Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[O:22][CH2:23][C:24]#[N:25])=[CH:15][CH:14]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[O:22][CH2:23][C:24]2[NH:33][N:32]=[N:31][N:25]=2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1cccc(COc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cc(COc2ccc(OCc3ccc4ccccc4n3)cc2)cc(OCc2nnn[nH]2)c1

Procedure:
α-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile (8.12 mmol), sodium azide (24.4 mmol) and ammonium chloride (24.4 mmol) in dimethylformamide (10 ml) are heated at 115°-120° C. for 6 hrs. After cooling, the reaction mixture is diluted with ethyl acetate (150 ml), washed with water (6×100 ml) then dried and evaporated. The residue is chromatographed on a column of silica gel (360 g) and eluted with a gradient of isopropanol in methylene chloride to give 5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole (M.P. 131°-132° C.)
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18]Br.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC>CN(C)C=O>[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1
Reactant: COC(CBr)OC
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(CNc1ccc(Oc2ccccc2)cc1)OC
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 4-phenoxyaniline (915 mg) in dimethylformamide (5 ml) was mixed with bromoacetaldehyde dimethyl acetal (1.1 ml) and BEMP (1.9 ml). The reaction mixture was shaken at 100° C. for 16 hours. Volatiles were removed and the residue was purified by chromatography on silica gel (eluent: dichloromethane/hexane 1:2, later 1:1 with in each case 1% v/v 7N ammonia solution in methanol). The product with the molecular weight of 273.33 (C16H19NO3); MS (ESI): 274 ([M+H]+), was obtained in this way.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>O=S(Cl)Cl>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(Br)ccc1C(=O)OCc1ccccc1
Yield: 78.6 %

Procedure:
Using General Esterification Method C; 2-methyl-4-bromo-benzoic acid (2.15 g, 10.0 mmols) was refluxed for 3 h with 10 mL SOCl2. The resulting solution concentrated under reduced pressure and the crude acyl chloride was combined with benzyl alcohol (1.08 g, 10.0 mmols) and pyridine (1.6 mL, 20.0 mmols) to give the title compound (2.4 g, 80%) after work-up and column chromatography (2-5% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([O:13]C)=[O:12])([CH2:7][CH2:8]1)[CH2:5][CH2:4]2.Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]([OH:13])=[O:12])([CH2:5][CH2:4]1)[CH2:7][CH2:8]2
Reactant: COC(=O)C12CCC(OC)(CC1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COC12CCC(C(=O)O)(CC1)CC2
Yield: 97 %

Procedure:
Methyl 4-methoxybicyclo[2.2.2]octane-1-carboxylate (6.5 g, 33 mmol) was refluxed in aqueous sodium hydroxide solution (5%, 150 mL) for 2 h. After cooling down, the reaction solution was acidified with hydrochloric acid solution (6 N, 50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over magnesium sulfate and concentrated to afford the title compound (5.9 g, 32 mmol, yield 97%) which was used in the next step without further purification. MS (ESI) m/z=183.2 [M+H]−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8](Br)[S:7][CH:6]=1)=[O:4].C([Sn](CCCC)(CCCC)[C:16]1[O:17][CH:18]=[CH:19][N:20]=1)CCC>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:16]2[O:17][CH:18]=[CH:19][N:20]=2)[S:7][CH:6]=1)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: COC(=O)c1csc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1csc(-c2ncco2)c1
Temperature: 100 °C
Yield: 37.2 %

