Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:23](=[O:37])[C@@H:24]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25].C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:23](=[O:37])[C@@H:24]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COCn2ccnc2)cc1
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1nccn1COCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[(benzyloxy)methyl]-1H-imidazole (706 mg, 3.75 mmol) in THF (4 mL) at −78° C. under N2, was added n-Butyllithium (2.3 mL of a 1.6 M solution in hexanes). The mixture was stirred at −78° C. for 30 min. To a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (200 mg, 0.75 mmol) in THF (2 mL) under N2 at −15° C., was added isopropylmagnesium chloride (375 μL of a 2.0 M solution in THF). The resulting mixture was stirred at −15° C. for 15 min. This mixture was then added, by cannula to the solution above at −78° C. The mixture stirred at −78° C. for about 3 h, then warmed up gradually to room temperature and stirred overnight. The mixture was quenched with saturated NH4Cl. The aqueous layer was extracted with CH2Cl2 (3×25 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl ((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carbamate contaminated with about 30% of the unreacted starting material benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate. The mixture was carried forward to the next step without further purification. LCMS calc.=394.18; found=394.2 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[Cl-].[Cl-].[Mg+2].C(N(CC)CC)C.[CH2:20]=[O:21].Cl>C(#N)C>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:20]=[O:21]
Reactant: COc1ccc(O)cc1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(O)c(C=O)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a mixture of compound p-methoxyphenol (3 g, 24.2 mmol), anhydrous magnesium dichloride (3.48 g, 37.0 mmol) and dry triethylamine (12.8 mL, 92.1 mmol) in 100 mL of acetonitrile was added dry paraformaldehyde (5 g, 167 mmol). The reaction mixture was refluxed for 8 hours and cooled down to room temperature. Then the reaction mixture was poured into 5% HCl (300 mL) and extracted with diethyl ether (200 mL) for three times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (20% EtOAc in n-hexane) to yield 3.35 g of 2-hydroxy-5-methoxybenzaldehyde (91% yield).
Reaction SMILES: [C:1]1(C#N)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C[Mg]Br.CC[O:18][CH2:19][CH3:20]>C1COCC1>[C:1]1([C:19](=[O:18])[CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CCOCC
Reactant: N#Cc1nccc2ccccc12
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of isoquinoline-1-carbonitrile (Intemediate H1) (commercially available from Aldrich) (4.40 g, 28.5 mmol) in THF at 0° C. was treated with methylmagnesium bromide (20 mL, of a 3M soln in ether) for 3 h. (see procedure found in Vacher, B. et al J. Med. Chem. 1998 41, 5070; incorporated herein by reference). The mixture was quenched with a sat. solution of NH4Cl and stirred for 3 h at rt. The aqueous layer was basified with NaOH and extracted with ethyl acetate. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel with 10% ethyl acetate: hexane to give 1-isoquinolin-1-yl-ethanone (Intermediate H2) 3.65 g (75%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[N+:19]([C:13]1[CH:12]=[C:11]([C:10]2[O:22][C:2]3[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=3[N:9]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18])([O-:21])=[O:20]
Reactant: COc1ccc(C(=O)Nc2cc(Br)ccc2O)cc1[N+](=O)[O-]
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Yield: 91 %

Procedure:
A suspension of N-(2-hydroxy-5-bromophenyl)-3-nitro-4-methoxybenzamide (5.24 g, 14.2 mmol) and toluenesulfonic acid monohydrate (5.36 g, 31.2 mmol) in toluene (100 ml) was heated to reflux overnight. The cooled reaction mixture was washed with saturated sodium hydrogen carbonate solution (care foaming) and the organic layer separated. The aqueous layer was extracted with ethyl acetate (2×50 ml) and the combined organic layers dried over sodium sulfate and the solvent removed under reduced pressure. The residue was triturated with ether, filtered and dried under vacuum to give the subtitle compound as a pale pink solid (4.51 g, 93%). 1H NMR (DMSO) δ 8.61(d, 1H), 8.42(dd, 1H), 8.05(d, 1H), 7.79(d, 1H), 7.61(m, 2H), 4.05(s, 3H). MS m/z 349.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][N:8]=[C:7](O)[CH:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.P(Cl)(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][C:7]1[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[N:10]=[CH:9][N:8]=1
Reactant: CC(C)(C)c1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(Cl)ncn1

