Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>ClCCl.CN(C)C1C=CN=CC=1>[C:15]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[N:13]=[C:12]([NH:14][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH:11]=[CH:10][CH:9]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cccc(P(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
2.0 g (7.2 mmol) of 6-(diphenylphosphino)-2-aminopyridine from example 14.3.1 were dissolved in 40 ml of dichloromethane and admixed with 1.6 ml (1.2 g, 10.8 mmol) of triethylamine and 0.16 g (0.7 mmol) of 4-dimethylaminopyridine (DMAP). After cooling to 0° C. (H2O/ice), 1.2 ml (1.2 g, 8.8 mmol) of pivaloyl chloride were slowly added dropwise and the mixture was kept at this temperature for 3 h. The mixture was allowed to warm to room temperature overnight and the solvent was then removed under reduced pressure. The residue was purified by filtration together with cyclohexane/ethyl acetate (1:1) through a short silica gel column (3×10 cm). The solvent was removed under reduced pressure and the resulting oil crystallized by digesting with petroleum ether (40/60). The solid was filtered off, washed with petroleum ether (40/60) and dried under reduced pressure. 2.25 g (6.2 mmol, 86.1%) of 6-(diphenylphosphino)-2-pivaloylaminopyridine were obtained as a beige-colored solid.
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]1([S:18]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Fe].C(Cl)(Cl)(Cl)Cl>[C:1]1([C:7]2[S:8][C:9]([S:18][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClSc1ccccc1
Reactant: c1ccc(-c2cccs2)cc1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: c1ccc(Sc2ccc(-c3ccccc3)s2)cc1
Reaction time: 96 h
Yield: 17.2 %

Procedure:
In a 500 ml flask were placed 36.9 g (0.23 mole) of 2-phenylthiophene, 200 ml of reagent carbon tetrachloride, 36.9 g (0.26 mole) of benzenesulfenyl chloride and 0.2 g of iron powder. The reaction mixture was allowed to stand four days at room temperature. Distillation of the carbon tetrachloride gave a crystalline residue which was recrystallized first from ethanol-ethyl acetate (9:1) and then from ethyl acetate-pentane (1:9) to give 10.6 g (17%) of 2-phenyl-5-(phenylthio)thiophene, m.p. 72.5°-74.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH3:14][NH2:15].[OH-].[Na+]>O>[CH3:14][NH:15][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
203.5 Parts of 99.5% 2,4-dinitrochlorobenzene are effectively stirred in 390 parts of water. The beige-coloured suspension is heated to 70° C in the course of 35 minutes, and at aprox. 46° C becomes a light brown emulsion. Then 120 parts by volume of a 41% aqueous solution of methylamine are added dropwise at 85° C bath temperature in the course of half an hour. During the dropwise addition the temperature rises to 88° C. The emulsion solidifies slowly and a thick yellow crust forms on the wall of the flask. Thereafter 103 parts by volume of 30% sodium hydroxide solution are added dropwise in the course of a further hour. The temperature falls to below 81° C. The crust gradually detaches itself from the wall of the flask and a yellow suspension forms. This suspension is heated to 90° C in the course of 15 minutes, stirred for 1 hour at 85° to 90° C, then cooled for 2 hours to 30° C and filtered by suction. As the filter cake still contains some lumps, it is stirred in 305 parts of water in a laboratory mixer, filtered by suction, washed with 1150 parts of water and dried at 60° C in vacuo, affording 193 parts of N-methyl-2,4-dinitro-aniline (97.8% of theory, referred to 2,4-dinitrochlorobenzene). The product has a melting point of 177°-178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]=[O:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=2)[CH:4]=1.[CH3:22][Mg]Br>O1CCCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([CH:12]([OH:13])[CH3:22])[C:9]2[C:5](=[CH:6][N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:20])([CH3:19])[CH3:21])[N:8]=2)[CH:4]=1
Reactant: C[Mg]Br
Reactant: COc1cc(C=O)c2nn(COCC[Si](C)(C)C)cc2c1
Solvent: C1CCOC1
Product: COc1cc(C(C)O)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 0 °C

