Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@:9]([CH3:39])([CH2:20][CH2:21][C:22]1[O:23][C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH:10]=[CH:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[C:1]([O:5][C:6]([NH:8][C@:9]([CH3:39])([CH2:20][CH2:21][C:22]1[O:23][C:24]([C:27](=[O:38])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:25][CH:26]=1)[CH2:10][CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(C=C[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)o1)NC(=O)OC(C)(C)C)OCC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CCOP(=O)(CC[C@@](C)(CCc1ccc(C(=O)CCCCc2ccccc2)o1)NC(=O)OC(C)(C)C)OCC
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of diethyl (3R)-3-t-butoxycarbonylamino-3-methyl-5-[5-(5-phenylpentanoyl)furan-2-yl]pent-1-enylphosphonate (127.8 mg, 0.23 mmol) obtained in Example (29c) in ethanol (2.3 ml) was added chlorotris(triphenylphosphine)rhodium(I) (22.0 mg, 0.024 mmol), and the resulting mixture was stirred at 50° C. under a hydrogen atmosphere for 8 hours. After cooling, to the reaction mixture was furthermore added chlorotris(triphenylphosphine)rhodium(I) (21.5 mg, 0.023 mmol), and the resulting mixture was stirred at 50° C. under a hydrogen atmosphere for 8 hours. After stirring, the reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using ethyl acetate as the eluent to afford the crude product (142.1 mg). Furthermore, the crude product obtained was purified using a preparative reversed phase HPLC column [Inertsil ODS-3 (2.0 cm×25 cm), GL Science, mobile phase: acetonitrile/water (75:25), flow rate: 10 ml/min] to afford the title compound (109.5 mg, yield: 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](C2C=CC=C3C=2C=CC=[C:13]3[CH2:18][OH:19])=[CH:4][CH:3]=1.[CH:20]1(B(O)O)[CH2:22]C1.C1(C)C=CC=CC=1.[OH2:33]>CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:20][CH2:22][O:33][C:18]([CH3:13])=[O:19].[CH3:6][CH2:7][CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: OCc1cccc2c(-c3ccc(Br)cc3)cccc12
Reactant: O
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCC
Temperature: 100 °C

Procedure:
(5-(4-Bromophenyl)naphthalen-1-yl)methanol (130 mg), cyclopropylboronic acid (71 mg, 2 eq.), Pd(OAc)2 (5 mg, 0.05 eq.), tricyclohexylphosphine (12 mg, 0.1 eq.), and K2PO4 (308 mg, 3.5 eq.) were combined in a flask with 3 mL toluene and 1 mL H2O and degassed. Reaction mixture was then refluxed at 100° C. for 3 hours. Solution was cooled to room temperature then diluted with EtOAc and washed with saturated NaHCO3. The organic layer was dried over sodium sulfate and concentrated. Chromatography achieved using ISCO max gradient 35% EtOAc/hexane yielding product as a brown oil (86 mg, 75% yield). 1H NMR (400 MHz) (CDCl3) δ 8.17-8.15 (m, 1H), 7.96-7.94 (m, 1H), 7.61 (dd, J=8 Hz, J=8 Hz, 1H), 7.56-7.53 (m, 2H), 7.49-7.47 (m, 1H), 7.43-7.40 (m, 2H), 7.25-7.23 (m, 2H), 5.19 (s, 2H), 2.08-2.01 (m, 1H), 1.11-1.06 (m, 2H), 0.87-0.83 (m, 2H). 13C NMR (100 MHz) (CDCl3) δ143.16, 141.02, 138.03, 136.48, 132.17, 131.62, 130.13, 130.05, 138.27, 126.80, 125.84, 125.55, 125.36, 125.27, 123.00, 63.90, 15.28, 9.41.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH:6]([OH:9])[CH2:7][OH:8].Cl.O1CCOCC1.CO[C:19](OC)([CH3:21])[CH3:20]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.CC(N(C)C)=O>[CH3:20][C:19]1([CH3:21])[O:9][CH:6]([CH2:5][NH:4][CH2:3][CH2:2][OH:1])[CH2:7][O:8]1
Reactant: OCCNCC(O)CO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CNCCO)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