Procedure:
6-(1,1-Dimethylethyl)-4-pyrimidinol (Intermediate 9, 1.66 g, 10.91 mmol) was suspended in DCM (10 mL), treated with triethylamine (1.520 mL, 10.91 mmol), followed by phosphorus oxychloride (1.118 mL, 12.00 mmol) dropwise. An exotherm was observed. The resulting mixture was heated under reflux for 3 hours. LCMS indicates no desired product present and starting material remaining. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was treated with phosphorus oxychloride (5.08 mL, 54.5 mmol) and the resulting mixture was heated under reflux for 30 minutes. The reaction mixture was allowed to cool to room temperature, evaporated under reduced pressure and the residue was poured into 2M aqueous hydrochloric acid solution (10 mL). This solution was extracted with DCM (×2). The DCM layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (1.17 g);
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:9]1
Reactant: Cc1nc(N)nc(N2CCCC(NC(=O)OC(C)(C)C)C2)c1C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(N)nc(N2CCCC(N)C2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C

Procedure:
3.3 g (7.8 mmol) of {1-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperidin-3-yl}-carbamic acid tert-butyl ester are dissolved in DCM (50 mL) and 26 mL TFA are added. The reaction mixture is stirred over night at RT. The reaction mixture is adjusted to neutral pH using concentrated aqueous Na2CO3 solution and the DCM is evaporated at reduced pressure. The residue is washed with water, taken up in acetonitrile and freeze dried. The crude product is used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18]O)=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.O=S(Cl)[Cl:23]>>[Cl:23][CH2:18][C:17]1[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:20]
Reactant: Cc1cccc2cc(CO)c(-c3ccccc3F)nc12
Reactant: O=S(Cl)Cl
Product: Cc1cccc2cc(CCl)c(-c3ccccc3F)nc12
Yield: 88.8 %

Procedure:
Prepared according to Procedure C using (2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanol (0.700 g, 2.62 mmol) in SOCl2 (2 mL, 27.4 mmol, 10.5 eq). 3-(chloromethyl)-2-(2-fluorophenyl)-8-methyl-quinoline (0.665 g, 89%) was obtained after purification as a brown foam. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.61 (1 H, s), 7.92 (1 H, d, J=7.9 Hz), 7.71 (1 H, d, J=6.7 Hz), 7.53-7.66 (3H, m), 7.40 (2 H, t, J=7.9 Hz), 4.81 (2 H, s), 2.69 (3 H, s) Mass Spectrum (ESI) m/e=286.1 and 288.1 (M+1)
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1([CH3:17])[C:8]2[O:9][C:10]3[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=3[C:7]=2[CH2:6][CH2:5][NH:4]1.[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[S:27][Si](C(C)C)(C(C)C)C(C)C.[F-].[Cs+].C(O)CO.CN(C=O)C>[Cu]I>[F:1][CH:2]([F:18])[C:3]1([CH3:17])[C:8]2[O:9][C:10]3[CH:15]=[C:14]([S:27][C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[F:19])[CH:13]=[CH:12][C:11]=3[C:7]=2[CH2:6][CH2:5][NH:4]1
Reactant: CC1(C(F)F)NCCc2c1oc1cc(I)ccc21
Reactant: CC(C)[Si](Sc1cccc(F)c1F)(C(C)C)C(C)C
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: OCCO
Solvent: CN(C)C=O
Product: CC1(C(F)F)NCCc2c1oc1cc(Sc3cccc(F)c3F)ccc21
Temperature: 105 °C
Yield: 135.5 %

Procedure:
Into a Schlenk flask equipped with a magnetic stir bar was added 1-difluoromethyl-7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-C]pyridine (enantiomer 1, 100 mg, 0.30 mmol), (2,3-difluorophenylsulfanyl)-triisopropylsilane (125 mg, 0.43 mmol), CsF (189 mg, 1.24 mmol), CuI (25 mg, 0.13 mmol), ethylene glycol (85 μL, 1.5 mmol) and anhydrous DMF (3 mL, 0.30 mmol). The Schlenck flask was evacuated and flushed with argon three times. The reaction mixture was heated at 105° C. under argon for 17 h. Upon cooling, the reaction was diluted with DCM, filtered through celite and solvent was evaporated. Purification using preparative TLC (2000 micron silica gfel plate; elution with 15% EtOAc in dichloromethane) afforded 155 mg of product as a viscous, pale oil. MS m/z: 382 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([OH:17])[CH2:14][N:13]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])(=O)=O)=CC=1.[C:31]1(=[O:41])[NH:35][C:34](=[O:36])[C:33]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]12.[K]>CN(C)C=O.C(OCC)(=O)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][O:20][C:18]([N:13]2[CH2:14][C@H:15]([OH:17])[CH2:16][C@H:12]2[CH2:11][N:35]2[C:34](=[O:36])[C:33]3=[CH:37][CH:38]=[CH:39][CH:40]=[C:32]3[C:31]2=[O:41])=[O:19])=[CH:27][CH:26]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol p-toluenesulfonate (24 g: 55.1 mmole) in dimethylformamide (200 ml), potassium phthalimide (15.3 g) is added. The mixture is stirred at 80° C. for 4 hours. The reaction mixture is diluted with ethyl acetate, successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene:ethyl acetate=1:2) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-2-phthalimidomethylpyrrolidine (18.1 g). Yield: 80%. NMR δ(CDCl3) ppm: 1.9 to 2.2(m, 2H), 3.4 to 4.05(m, 5H), 3.80(s, 3H), 4.3 to 4.6(m, 2H), 4.8 to 5.1(m, 2H), 6.83(d, J=8.2 Hz, 2H), 7.25(d, J=8.2 Hz, 2H), 7.6 to 7.9(m, 4H). IR ν (CHCl3) cm-1 : 3458, 1773, 1712.
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:17]([O-])=O)[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[N:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2ccc(N)cc21
Reaction time: 12 h