Procedure:
To a solution of 5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carbaldehyde (1.32 g, 4.31 mmol) in tetrahydrofuran (27 mL) at −78° C. was added methyl magnesiumbromide (3M in diethyl ether, 2.87 mL, 8.62 mmol). The reaction was allowed to gradually warm in the ice bath (ca. 1 h) to 0° C. The reaction which had been a suspension became a solution. The reaction was quenched by addition of saturated ammonium chloride and poured into diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated to give 1.44 g (quant.) as oil. 1H-NMR (CDCl3, 300 MHz) δ 7.92 (s, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 5.63 (s, 2H), 5.26 (q, J=6 Hz, 1H), 3.8 (s, 3H), 3.6 (m, 2H), 1.65 (d, J=6 Hz, 3H), 0.9 (m, 2H), -0.06 (s, 9H); Mass spec.: 323.42 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.N1C=CN=C1.[C:18]([Si:22]([CH3:25])([CH3:24])Cl)([CH3:21])([CH3:20])[CH3:19].CCOCC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:22]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:25])[CH3:24])[CH:6]=[CH:5]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Yield: 99.2 %

Procedure:
10 g of 6-bromo-2-naphthol, 13.4 g of imidazole and 15 g of t-butyldimethylchlorosilane were stirred at room temperature in 75 ml of dimethylformamide for 18 hrs. Thereafter, 500 ml of ether were added thereto and the organic phase was washed 5 times with 100 ml of water each time. The organic phases were concentrated and the residue was dried in a high vacuum. 15.0 g of 6-bromo-2-t-butyl-dimethylsilyloxy-naphthaline were isolated as a yellowish solid. Yield: 99%. Mass spectrum (ISP): peaks inter alia at m/e: 338 and 336 (M+, in each case 34%), 281 (100%), 279 (98%), 200 (98%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>>[CH2:1]([NH:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:17]([CH3:19])([CH3:18])[CH3:16])=[O:5])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCNC(=O)c1cccc2ccccc12
Product: CCNC(=O)c1c([Si](C)(C)C)ccc2ccccc12
Yield: 58 %

Procedure:
N-Ethyl-1-naphthalenecarboxamide was reacted with 2 eq TMSCl according to General Method C. The resulting reaction mixture was worked up in the usual manner, then purified by recrystallization from cold ethyl acetate/hexanes to afford 1.6 g of desired compound as a white solid, a 58% yield. m.p. 141-143° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH:7]1[C:11]([C:12]2[CH:13]=[C:14]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)=[C:23]([C:33]([NH:35][CH3:36])=[O:34])[C:22]=4[CH:37]=3)[CH:15]=[CH:16][CH:17]=2)=NN=[N:8]1>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24]2[O:25][C:21]3[CH:20]=[CH:19][C:18]([C:14]4[CH:15]=[CH:16][CH:17]=[C:12]([C:11]5[O:5][C:1]([CH:2]([CH3:4])[CH3:3])=[N:8][N:7]=5)[CH:13]=4)=[CH:37][C:22]=3[C:23]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:31][CH:30]=1
Reactant: CC(C)C(=O)Cl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnc(C(C)C)o4)c3)cc12
Reaction time: 8 h
Yield: 20.7 %

Procedure:
Isobutyryl chloride (90 mg, 0.847 mmol) was added to a stirring solution of 5-(3-(1H-tetrazol-5-yl)phenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (50 mg, 0.085 mmol) in pyridine (1 mL) at 100° C. It was allowed to stir overnight. The reaction was concentrated and diluted with EtOH (3 mL) and treated with excess 1N NaOH (500 μL) and stirred at 60° C. for 2 hours to hydrolyze the acylated amide. The mixture was filtered and the filtrate was diluted with EtOAc and washed with sat NaHCO3, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (8 mg, 20%). 1H NMR (500 MHz, CD3OD) δ ppm 8.31-8.35 (1H, m), 8.03 (1H, d, J=7.94 Hz), 7.95-8.00 (3H, m), 7.93 (1H, d, J=7.93 Hz), 7.67-7.74 (3H, m), 7.25-7.30 (2H, m), 3.37-3.40 (1H, m), 2.99 (3H, s), 1.49 (6H, d, J=7.02 Hz). LC-MS retention time: 2.28 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 μm, Rt=14.30 min, purity=94%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=12.50 min, purity=93%.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[C:11]1(=[O:18])[O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C1C=CC=CC=1)([O-])=O>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)CCCC(=O)O)cc1OC
Reaction time: 18 h

Procedure:
A solution containing 36 g of veratrole and 30 g glutaric anhydride in 120 ml of nitrobenzene was gradually added while stirring and cooling at 0° C. to a mixture of 72 g of anhydrous aluminium chloride and 240 ml of nitrobenzene. The mixture was stirred for 1 h at 0° C. and then for 18 h at 20° C. Ice and hydrochloric acid were added to the reaction mixture. Nitrobenzene layer was separated and to this ethyl acetate was added whereupon the product crystallized. After filtering the crystals were washed with ethyl acetate. Yield 42.3 g (64%).
Reaction SMILES: [O:1]=[C:2]1[CH:14](C(OC(C)(C)C)=O)[N:6]2[C:7]3[C:12]([CH:13]=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3>C1(C)C=CC=CC=1>[CH:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH:13]=[C:5]1[CH2:4][CH2:3][C:2](=[O:1])[CH2:14][N:6]12
Reactant: CC(C)(C)OC(=O)C1C(=O)CCc2cc3ccccc3n21
Solvent: Cc1ccccc1
Product: O=C1CCc2cc3ccccc3n2C1