The N-(hydroxyethyl)-amino-2,3-propanediol (16.5 g, 122 mmol) was treated with a solution of HCl in dioxane (33.5 ml, 134 mmol). To this solution were added 2,2-dimethoxypropane (15.3 g, 147 mmol), DMAC (50 mL), and a catalytic amount of para-toluene sulphonic acid (0.006 mol, 1.16 g). The mixture stirred at room temperature for 24 hours. Triethylamine (1 mL) was then added, and the solvents removed by rotary evaporation. The viscous crude mixture was dissolved into triethylamine (30 mL) and ethyl acetate (500 mL) and stirred at RT for 30 min. The mixture was filtered and the collected solid washed several times with ethyl acetate. The filtrate was then evaporated on a high vacuum rotary evaporator at 40° C. to give a yellow liquid (0.122 mol, 99% yield).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:15]([CH2:39][C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]([CH3:49])[N:41]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:15]([CH2:39][C:40]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]([CH3:49])[N:41]=2)[C:16](=[O:38])[C:17]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:3][C:4](=[O:7])[O:5][N:37]=3)=[CH:26][CH:25]=2)=[C:18]([CH2:20][CH2:21][CH3:22])[N:19]=1
Reactant: CCCc1nc(C)n(Cc2nn(C)c3ccccc23)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(Cc2nn(C)c3ccccc23)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
A mixture of hydroxylammonium chloride (1.43 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({2-methyl-1-[(1-methyl-1H-indazol-3-yl)methyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.67 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.27 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 5 with water and 1 M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.38 g, 51%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[C:17]1[CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])C1C=CC=CC=1.C(OC(OC)=O)(OC)=O.[H][H]>C(OCC)(=O)C.C(Cl)Cl.[Pd]>[CH3:1][O:8][C:9]([NH:11][CH:12]([CH:17]1[CH2:20][O:19][CH2:18]1)[C:13]([O:15][CH3:16])=[O:14])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)=C1COC1
Agent: [Pd]
Agent: COC(=O)OC(=O)OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)OC)C1COC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114 %

Procedure:
A solution of methyl 2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (intermediate LS28; Source: Moldes et al, Il Farmaco, 2001, 56, 609 and Wuitschik et al, Ang. Chem. Int. Ed. Engl, 2006, 45, 7736; 200 mg, 0.721 mmol) in ethyl acetate (7 mL) and CH2Cl2 (4.00 mL) was degassed by bubbling nitrogen for 10 min. Dimethyl dicarbonate (0.116 mL, 1.082 mmol) and Pd/C (20 mg, 0.019 mmol) were then added, the reaction mixture was fitted with a hydrogen balloon and allowed to stir at ambient temperature overnight. The reaction mixture was filtered through diatomaceous earth (Celite®) and concentrated. The residue was purified via Biotage (load with dichloromethane on 25 samplet; elute on 25S column with dichloromethane for 3CV then 0 to 5% methanol/dichloromethane over 250 mL then hold at 5% methanol/dichloromethane for 250 mL; 9 mL fractions). Fractions containing the desired product were concentrated to provide 167 mg methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil which solidified on standing. 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 3.29-3.40 (m, 1H) 3.70 (s, 3H) 3.74 (s, 3H) 4.55 (t, J=6.41 Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m, 2H) 5.31 (br s, 1H). MS: Anal. Calcd. for [M+H]+ C8H13NO5: 204.1; found 204.0. To methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246 mmol) in THF (2 mL) and Water (0.5 mL) was added lithium hydroxide monohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowed to stir overnite at ambient temperature then concentrated to dryness to provide intermediate LS29 as a colorless powder. 1H NMR (500 MHz, CH3OD) δ ppm 3.38-3.50 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.63 Hz, 1H) 4.57-4.79 (m, 4H).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([CH:27]2[O:31][C:30](=[O:32])[NH:29][CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22](O)[CH3:23])[CH:21]=1.