirred solution of tert-butyl 2-propenyloxycarbamate (2.0 g, 8.8 mmol, 1.0 equiv) in tetrahydrofuran (THF; 23 mL) at 0° C. The resulting bubbling white mixture was warmed to 23° C. and stirred for 15 minutes (min). Iodomethane (660 μL, 11 mmol, 1.2 equiv) was added and the resulting colorless solution was stirred at 23° C. for 18 h. The reaction mixture was diluted with H2O (100 mL) and extracted with CH2Cl2 (3×75 mL). The combined organic layers were dried over magnesium sulfate (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford a yellow oil (1.6 g, 99%): 1H NMR (300 MHz, CDCl3) δ 5.98 (m, 1H), 5.37-5.24 (m, 2H), 4.33 (dt, J=6, 1 Hz, 2H), 3.10 (s, 3H), 1.49 (s, 9H).
Reaction SMILES: [OH-:1].[Na+].Cl.[CH:4]1[CH:5]=[CH:6][C:7]2[C:13](C3C=CC(O)=CC=3)(C3C=CC(O)=CC=3)OC(=O)[C:8]=2[CH:9]=1.[CH2:28]([OH:30])[CH3:29]>>[CH:29]([C:28]([OH:1])=[O:30])=[CH:13][C:7]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: O=C1OC(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: O=C(O)C=Cc1ccccc1

Procedure:
Titration was effected by suspending the product (0.500g) in 95% ethanol (50 ml.) adding 0.5M sodium hydroxide (50 ml.), warming the mixture to reflux, cooling and back titrating with 0.5M hydrochloric acid using phenolphthalein as the indicator; it was found that 47.12 ml. of acid were required for neutralisation indicating 2.88 m.mole carboxyl/g of polymer.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14](O)=[O:15])[N:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:9]=[CH:8]2.C1C=CC2N(O)N=[N:32]C=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:48][O:49][C:50]1[CH:74]=[CH:73][C:53]([CH2:54][N:55]([CH:70]([CH3:72])[CH3:71])[CH2:56][CH2:57][C@H:58]([C:63]([O:65][C:66](C)(C)C)=[O:64])C(OC)=O)=[CH:52][CH:51]=1.C(N(CC)CC)C>ClC(Cl)C.ClCCl>[CH3:48][O:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:54][N:55]([CH:70]([CH3:71])[CH3:72])[CH2:56][CH2:57][C@H:58]([NH:32][C:14]([C:13]2[CH:12]=[C:11]3[C:7]([CH:8]=[N:9][N:10]3[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:6][C:5]=2[O:4][C:3]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:2]=2[F:1])=[O:15])[C:63]([O:65][CH3:66])=[O:64])=[CH:73][CH:74]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)O)cc21
Reactant: COC(=O)[C@H](CCN(Cc1ccc(OC)cc1)C(C)C)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COC(=O)[C@H](CCN(Cc1ccc(OC)cc1)C(C)C)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.8 %