Procedure:
A solution of the crude product of Step 4 in 1.2 L of toluene was treated with 100 g of silica gel and the mixture was heated to reflux for 6 h. After cooling, the mixture was filtered and the filtrate was concentrated to give the title compound as a dark solid. 1H NMR (500 MHz, acetone-d6) δ 7.52 (d, 1H), 7.35 (d, 1H), 7.11 (t, 1H), 7.05 (t, 1H), 6.32 (s, 1H), 4.74 (s, 2H), 3.29 (m, 2H), 2.78 (m, 2H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].Cl[CH2:16][CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:16][CH:17]=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Reactant: ClCC=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)cc(OCC=Cc2ccccc2)c(C)c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of 4-hydroxy-2,3,6-trimethylphenyl acetate (10.0 g, 51.5 mmol) in N,N-dimethylformamide (100 mL) was added 1-chloro-3-phenyl-2-propene (7.86 g, 51.5 mmol) and potassium carbonate (7.10 g, 51.5 mmol) and the mixture was stirred under an argon atmosphere at 60° C. for 2 hours. This reaction mixture was poured into water and extracted twice with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol to obtain the title compound (13.0 g, yield 81%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12](=O)[CH2:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[NH2:21][C:22]1[C:26]([C:27]#[N:28])=[CH:25][NH:24][N:23]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[N:23]3[N:24]=[CH:25][C:26]([C:27]#[N:28])=[C:22]3[N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: N#Cc1c[nH]nc1N
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(F)c1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(F)c3)nc12
Yield: 37.1 %

Procedure:
Reaction of 1-(3-fluoro-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (302 mg, 1.0 mmol), prepared from commercially available 3-fluoro-4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (139 mg, 37%). MS (ISP) 375.0 [(M+H)+]; mp 184° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:7]=[N:6][C:5]([C:8]2[N:9]=[N:10][C:11]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:20][N:21]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)nn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: c1ccc(-c2ccc(-c3ccc(-c4ccccn4)nn3)nn2)nc1
Temperature: 95 °C

Procedure:
The 6,6′-bis(pyridin-2-yl)-3,3′-bipyridazine 19 was prepared according to the general Stille coupling procedure, starting from a reaction mixture of 500 mg (4.42 mmol) of dichlorobipyridazine 17, 2.03 g (5.52 mmol) of 6-tributylstannylpyridine 18 and 387 mg (0.55 mmol) of dichlorobis(triphenylphosphine)-palladium(II), in 40 ml of DMF. The reaction mixture is heated at 95° C. for 24 h. The residue obtained is purified by silica gel chromatography (eluent: ethyl acetate/petroleum ether=1/9). The disubstituted product 19 is isolated with a yield of 62%.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13])([O-])=O.[F:14][C:15]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[F:14][C:15]([F:22])([C:18]([F:21])([F:20])[F:19])[CH2:16][O:17][C:4]1[CH:11]=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[C:5]=1[C:12]#[N:13]
Reactant: OCC(F)(F)C(F)(F)F
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cccc(OCC(F)(F)C(F)(F)F)c1C#N
Temperature: 50 °C
Yield: 95.1 %

Procedure:
A reaction flask was loaded with 8.7 g of 3-nitrophthalonitrile, 9.0 g of 2,2,3,3,3-pentafluoropropanol, 13.8 g of anhydrous potassium carbonate, and 350 ml of dimethyl sulfoxide, and the temperature was raised to 50° C. with stirring under nitrogen flow. After stirring at 50° C. for 4 hours, the heating was stopped. The reaction liquid was cooled and added into 500 ml of water, and the precipitated crystal was collected and dried to yield 13.2 g of the intended compound.
Reaction SMILES: C[O-].[Na+].C([N:10]1[CH2:13][CH:12]([NH:14][C:15](=[O:24])[CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:11]1=[O:25])(C(OC)=O)=O>CO>[O:17]([CH2:16][C:15]([NH:14][CH:12]1[CH2:13][NH:10][C:11]1=[O:25])=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)C(=O)N1CC(NC(=O)COc2ccccc2)C1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(COc1ccccc1)NC1CNC1=O
Yield: 57.7 %