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:15][C:16]1[C:17]([CH3:33])=[C:18]([CH:27]2[O:31][C:30](=[O:32])[NH:29][CH2:28]2)[C:19]([O:25][CH3:26])=[C:20]([CH:22]([Cl:3])[CH3:23])[CH:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1c(C(C)O)cc(Cl)c(C)c1C1CNC(=O)O1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C(C)Cl)cc(Cl)c(C)c1C1CNC(=O)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of cyanuric chloride (16 mg, 0.084 mmol) and N,N-dimethylformamide (15 μL) was stirred at room temperature for 10 minutes. A solution of 5-[3-chloro-5-(1-hydroxyethyl)-6-methoxy-2-methylphenyl]-1,3-oxazolidin-2-one (16 mg, 0.056 mmol) (racemic mixture of two diastereomers from step 2) in methylene chloride (0.3 mL) was added and the reaction was stirred at room temperature overnight. Thionyl chloride (12 μL, 0.17 mmol) was added and stirred for 10 min. The mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, water, brine, dried over sodium sulfate, filtered and concentrated to give the desired compound as a racemic mixture of two diastereomers, 17 mg, 100%. LCMS calculated for C13H16Cl2NO3 (M+H)+: m/z=304.0; found: 304.1.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](O)=O>>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccccn1
Product: c1ccc(-c2nc3ccccc3[nH]2)nc1
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A 2 liter 3-neck round-bottom flask fitted with a reflux condenser, N2 (g) inlet, mechanical stirrer, and heating mantle was charged with 88.7 g of 1,2-phenylenediamine, 100.0 g of picolinic acid, and 500 g of polyphosphoric acid. The resulting slurry was slowly heated (over a period of approximately three hours) to 210° C. under a positive nitrogen atmosphere, with mechanical stirring. The reaction mixture was heated for an additional six hours while maintaining the temperature between 200°-220° C. The reaction mixture was cooled to below 100° C. and cautiously poured into 2 liters of hot distilled water. The resulting slurry was stirred for approximately one hour, cooled and the pH adjusted to approximately 6-7 using concentrated aqueous NaOH. The slurry was stirred for an additional hour, cooled, and filtered. The precipitate was thoroughly washed with distilled water and dried.
Reaction SMILES: C1(C[O:8][C:9](=[O:52])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48]([O:50][CH3:51])=[O:49])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH:26]=[C:25]([C:48]([O:50][CH3:51])=[O:49])[CH:24]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:52])=[O:8]
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc(N(CC(=O)O)CC(=O)O)c1
Yield: 93.6 %

Procedure:
A mixture of 2.63 g (3.67 mmol) of N-[3-(methoxycarbonyl)-5-(octadecyloxy)phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.5 g of 10% palladium on carbon in 150 ml of THF was shaken in a hydrogen atmosphere at room temperature for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated to a solid which was recrystallized from methanol-water to give 1.84 g (93% yield, mp 119°-123°) of N-(carboxymethyl)-N-[3-(methoxy-carbonyl)-5-(octadecyloxy)phenyl]glycine.
Reaction SMILES: [C:1]([CH2:5][NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])(=O)[CH:2]=C.Cl[C:13](OCC)=O>>[CH3:13][C:7]1([CH3:8])[N:6]=[C:5]([CH:1]=[CH2:2])[O:10][C:9]1=[O:11]
Reactant: C=CC(=O)CN[C@@H](C)C(=O)O
Reactant: CCOC(=O)Cl
Product: C=CC1=NC(C)(C)C(=O)O1
Temperature: -78 °C

Procedure:
2-Vinyl-4,4-Dimethylazlactone (VDM) was prepared from N-acryloylmethylalanine (S. M. Heilmann and H. K. Smith II, J. Appl. Polym. Sci., 24, 1551 (1979)) by the Taylor and Platt procedure (L. D. Taylor and T. E. Platt, J. Polym. Sci. Polym. Lett. Ed., 7, 597 (1969)) with ethyl chloroformate as the dehydrating agent. A modified workup procedure was used in which, instead of cooling the filtrate to crystallize the product, the filtrate was concentrated on a rotary evaporator, and the crude product was distilled just above room temperature at 0.5 Torr. Receiving flasks were cooled to −78° C. to collect the product. Typical distilled yields were approximately 80%.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([F:4])[F:3].[F:20][C:21]([F:27])([F:26])[S:22]([OH:25])(=[O:24])=[O:23].CCOCC>C(Cl)Cl.C(#N)C>[F:20][C:21]([F:27])([F:26])[S:22]([O-:25])(=[O:24])=[O:23].[F:1][C:2]([F:4])([F:3])[S+:5]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]1=2
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: FC(F)(F)Sc1ccccc1C#Cc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CC#N
Product: FC(F)(F)[s+]1c(-c2ccccc2)cc2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: -80 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
A solution of (trifluoromethyl)-(2-(2-phenylethynyl)phenyl)sulfide (1.5 g, 5.4 mmol) prepared in Example 2 in 10 ml of methylene chloride was charged into a 50-ml eggplant flask equipped with a stirrer, and cooled to −80° C. Then, trifluoromethanesulfonic acid (1.62 g, 10.8 mmol) was added dropwise to the solution, and the solution was gradually heated to room temperature, and stirred overnight. After completion of the reaction, a solvent was removed, ether was added to the obtained residue to cause solidification, and the solidified product was filtered and washed with ether. The obtained crude product was dissolved in acetonitrile, and ether was added to the solution to cause crystallization to obtain target S-(trifluoromethyl)-2-phenylbenzo[b]thiophenium trifluoromethanesulfonate (1.8 g, 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[O:12])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-hydroxypyrrolidine-2-carboxylic acid methyl ester (59.44 g: 0.183 mole) in dichloromethane (150 ml) stirring at -20° C., triethylamine (30.5 ml: 1.2 eq.) and methanesulfonyl chloride (17 ml: 1 eq.) are added. The mixture is stirred at the same temperature for 35 minutes. To the mixture is added ice water and ethyl acetate. The organic layer is taken, washed with water, dried over magnesium sulfate, and concentrated in vacuo to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-carboxylic acid methyl ester (74.05 g). Yield: Quantitative.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3].CCN(C(C)C)C(C)C.Cl[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36]>C(Cl)Cl>[CH2:38]([O:37][C:35]([NH:1][CH:2]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:13]2)[C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)[CH3:3])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1c(C(C)N)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1c(C(C)NC(=O)OCc2ccccc2)cc(Cl)c(Cl)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 20 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution of tert-butyl 3-[3-(1-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate (4.1 g, 9.7 mmol) and DIPEA (3.4 mL, 20 mmol) in methylene chloride (49 mL) at 0° C. was treated with benzyl chloroformate (1.8 mL, 13 mmol) and stirred at 20° C. for 1 hour. The reaction mixture was diluted with dichloromethane (300 mL), washed with saturated sodium bicarbonate solution, water, and brine, dried with sodium sulfate, filtered and concentrated to a crude residue that was purified by flash column chromatography using EtOAc in hexanes (5%-40%) to give the desired racemic product (4 g, 81%). This racemic material was separated by chiral HPLC (ChiralPak AD-H column, 20×250 mm, 5 micron particle size, eluting with 30% ethanol in hexanes at 12 mL/min, column loading ˜135 mg/injection) to give the desired peak 2 isomer (1.9 g, 38%). Peak 2 isomer: LCMS for C25H30Cl2N2O5Na (M+Na)+: m/z=531.2. Found: 531.2.