Procedure:
To a stirring solution of 1-Boc-6-nitroindazole (2.5 g, 9.5 mmol) in ethyl acetate (75 mL) under nitrogen was added 10% Pd/C (500 mg). The mixture was placed under vacuum and the atmosphere was replaced with hydrogen (1 atm). After stirring for 12 h, the hydrogen balloon was removed and diatomaceous earth was added. The mixture was then filtered over a pad of diatomaceous earth and the solvent was removed by rotary evaporation to give 2.17 g (98%) of light pink solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12](C(O)=O)[C@H:7]3[C:6]=2[C:5]([F:16])=[CH:4][CH:3]=1.C([N:19](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH2:19])[C@H:7]3[C:6]=2[C:5]([F:16])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@@H]21
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: N[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@H]12
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 50 %

Procedure:
(1S,1aR,7bS)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-carboxylic acid (0.5 g, 2.2 mmol, ˜95% ee) was mixed with toluene (3 ml), triethylamine (0.34 ml, 1.1 eq), DPPA (0.52 ml, 1.1 eq) and bubbled with argon for about 5 min. The reaction mixture was then heated at stirring at 120° C. for 1.5 h under argon. The temperature was then decreased to 50° C. and a mixture of 3 ml of 10% hydrochloric acid in 10 ml dioxane was added. The reaction mixture was stirred for 2 h at 50° C. and then concentrated by rotary evaporation. The residue was mixed with water ant diethyl ether. Water phase was collected and basified with 28% aqueous ammonia to pH 11 and extracted into ether (3×20 ml). Combined organic phases were washed with water and brine and dried over magnesium sulfate. Concentration by rotary evaporation gave 310 mg of crude product as yellow orange oil. The product was purified by column chromatography on silica (30 g, EtOAc/hexane 1:2) to give 220 mg of colorless oil (50% yield).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:38])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH2:22][CH3:23])=[N:19][CH:20]=3)[N:14]=1)[N:11](CC1CCCCC1)[C:10](=[O:31])[C:9]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:8]2)=[O:4].[NH2:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:32]1([CH2:9][N:14]2[C:13]([C:15]3[CH:20]=[N:19][C:18]([O:21][CH2:22][CH3:23])=[N:17][CH:16]=3)=[C:12]3[C:7](=[CH:8][CH:9]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:10](=[O:31])[NH:11]3)[C:6]([OH:38])=[C:5]2[C:3]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[O:4])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NCCC(=O)O
Reactant: CCOc1ncc(-c2nc(C(=O)OC)c(O)c3cc(-c4ccccc4)c(=O)n(CC4CCCCC4)c23)cn1
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ncc(C2=C3NC(=O)C(c4ccccc4)C=C3C(O)=C(C(=O)NCCC(=O)O)N2CC2CCCCC2)cn1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A mixture of 1-cyclohexylmethyl-8-(2-ethoxy-pyrimidin-5-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.068 mmol), β-alanine (607 mg, 6.8 mmol) and NaOMe solution (11 mL, 5.4 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-40% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound. MS: (+) m/z 572.36 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12]O)([CH2:10]O)[CH2:8]O)([CH3:4])([CH3:3])[CH3:2].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1.ClCCl>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:14])[C:7]([CH2:12][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH2:10][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])[CH2:8][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(CO)(CO)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CC(CS(=O)(=O)c2ccc(C)cc2)(CS(=O)(=O)c2ccc(C)cc2)C(=O)OC(C)(C)C)cc1
Reaction time: 15 h

Procedure:
A solution of t-butyl-tris(hydroxymethyl)acetate (9.9 g, 0.048 mol) in 50 mL of pyridine is cooled to 0° C. and then portions of p-toluenesulfonyl chloride (30.1 g, 0.158 mol) are added over 1 hr. The mixture is kept at 0° C. for 15 hrs. Then dichloromethane (200 mL) is added and the solution is washed four times with 100 mL of 10% hydrochloric acid, once with 100 mL of saturated sodium bicarbonate and once with 100 mL of saturated sodium chloride. The organic layer is dried over anhydrous sodium sulfate and evaporated under reduced pressure to give t-butyl-tris(tosylmethyl)acetate.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][N:11]=1.O>CCOCC>[F:9][C:10]1[N:11]=[CH:12][C:13]([C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:15])=[CH:17][CH:18]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: Cl[Mg]c1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=C(c1ccccc1)c1ccc(F)nc1