Procedure:
5-(2,4-Difluorophenoxy)-1-isobutyl-1H-indazole-6-carboxylic acid (17d; prepared according to Example 110) (0.022 g, 0.064 mmol) was stirred with HOBt (0.011 g, 0.070 mmol) and EDCI (0.014 g, 0.070 mmol) in dichloroethane (1 mL) for 10 minutes at room temperature. To this mixture was then added a suspension of (S)-methyl 4-((4-methoxybenzyl)(isopropyl)amino)-2-(tert-butoxycarbonyl)butanoate hydrochloride (0.025 g, 0.067 mmol) and triethylamine (0.054 mL, 0.384 mmol) in dichloromethane (2 mL). The mixture was stirred at room temperature for 16 hours. The solution was filtered through Celite and concentrated under reduced pressure. The crude oil was chromatographed eluting with 2% MeOH in dichloromethane with 1% triethylamine to provide 0.035 g of viscous pale yellow oil (89% yield).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:8]1[CH2:13][CH2:12][O:11]CC1.OO>C1COC(N2C(=O)NC(=O)C(F)=C2)C1.O>[C:1]1([CH:6]=[CH:5][C:4]([OH:8])=[CH:3][CH:2]=1)[OH:7].[C:13]1([C:12](=[CH:6][CH:1]=[CH:2][CH:3]=1)[OH:11])[OH:8]
Reactant: Oc1ccccc1
Reactant: C1COCCO1
Agent: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Agent: OO
Solvent: O
Product: Oc1ccc(O)cc1
Product: Oc1ccccc1O
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
A stirrer, a cooler and a temperature indicator were provided to a four-necked flask having an internal volume of 200 ml; to this flask, 13.0 g of phenol, 4.0 g of 1,4-dioxane, 6.0 g of water and 1.3 g of TS-1 catalyst, prepared according to the above described procedure, were added, and heated to 70° C. by an oil bath. After the temperature of the mixture reached 70° C., 3.0 g of 31 weight % of hydrogen peroxide was added dropwise using a quantitative pump over 2 hours, and stirred further for 20 minutes after the addition. The reaction solution was analyzed by liquid chromatography, and the yields of hydroquinone and catechol were calculated. The results are shown in Table 1.
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[C:8]([F:17])[CH:7]=2)[CH2:3][CH2:2]1.[CH3:25][C:26]1([CH3:29])[O:28][CH2:27]1>>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]([OH:28])([CH3:29])[CH3:27])[CH2:21][CH2:20]2)[C:5](=[O:18])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[C:8]([F:17])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(c1ccc(-c2cnco2)c(F)c1)N(C1CCNCC1)C1CC1
Reactant: CC1(C)CO1
Product: CC(C)(O)CN1CCC(N(C(=O)c2ccc(-c3cnco3)c(F)c2)C2CC2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-3-fluoro-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 1,1-dimethyloxirane following a procedure analogous to that described for Intermediate 2. LC (method 2): tR=0.98 min; Mass spectrum (ESI+): m/z=402 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[ClH:16]>C(O)C.C(O)(C)C.O=[Pt]=O>[ClH:16].[CH:9]1([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: Nc1ccccc1O
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: Oc1ccccc1NC1CCCCC1

Procedure:
A mixture of 10.9 g (0.1 mol) of 2-aminophenol and 10.4 g (0.1 mol) of cyclohexanone in 200 ml of ethanol is hydrogenated over 0.2 g of PtO2 under standard conditions, 0.1 mol of HCl in isopropanol is added to the reaction mixture, the catalyst is filtered off and the filtrate is evaporated in vacuo and the residue is precipitated with ether.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[C:21](Cl)=[O:22]>O1CCOCC1>[OH:4][CH2:3][CH:2]([NH:1][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([N+:27]([O-:29])=[O:28])=[C:18]([O:17][CH3:16])[CH:19]=1)[CH2:5][OH:6]
Reactant: NC(CO)CO
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC(CO)CO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2-amino-propane-1,3-diol (1 equiv) in 1,4-dioxane (0.062 M) was added DIEA (2 equiv) and a solution of 3-methoxy-4-nitrobenzoyl chloride (1 equiv) in 1,4-dioxane (1.86 M) dropwise at room temperature. The resulting mixture was stirred at room temperature for 15 min. The solution was concentrated and the crude material was triturated in a 5:1 mixture of water:DCM (0.5 M), filtered, and dried to afford the title compound the solid (85% yield) that was used in the next step without further purification. MS (ESI) m/z 271.1 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C>CO.O1CCOCC1>[CH:8]1([C:7]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)([O:20][CH3:21])[CH:2]([OH:1])[C:3]([O:5][CH3:6])=[O:4])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COC(=O)C(O)C(OC)(C1CCCCC1)C1CCCCC1
Reaction time: 30 h
Yield: 97 %