Procedure:
5-Bromo-thiophene-3-carboxylic acid methyl ester (0.3 g, 1.35 mmol) was dissolved in toluene (5 mL), 2-tributylstannyl oxazole (0.311 mL, 1.48 mmol) was added then the reaction mixture was purged with nitrogen before addition of palladium tetrakis(triphenylphosphine) (0.14 g, 0.12 mmol). The reaction mixture was heated at 100° C. over the weekend. The mixture was filtered then evaporated and the residue was purified by chromatography on a silica II cartridge, eluting with 10-20% DCM in pentane to give the title compound as a yellow solid (0.105 g). LCMS m/z 210 [M+H]+ and 251.23 [M+MeCN+H]+ R.T.=3.03 min (Analytical Method 6).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](OCC)=[O:12])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C>CCOCC.CCCCCC>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[CH2:11][OH:12])=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: OC/C=C/c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
(E)-Ethyl 3-(4-(trifluoromethyl)phenyl)acrylate (25.00 g, 102 mmol) in 100 mL ether was cooled in an ice-water bath. To this solution, di-iso-butylaluminum hydride (205 mL, 205 mmol) in hexane was added. After addition, the ice-water bath was removed. After 2 hours of stirring at room temperature, the reaction mixture was diluted with 200 mL diethyl ether, cooled to 0° C. and quenched with careful addition of 200 mL brine and 200 mL of 5.0 M HCl. The aqueous solution was extracted with diethyl ether twice (200 mL each time). The combined organic phases were washed with brine and dried over sodium sulfate. The product was chromatographed eluting with 20% EtOAc in hexane. After removing the solvent, a white solid was obtained as the desired product (15.3 g, yield=74%). 1H NMR (400 MHz, CD3OD) δ ppm 4.28 (dd, J=5.28, 1.57 Hz, 2H) 6.55 (dt, J=15.94, 5.23 Hz, H) 6.67-6.75 (m, 1H) 7.58-7.67 (m, 4H).
Reaction SMILES: N=O.[CH3:3][CH:4]([OH:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[O-]Cl.[Na+]>ClCCl>[CH3:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(C)O
Agent: N=O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCCCCC(C)=O
Reaction time: 3 h
Yield: 98.6 %

Procedure:
In a flask 0.072 g (0.05 mmol) of the product from example 1, 2.5 g (19.2 mmol) of 2-octanol and 10 ml of dichloromethane and 2.8 gr of KHCO3 (20% sol.) were added; the heterogeneous mixture was cooled to 10–15° C. then was dropped 13.8 g of an aqueous solution of NaOCl (10.5%). After 3 hours the crude organic layer was analyzed using GC: 98.6% of 2-octanone was obtained as desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:10][C@H:9]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH2:11]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]1Cc1ccccc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CNCc1ccccc1)Cc1ccccc1
Temperature: 100 °C
Yield: 99.7 %

Procedure:
The product from Example 70A (1.77 g, 7.6 mmol) in toluene (15 mL) was treated with benzylamine (8.4 mL, 76 mmol) in a sealed tube. After heating at 100° C. for 4 days, the mixture was allowed to cool to ambient temperature and was concentrated. The residue was dissolved in ethyl acetate (50 mL) and the ethyl acetate was washed with 10% citric acid (2×50 mL) and brine (50 mL). A precipitate fell out of the brine. The brine wash was filtered and the filter cake dissolved in ethyl acetate. All the ethyl acetate solutions were combined, wash with aqueous 10% NaHCO3 (2×100 mL), brine, (100 mL), dried over magnesium sulfate, filtered, and the filtrate was concentrated to provide the title compound as a white solid (2.58 g). 1H NMR (CDCl3) δ 7.49-7.12 (m, 10H), 4.98 (m, 1H), 4.00 (br s, 1H), 3.87 (q, 2H), 2.94-2.73 (m, 5H); MS (ESI+) m/z 341 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12](O)[C:11]=1[I:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[CH2:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([Cl:20])[C:11]=1[I:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc(COCc2ccccc2)c1I
Product: Clc1ncnc(COCc2ccccc2)c1I
Yield: 97 %

Procedure:
A solution of 6-benzyioxymethyl-4-hydroxy-5-iodo-pyrimidine (6.56 g, 1.9 mmol) dissolved in phosphorus oxychloride (200 ml) was stirred at reflux for 20 min. The POCl3 was removed under reduced pressure and the residue evaporated from toluene. The reddish residue was partitioned between ice-water and t-butyl methyl ether, then treated with NaHCO3, and the layers separated, and the aqueous layer was further extracted (×2). The combined organic extracts were washed twice with 5% sodium bicarbonate solution and once with brine, and then dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product as a brown oil (6.64 g, 97%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)[NH2:31]>>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([C:30]2[N:31]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:29]=2)[CH:33]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccnc3)no2)C1