Procedure:
A 3M etheral solution of phenyl magnesium chloride (4.67 ml, 14 mmol) was slowly added at −30° C. to a solution of 6-fluoronicotinoyl chloride (3.35 g, 21 mmol) in ether (25 ml). After complete addition, the cooling bath was removed and the reaction was allowed to reach 10° C. Hydrolysis was performed by addition of water, and the mixture is then diluted with ether. After separation of the layers, the ether solution was washed with brine, dried over Na2SO4 and evaporated in vacuum to yield a yellowish oil. After purification by chromatography on silica gel (CH2Cl2/Hexane 85/15), the (6-fluoro-3-pyridinyl)(phenyl)methanone 39 was obtained as a yellow oil (980 mg, 35%).
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.F[B-](F)(F)F.[F:13][S:14]([F:26])([F:25])([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([N+]#N)=[CH:17][CH:16]=1>>[F:13][S:14]([F:23])([F:24])([F:25])([F:26])[C:15]1[CH:16]=[CH:17][C:18]([N:5]=[N+:6]=[N-:7])=[CH:19][CH:20]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Product: [N-]=[N+]=Nc1ccc(S(F)(F)(F)(F)F)cc1
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
(Sheppard, J. Am. Chem. Soc. 1962, 84, 3064-3072) Trimethylsilyl azide (6.5 mg, 0.056 mmol) was added to a solution of 1 (10.2 mg, 0.0321 mmol) in [BMIM][BF4] (65.0 mg). After stifling for 5 min, the mixture was extracted with hexane (0.5 mL×3) and the combined extracts was evaporated to give pure 25a as a colorless oil (6.8 mg, 86%): IR (ATR): {tilde over (v)}=2124, 2099, 1586, 1501, 1287, 843 cm−1. MS (GC, EI): m/z=245 [M30 ], 219 [M+-CN], 200 [M+-CFN], 111. 1H NMR (500 MHz, CDCl3): δ=7.74 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): δ=150.3 (C), 143.3 (C), 127.7 (2CH), 118.9 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.4 (quint, J=150 Hz, 1 F), 63.5 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[Br:1][C:2]1[C:3]([O:13][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: C1=COCCC1
Reactant: COC(=O)c1cc(Br)c(O)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC(=O)c1cc(Br)c(OC2CCCCO2)cc1F
Temperature: 50 °C
Reaction time: 24 h
Yield: 75.9 %

Procedure:
To a round bottom containing 66.43B (13.15 g, 52.8 mmol) in dry DCM (90 mL) was added 3,4-dihydro-2H-pyran (10 mL, 110 mmol) followed by PPTS (0.13 g, 0.53 mmol). The reaction mixture was heated to a gentle reflux (50° C.) and monitored with TLC and LC-MS. After 24 hours, the reaction was concentrated under reduced pressure and then diluted with MeOH. After concentration, the residue was heated in a round bottom flask containing MeOH on the rotary evaporator (without vacuum.) at 40° C. After about 30 minutes, the solution was concentrated to a volume of about 5 mL. After cooling to room temperature, the white solid was filtered and rinsed once with MeOH to yield 66.43C (13.35 g, 76% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, m), 6.96 (1H, d, J=12.5 Hz), 5.56 (1H, m), 3.91 (3H, s), 3.79 (1H, td, J=11.1, 2.5 Hz), 3.65 (1H, d, J=10.6 Hz), 2.23 (2H, m), 1.96 (3H, m), 1.68 (1H, m).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:11])/[CH:6]=[CH:7]\[C:8]([OH:10])=[O:9])([CH3:3])[CH3:2].[CH3:12][N:13]([CH3:18])[CH2:14][CH2:15][CH2:16][NH2:17]>C(N(CC)CC)C>[CH:1]([O:4][C:5](=[O:11])[CH2:6][C@@H:7]([C:8]([OH:10])=[O:9])[NH:17][CH2:16][CH2:15][CH2:14][N:13]([CH3:18])[CH3:12])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)/C=C\C(=O)O
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)C[C@H](NCCCN(C)C)C(=O)O
Yield: 94.7 %

Procedure:
395.2 g (2.5 mols) of maleic acid-monoisopropyl ester, 500 ml of triethylamine and 306.5 g (2.5 mols+20% excess) of 3-dimethylaminopropylamine are reacted according to Example 1, and the reaction product is subsequently purified to yield 616.4 g (94.7% of theory) of a white crystalline aspartic acid derivative of which the melting point is 163.5°-165.5° C.