Procedure:
10 g (34.9 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate were dissolved in 50 ml each of methanol and glacial acetic acid, 1 ml of RuO(OH)2 in dioxane was added, and hydrogenation was carried out with H2 in an autoclave at 100° C. under 100 bar for 30 h. The catalyst was filtered off, the mixture was concentrated, mixed with ether and washed with NaCl solution, and the organic phase was dried and concentrated. 10,1 g of methyl 3,3-dicyclohexyl-2-hydroxy-3-methoxypropionate were obtained as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:8]2=[N:9][CH:10]=[C:11](SC)[N:12]=[C:7]2[CH:6]=1)=[O:4].O[O:25][S:26]([O-:28])=O.[K+].O1CCC[CH2:31]1>CO.O>[CH3:1][O:2][C:3]([C:5]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:8]2=[N:9][CH:10]=[C:11]([S:26]([CH3:31])(=[O:28])=[O:25])[N:12]=[C:7]2[CH:6]=1)=[O:4]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: COC(=O)c1cc2nc(SC)cnc2n1Cc1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2nc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a suspension of the compound obtained in Example 34 (7) (1.06 g) in tetrahydrofuran (40 ml), methanol (40 ml) and water (20 ml), OXONE (2.16 g) was added at 0° C. and the mixture was stirred at 15 to 30° C. for 4 hours. Further, OXONE (1.08 g) was added thereto and the mixture was stirred at 15 to 30° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated and poured into a saturated aqueous sodium hydrogencarbonate solution. The mixture was extracted with ethyl acetate, washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was then separated using silica gel column chromatography (ethyl acetate:hexane=1:2 and 2:1) to obtain 852 mg (73%) of the desired product as a pale yellow crystal.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[F:6][CH:7]([F:14])[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[F:6][CH:7]([F:14])[C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C:3]#[CH:2]
Reactant: CCCCC(=O)C(F)F
Reactant: C#CCBr
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(CCCC)C(F)F

Procedure:
To a stirred suspension of 3.6 g. of magnesium and 30 mg. of mercuric chloride in 0.33 ml. of ether is added 1.5 ml. of propargyl bromide. The mixture is stirred vigorously for several minutes to initiate reaction, then a solution of 15.5 g. of 1,1-difluoro-2-hexanone and 12.1 ml. of propargyl bromide in 33 ml. of ether is added slowly (dropwise) over a 1.5 hour period, so that the mixture remains gently refluxing (25°-30° C.). After addition, the mixture is stirred at room temperature for 30 minutes, then cooled in an ice bath to 0°-5° C. and quenched by adding 35 ml. of saturated ammonium chloride solution dropwise (exothermic) and stirred for 30 minutes. The mixture is filtered through Celite and washed with ether. The filtrate is concentrated in vacuo giving a yellow oil. This oil is vacuum distilled at 71° C., 12 mm giving the product as 10.54 g. of colorless oil which becomes pale yellow on standing at room temperature.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.Br[CH2:14][CH2:15][CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18]Br.C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(#N)C>[C:20]1([CH:16]2[CH2:17][CH2:18][N:2]([CH:3]3[CH2:4][CH2:5][CH:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]3)[CH2:14][CH2:15]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCC(CCBr)c1ccccc1
Reactant: COC(=O)C1CCC(N)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCC(N2CCC(c3ccccc3)CC2)CC1

Procedure:
A solution of 3.896 g (20.117 mM) of methyl 4-aminocyclohexanecarboxylate hydrochloride, 6.77 g (22.1 mM) of 1,5-dibromo-3-phenylpentane, and 14.0 ml (80.5 mM) of N,N-diisopropylethylamine in 100 ml of acetonitrile was refluxed for one day. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([OH:19])=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1.Cl.[N:31]1([CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:60]>C(Cl)Cl.C1CCCCC1.CO.C(Cl)(Cl)Cl>[ClH:60].[CH3:29][C:2]1([CH3:1])[C:21]2[CH2:22][CH2:23][N:24]([CH2:26][C:27]#[CH:28])[CH2:25][C:20]=2[C:5]2[C:6]([O:19][C:41](=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:7][C:8]([CH:10]([CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH3:11])=[CH:9][C:4]=2[O:3]1
Reactant: C#CCN1CCC2=C(C1)c1c(O)cc(C(C)C(C)CCCCC)cc1OC2(C)C
Reactant: O=C(O)CCCCN1CCCCC1
Reactant: ClCCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: C1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C#CCN1CCC2=C(C1)c1c(OC(=O)CCCCN3CCCCC3)cc(C(C)C(C)CCCCC)cc1OC2(C)C