Procedure:
250 mg (about 0.65 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 98 mg (0.71 mmol) of N′-hydroxypyridine-3-carboximidamide were reacted according to the General Method 1. Yield: 35 mg (11% of theory)
Reaction SMILES: [C:1]1([C:7]2([CH2:12][C:13]#[N:14])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:16]C1C=CC=CC=1C1C=CC=CC=1CC(N)=[NH:31]>>[ClH:16].[C:1]1([C:7]2([CH2:12][C:13]([NH2:31])=[NH:14])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(N)Cc1ccccc1-c1ccccc1Cl
Reactant: N#CCC1(c2ccccc2)CCCC1
Agent: Cl
Product: N=C(N)CC1(c2ccccc2)CCCC1
Yield: 77.7 %

Procedure:
2-(1-Phenyl-cyclopentyl)-acetamidine HCl salt (26-01) (4.2 g, 77.7%) was synthesized from (1-phenyl-cyclopentyl)-acetonitrile (25-01) (4.2 g, 22.703 mmol) as a white gummy solid as a crude product following the procedure as described for 2-(2′-chloro-biphenyl-2-yl)-acetamidine hydrochloride salt (5-02).
Reaction SMILES: C([NH:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][CH:15]([CH2:28][O:29][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)/[CH:16]=[CH:17]/[P:18]([O:24][CH:25]([CH3:27])[CH3:26])([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[C:7](Cl)[N:6]=1)(=O)C.[C:48](=O)(O)[O-:49].[Na+]>Cl>[NH2:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][CH:15]([CH2:28][OH:29])/[CH:16]=[CH:17]/[P:18]([O:20][CH:21]([CH3:23])[CH3:22])([O:24][CH:25]([CH3:27])[CH3:26])=[O:19])=[C:7]([O:49][CH3:48])[N:6]=1
Reactant: O=C([O-])O
Reactant: CC(=O)Nc1nc(Cl)c2ncn(CC(/C=C/P(=O)(OC(C)C)OC(C)C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2n1
Agent: Cl
Agent: [Na+]
Product: COc1nc(N)nc2c1ncn2CC(/C=C/P(=O)(OC(C)C)OC(C)C)CO
Yield: 72 %

Procedure:
A solution of (E)-2-acetamido-9-[2-(t-butyldiphenylsilyloxy)methyl-4-(diisopropoxyphosphoryl)but-3-enyl]-6-chloropurine (330 mg, 473 μmol) in 7% methanolic hydrogen chloride (15 ml) was stirred at room temperature for 7 h. The solution was reduced to 1/3 volume then neutralised by addition of saturated sodium bicarbonate solution. The solvent was removed and the residue purified by column chromatography on silica gel eluting with dichloromethane-methanol (19:1, 6:1) to give (E)-2-amino-9-[4-(diisopropoxyphosphoryl)-2-(hydroxymethyl)but-3-enyl]-6-methoxypurine as a colourless gum (140 mg, 72%); λmax (EtOH) 249 (8,632) and 283 (9,086)nm; υmax (KBr) 3335, 2980, 1610, 1585, 1475, 1410, 1400 and 1250 cm-1 ; δH [(CD2)2SO] 1.10 (12H, m, CH(CH3)2), 3.02 (1H, m, CH), 3.50 (2H, t, J 5 Hz, CH2O), 3.94 (3H, s, CH3O), 4.10-4.40 (4H, m, CH2N and CH(CH3)2), 4.97 (1H, t, J 5 Hz, D2O exchangeable, OH), 5.61 (1H, dd, J 17 Hz and 20 Hz, PCH=CH), 6.43 (2H, br.s, D2O exchangeable, NH2), 6.50 (1H, ddd, J 8 Hz, 17 Hz and 22 Hz, PCH=CH), 7.80 (1H, s, H-8) (Found: MH+ 414. 1900). C17H28N5O5P requires MH+ 414.1906).
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.[Li]CCCC.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH2:21][C:20]2=O.O>C1COCC1>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][C:3]1=[C:20]1[C:19]2[C:24](=[CH:25][CH:26]=[C:17]([F:16])[CH:18]=2)[O:23][CH2:22][CH2:21]1
Reactant: C[Si](C)(C)C1SCCCS1
Reactant: O=C1CCOc2ccc(F)cc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)C(=C1SCCCS1)CCO2
Temperature: 0 °C