Reaction SMILES: Cl[C:2]([C:4]1[C:5]([Cl:15])=[C:6]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:7]([O:9][CH3:10])=[O:8])=[O:3].Cl.[CH2:17]([O:20][NH2:21])[CH2:18][CH3:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:15][C:5]1[C:4]([C:2]([NH:21][O:20][CH2:17][CH2:18][CH3:19])=[O:3])=[C:13]([Cl:14])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCCON
Reactant: COC(=O)c1ccc(Cl)c(C(=O)Cl)c1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCONC(=O)c1c(Cl)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.7 g (0.04 mol) of methyl 3-chlorocarbonyl-2,4-dichlorobenzoate in 100 ml of methylene chloride were slowly added dropwise at 30° C. to a solution of 4.50 g ((0.04 mol) of propoxyamine hydrochloride and 4.05 g (0.04 mol) of triethylamine in 200 ml of methylene chloride. After the reaction mixture had been stirred for 2 hours at room temperature, it was washed with dilute phosphoric acid, dried and concentrated. The residue obtained was chromatographed on silica gel (eluant:toluene/ethyl acetate=9/1). This gave 11.50 g of methyl 2,4-dichloro-3-propoxyaminocarbonylbenzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=1[O:21][CH3:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[O:21][CH3:22])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1Oc1ccc(N)c([N+](=O)[O-])c1

Procedure:
4-Amino-3-nitrophenol (2 g, 13 mmol), 4-fluoro-3-(methyloxy)benzaldehyde (2 g, 13 mmol) and Cs2CO3 (5.1 g, 15.6 mmol) were stirred in dimethylformamide at 100 degrees Centigrade for approximately 18 hours. The reaction was filtered through an Alltech 75 mL Extract-Clean™ filter column packed with glass wool and eluted with ethyl acetate. The eluent was stirred with 5 mL of water then passed through a Varian Chem Elute™ 1010 column which was rinsed with 4-6 mL of ethyl acetate (gravity filtration). The eluent was dried over MgSO4, concentrated onto basic alumina and purified by silica gel column chromatography (hexanes/ethyl acetate gradient) to give 4-[(4-amino-3-nitrophenyl)oxy]-3-(methyloxy)benzaldehyde. (M+1) 289.0, 2.26 min (LC/MS method A)
Reaction SMILES: [Mg].II.[C:4]1([CH3:11])[C:5](Br)=[CH:6][CH:7]=[CH:8][CH:9]=1.[P:12]([O-:19])(OCC)OCC.Cl>C1COCC1.C1(C)C=CC=CC=1.O>[CH3:11][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[PH:12](=[O:19])[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:11]
Reactant: Cc1ccccc1Br
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1[PH](=O)c1ccccc1C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 39.8 %

Procedure:
Under an argon atmosphere, a solution of magnesium (3.55 g, 1.0 equivalent) and a small amount of iodine in THF (40 mL) was stirred at room temperature for 1 hr. A solution of o-tolyl bromide (25 g, 0.146 moL) in THF (5 mL) was added at 30° C. After stirring at 40° C. for 30 min., the mixture was stirred at 5° C. for 1 hr. Then, a solution of diethyl phosphite (10.08 g, 0.5 equivalent) in THF (10 mL) was added at 5° C., and the mixture was stirred at 5° C. for 1 hr. Water (20 mL) was added at 3° C., and then toluene (50 mL) and 6M-HCl (20 mL) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned, and the organic layer was washed successively with water (10 mL), 5% aqueous NaHCO3 solution (10 mL) and 5% aqueous NaCl solution (10 mL). Then the organic layer was dried over anhydrous magnesium sulfate, filtered by gravity, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from heptane to give the title compound (6.70 g, white crystals). yield 39.9%. melting point: 91.3° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=[O:12])/[CH:9]=[CH:10]/[CH3:11].[C:13]1([Si:19]([CH3:22])([CH3:21])Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH:8]([O:12][Si:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:22])[CH3:21])=[CH:9][CH:10]=[CH2:11]
Reactant: C/C=C/C=O
Reactant: C[Si](C)(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC=CO[Si](C)(C)c1ccccc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A 250 mL flask, fitted with a magnetic stirrer, a reflux condenser and an addition funnel, was charged with zinc chloride (0.25 g, 1.83 mmol, anhydrous), triethylamine (36.2 mL, 0.260M, distilled from CaH2), crotonaldehyde (21.0 mL, 0.257M, dried over MgSO4 and distilled), and toluene (35 mL, distilled from sodium). 42 mL of phenyldimethyl chlorosilane (0.254M) were added dropwise via the addition funnel over one hour with stirring. The resulting mixture was heated slowly to about 65° and maintained at 65°-75° for a total of 6.5 hours with stirring. The mixture was cooled to ambient temperature and filtered to remove precipitated triethylamine hydrochloride (32 g, 92%) which was rinsed on the filter with 35 mL of dry toluene. The resulting filtrate and rinse were combined and distilled on a water pump at about 110 mm to remove solvent and unreacted starting materials. The resulting residue was distilled on an oil pump to give (1,3-butadienyloxy)phenyldimethylsilane (30.9 g, 59%) as a colorless liquid boiling at 57.8°-59.0°/0.10 mm (13 Pa).