Procedure:
A mixture of 2.4 g. (6.06 mm.) of 5,5-dimethyl-10-hydroxy-8-(3-methyl-2-octyl)-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-d]pyridine, 1.35 g. (6.06 mm.) of δ-piperidinovaleric acid hydrochloride and 1.30 g. (6.30 mm.) of dicyclohexylcarbodiimide in 100 ml. of methylene chloride was stirred at room temperature for 5 hours. The reaction mixture was cooled overnight in the refrigerator and the by-product of dicyclohexylurea removed by suction filtration. The mother liquor was evaporated to give a golden, viscous residue which was dissolved in a mixture of methylene chloride/cyclohexane and allowed to stand in the cold for 2 hours. Gravity filtration separated a small amount of solid which had appeared, and the solvents were removed using a rotary evaporator. Crystallization from methylene chloride/diethyl ether gave 2.5 g. (69%) of colorless crystals, m.p. 140°-144° C., The sample was pure by thin layer chromatography (10% MeOH/CHCl3) and the infrared and nuclear magnetic resonance spectra were in agreement with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH:7]([CH:19]1[CH2:24][C:23](=[O:25])[O:22][C:20]1=[O:21])=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CC>C[O-].[Na+]>[C:23]([OH:22])(=[O:25])[CH2:24][CH2:19][C:20]([OH:21])=[O:5].[CH:20]([CH:4]([OH:5])[CH:3]([OH:6])[CH:2]=[NH:1])=[CH:19][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: NCC(O)CO
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCCCC=CC(O)C(O)C=N
Product: O=C(O)CCC(=O)O
Temperature: 135 °C
Yield: 172.6 %

Procedure:
A 100 ml four necked round bottom flask equipped with a mechanical stirrer, thermometer, nitrogen inlet and short path distillation head was charged with 3-amino-1,2-propandiol (8.0 g, 8.78×10-2 mole), dodecenyl succinic anhydride (23.4 g, 8.78×10-2 mole) and sodium methoxide (0.05 g, 9.26×10-4 mole). The reaction mixture was heated to 135° C. for 6 hours under a mild nitrogen blanket giving 28.3 g (94.9% yield) of dodecenyl 3-imino-1,2-propanediol succinate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=1)=[O:4].[NH:15]1[CH2:20][CH2:19]O[CH2:17][CH2:16]1.[C:21](=O)(O)[O-].[Na+].C([O-])=O.[NH4+]>C1COCC1.C(Cl)Cl>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:15]2[CH2:20][CH2:19][CH2:21][CH2:17][CH2:16]2)=[N:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: C1COCCN1
Reactant: O=C(CCl)Nc1ccc([N+](=O)[O-])cn1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1ccc(NC(=O)CN2CCCCC2)nc1
Temperature: 25 °C
Yield: 63 %

Procedure:
Compound 20 (3.0 g, 13.9 mmol), was dissolved in THF (100 mL). Morpholine (20 mL, 229 mmol) was added and the mixture stirred at reflux for 1 hour. DCM (200 mL) and saturated aqueous sodium bicarbonate solution (200 mL) were added and the layers separated. The organic phase was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was dissolved in EtOH (200 mL) and 10% Pd/C (wet, ˜300 mg) followed by ammonium formate (880 mg, 14.0 mmol) added. The mixture was stirred at reflux for 1 hour. The mixture was cooled to rt, filtered through celite, washing the precipitate with EtOAc. The collected filtrate was diluted with saturated ammonium bicarbonate solution (100 mL) and the layers separated. The organic phase was dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was triturated with EtOAc-isohexane to afford the title compound as an off-white solid (2.1 g, 63%); (m/z): 237 [MH]+.