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (5.10 g, 26.5 mmol) in 50 mL of anhydrous THF at −60° C. under N2 was added drop-wise n-BuLi (1.6 M solution in hexanes, 16.6 mL, 26.5 mmol). The mixture was left to warm slowly to 0° C. over 3 h and subsequently cooled to −60° C. A solution of 6-fluoro-2,3-dihydrochromen-4-one (4.40 g, 26.5 mmol) in 25 mL of THF was added drop-wise. The mixture was slowly warmed to ambient temperature overnight, then poured into water, and extracted with EtOAc. The combined organic portions were washed with brine, and conc. in vacuo. The crude product was purified by flash column chromatography (0 to 10% of EtOAc in hexanes). The title compound was obtained as a pale oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH2:12]O)[CH:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:12][C:4]1[CH:5]=[C:6]2[C:11]([CH2:10][CH2:9][CH2:8][CH2:7]2)=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(CO)cc2c1CCCC2
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(CCl)cc2c1CCCC2

Procedure:
Alcohol 46.5 (1.0 g, 5.7 mmol) is dissolved in anhydrous DCM (50 mL). Thionyl chloride (619 μL, 8.5 mmol) is slowly added dropwise to the solution. The resulting mixture is stirred until TLC confirms consumption of the starting material. The organic solvent is removed in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford chloride 46.6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[O:14][CH:13]([CH2:15][OH:16])[CH:12]([OH:17])[C:9]32[CH2:11][CH2:10]3)[C:4](=[O:18])[N:3]=1.Cl[C:20]1[CH:41]=[CH:40][CH:39]=[CH:38][C:21]=1[O:22][P:23](=[N:25][C@@H:26]([CH3:37])[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[O:24].CN1C=CN=C1>C1COCC1.N1C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:8]2[O:14][C@H:13]([CH2:15][O:16][C:38]3[CH:39]=[CH:40][CH:41]=[CH:20][C:21]=3[O:22][P:23](=[N:25][C@@H:26]([CH3:37])[C:27]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[O:28])=[O:24])[C@@H:12]([OH:17])[C:9]32[CH2:11][CH2:10]3)[C:4](=[O:18])[N:3]=1
Reactant: Nc1ccn(C2OC(CO)C(O)C23CC3)c(=O)n1
Reactant: C[C@H](N=[P+]([O-])Oc1ccccc1Cl)C(=O)OCc1ccccc1
Agent: Cn1ccnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C[C@H](N=[P+]([O-])Oc1ccccc1OC[C@H]1O[C@@H](n2ccc(N)nc2=O)C2(CC2)[C@@H]1O)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 35.6 %

Procedure:
Compound 1 (100 mg) was dissolved in dry THF/pyridine together with (2S)-benzyl 2-(chloro(phenoxy)phosphorylamino)propanoate (279 mg, 2.0 eq). The mixture was cooled to −78° C. N-methylimidazole (NMI) (259 mg, 8 eq) was added and this mixture was stirred for 15 minutes at −78° C. and then stirred at RT overnight. The resulting mixture was evaporated to dryness. 10 mL CH2Cl2 added and the residue washed with 10 mL 0.5N HCl. The organic layer was separated and washed with 10 mL water, dried on Na2SO4, filtered and evaporated. The compound was purified by silica gel chromatography using CH2Cl2 to CH2Cl2/MeOH 9-1 as the eluent. (Rf=0.2 in this eluent). A yellow solid was obtained, which was repurified using column chromatography using EtOAc to EtOAc/MeOH 8-2 as the eluent. After evaporation and drying overnight in vacuo, 80 mg (33.4%) of 2a was obtained (mixture of diastereomers). LC-MS: Rt: 3.37 min m/z: 569 (M−H)−. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.31-0.41 (m, 1H), 0.43-0.58 (m, 2H), 0.95-1.06 (m, 1H), 1.20-1.31 (m, 3H), 3.82-4.01 (m, 3H), 4.09-4.23 (m, 1H), 4.23-4.36 (m, 1H), 4.98-5.15 (m, 2H), 5.29-5.39 (m, 1H), 5.70 (d, J=7.43 Hz, 1H), 6.07 (s, 1H), 6.13 (dd, J=12.81, 10.47 Hz, 1H), 7.08-7.25 (m, 6H), 7.29-7.39 (m, 6H), 7.54 (d, 1H).
Reaction SMILES: [CH3:1][C@@:2]12[CH2:11][CH2:10][CH2:9][C@H:8]([CH3:12])[C:7]1=[CH:6][C:5](=[O:13])[CH2:4][CH2:3]2.CC([O-])(C)C.[K+].C(O)(=O)C.C([O-])(O)=O.[Na+]>C(O)(C)(C)C>[CH3:1][C:2]12[CH2:11][CH2:10][CH2:9][C:8]([CH3:12])=[C:7]1[CH2:6][C:5](=[O:13])[CH2:4][CH2:3]2
Reactant: C[C@H]1CCC[C@@]2(C)CCC(=O)C=C12
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: CC1=C2CC(=O)CCC2(C)CCC1
Yield: 90 %

Procedure:
A solution of 2.0 g (11.5 mM) of trans-6,10-dimethyl-bicyclo[4.4.0]dec-1-en-3-one and 12.0 g (ca. 110 mM) of potassium ter-butylate in 75 ml of ter-butanol, has been stirred during 2 hr at room temperature under an inert atmosphere of nitrogen. 400 ml of a 10% aqueous solution of acetic acid were then added thereto and the thus obtained mixture rapidly neutralized with a saturated aqueous solution of NaHCO3. By extraction with ether followed by washing, drying, evaporation and purification by column chromatography on silicagel (elution with CH2Cl2), there were obtained 1.80 g (90% yield) of the desired product. IR (neat) : 1710, 1600 cm-1NMR (CCl4) : 1.20 (3H,s); 1.58 (3H, large s); 2.27 (2H,t,J=5 cps); 3.10 (2H,m) δ ppm MS : M+ = 178 (57); m/e = 163 (100), 123 (45), 93 (42).
Reaction SMILES: [OH-].[K+].[CH2:3]([C:5]1([CH2:21][CH3:22])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[C:16][Si](C)(C)C)[CH:13]=2)[S:8][CH2:7][CH2:6]1)[CH3:4]>O.C(O)C>[CH2:21]([C:5]1([CH2:3][CH3:4])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[CH:16])[CH:13]=2)[S:8][CH2:7][CH2:6]1)[CH3:22]
Reactant: CCC1(CC)CCSc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#Cc1ccc2c(c1)C(CC)(CC)CCS2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2.21 g (39 mmol) of potassium hydroxide in 2.0 mL of water and 20.0 mL of ethanol was added to 1.49 g (4.93 mmol) of (4,4-diethylthiochroman-6-yl)(trimethylsilyl)acetylene (Compound 26) and the resulting mixture stirred at room temperature for 5 hours during which time it became homogeneous. The solvent was removed in-vacuo and the residue was acidified with 5% aqueous H2SO4. The product was extracted with 2×50 mL of ether.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>>[Cl:11][C:12]1[N:13]=[C:14]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH:15]=[N:16][CH:17]=1
Reactant: Clc1cncc(Cl)n1
Reactant: c1ccc2c(c1)CCNC2
Product: Clc1cncc(N2CCc3ccccc3C2)n1
Yield: 95 %

Procedure:
In a procedure analogous to Example 21, reaction of tetrahydroisoquinoline and 2,6-dichloropyrazine furnished the product (95%).
Reaction SMILES: [NH:1]([N:11]=[N+:12]=[N-:13])[C@H:2]([C:8](O)=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6].[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH:1]([N:11]=[N+:12]=[N-:13])[C@H:2]([C:8]([NH:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9])[CH2:3][C:4](=[O:7])[O:5][CH3:6]
Reactant: COC(=O)C[C@H](NN=[N+]=[N-])C(=O)O
Reactant: NCc1ccccc1
Product: COC(=O)C[C@H](NN=[N+]=[N-])C(=O)NCc1ccccc1
Yield: 90 %

Procedure:
Benzyl-protected L-aspartate was used in the procedure of Lundquist and Pelletier17 to give N3(L)Asp(OMe)OH (46-L). Under these conditions, we observed transesterification to give the methyl ester product as opposed to the benzyl ester. N3(L)Asp(OMe)OH (46-L) was produced as a yellowish oil in 78% yield. N3(L)Asp(OMe)OH (46-L) was then coupled with benzylamine as above to give N3(L)Asp(OMe)NHBn (49-L) as a yellowish oil in 90% yield (70% overall, two steps). The procedure above was repeated with benzyl-protected D-aspartate to give N3(L)Asp(OMe)NHBn (49-D) as a yellowish oil in 67% overall yield. Spectral Data. The spectral data for both N3Asp(OMe)OH (D and L enantiomers) and both N3Asp(OMe)NHBn (D and L enantiomers) products are identical. N3(L)Asp(OMe)OH (46-L) 1H NMR (500 MHz, CDCl3) δ 10.24 (bs, 1 H), 4.47 (dd, J=7.4, 5.3 Hz, 1 H), 3.76 (s, 3 H), 2.91 (dd, J=16.9, 5.1 Hz, 1 H), 2.79 (dd, J=16.8, 7.6 Hz) ppm; 13C NMR (125 MHz, CDCl3) δ 174.68, 170.12, 50.09, 52.44, 35.84 ppm; MS (ESI) m/z 196.0340 (MNa+ [C5H7N3O4Na]=196.0334). N3(L)Asp(OMe)NHBn (49-L) 1H NMR (500 MHz, CDCl3) δ 7.38-7.27 (m, 5 H), 6.83 (bs, 1 H), 4.54 (m, 3 H), 3.75 (s, 3 H), 3.18 (dd, J=17.1, 3.7 Hz, 1 H), 2.75 (dd, J=17.3, 8.7 Hz, 1 H) ppm; 13C NMR (125 MHz, CDCl3) δ 170.77, 167.90, 137.35, 128.81, 127.80, 127.77, 60.32, 52.24, 43.71, 37.00 ppm; MS (ESI) m/z 285.0953 (MNa+ [C12H12N4O3Na]=285.0964).
Reaction SMILES: C([O:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:12]#[CH:13])(=O)C1C=CC=CC=1.[OH-].[K+].CO.O.OC(CCCC)CC#C>C(OCC)(=O)C>[OH:9][C@@H:10]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:11][C:12]#[CH:13]
Reactant: C#CC[C@H](CCCC)OC(=O)c1ccccc1
Agent: C#CCC(O)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: C#CC[C@@H](O)CCCC
Reaction time: 24 h

Procedure:
A solution of 1.15 g. (5.0 mmoles) of (S)-4-benzoyloxy-1-octyne (Example 618) and 1.40 g. (25 mmoles) of potassium hydroxide in 50 ml. of 10:1 methanol-water is allowed to stand at room temperature for 24 hours. The bulk of the methanol is evaporated at room temperature, and the mixture is extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil, identical to 4-hydroxy-1-octyne [α]D25 =+17°±1.0° (C=0.77, ethyl acetate). This compound has the (S)-configuration.