Procedure:
Sodium methylate (15 mg.) and absolute methanol (20 ml.) were added to 1-methoxalyl-3-(2-phenoxyacetamido)-2-azetidinone (1.1 g.), and the mixture was heated under reflux for 30 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was dissolved in acetone, and then the insoluble material was filtered off. The filtrate was concentrated and allowed to stand cool, and then the precipitated crystals were collected by filtration. The crystals were washed with acetone and dried to give 3-(2-phenoxyacetamido)-2-azetidinone (456 mg.). Furthermore, the same compound (109 mg.) was recovered from the mother liquor. Total yields was 565 mg. Mp 153° to 155° C.
Reaction SMILES: [H-].[Li+].[C:3]([OH:12])(=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[CH3:13][Li]>CCOCC>[CH3:13][C:3](=[O:12])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCC(=O)O
Reactant: [Li]C
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: C=CCCCCCC(C)=O
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
To a stirred mixture of 11.0 g lithium hydride in 800 ml of anhydrous ether, there was added dropwise 164 g of oct-7-enoic acid (prepared in Example 22 B-2) in 800 ml of anhydrous ether and the mixture was cooled to 0° C. and 650 ml of 2 M methyllithium in ether was added dropwise and then allowed to warm to room temperature and stir for 4.5 hr. This mixture was quenched by pouring the slurry into rapidly stirred 10% aqueous hydrochloric acid (1.2 liter) and wet ice. The resulting mixture was extracted with ether (3×700 ml). The continued ether extracts were washed with 10% aqueous sodium hydroxide and then with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to yield 118.9 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:10]([CH2:19][CH2:20][CH2:21][N:22](C(OC(C)(C)C)=O)[CH3:23])[C:9]([O:31]C)=[N:8][C:7]=1[CH2:33][O:34][CH2:35][CH2:36][N:37]=[N+:38]=[N-:39])=[O:5])[CH3:2]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[N:10]([CH2:19][CH2:20][CH2:21][NH:22][CH3:23])[C:9](=[O:31])[NH:8][C:7]=1[CH2:33][O:34][CH2:35][CH2:36][N:37]=[N+:38]=[N-:39])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(COCCN=[N+]=[N-])N=C(OC)N(CCCN(C)C(=O)OC(C)(C)C)C1c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCN=[N+]=[N-])NC(=O)N(CCCNC)C1c1ccccc1Cl
Reaction time: 2 h

Procedure:
A solution of racemic 4-(2-azido-ethoxymethyl)-1-[3-(tert-butoxycarbonyl-methyl-amino)-propyl]-6-(2-chloro-phenyl)-2-methoxy-1,6-dihydro-pyrimidine-5-carboxylic acid ethyl ester (200 mg, 0.354 mmol) in CH2Cl2 (3 mL) and trifluoroacetic acid (1.5 mL) was stirred at RT under N2 to remove the BOC protecting group. After 2 h, 1N aqueous HCl (1 mL) and THF (3 mL) was added to the mixture. The mixture was left to stir overnight. The mixture was taken up in EtOAc (50 mL) and basicified with saturated NaHCO3 solution. The organic extract was washed with brine (25 mL), dried (Na2SO4), filtered, concentrated and dried in vacuo 150 mg (93% crude yield) of thick yellowish oil as crude product.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[CH3:10][O-:11].[Na+].O>C(#N)C>[Br:1][C:2]1[C:3]([O:11][CH3:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: Clc1ccc(Br)c(Cl)n1
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1nc(Cl)ccc1Br
Temperature: 25 °C
Yield: 93.2 %

Procedure:
To a solution of 3-bromo-2,6-dichloropyridine (3.00 g, 13.2 mmol) in acetonitrile (20 mL) was added sodium methoxide (methanol solution, 4.83 mol/L, 3.0 mL) dropwise at 0° C. The mixture was stirred at room temperature over night. To the mixture was added 30 mL of water, and the organic was evaporated. The resulting suspension was filtered, and the pad was washed with water for several times. The pad was dried under reduce pressure to give title compound (2.74 g, 93.2%) as white solid.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:34]=[CH:33][CH:32]=[CH:31][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([C:5]1[O:6][C:7]2[CH:34]=[CH:33][CH:32]=[CH:31][C:8]=2[C:9]=1[C:10]1[O:11][C:12]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[CH:21]=[C:20]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:19]=[CH:18]3)=[CH:13][N:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC(=O)OC)ccc3c2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1oc2ccccc2c1-c1ncc(-c2ccc3cc(OCC(=O)O)ccc3c2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of methyl ({6-[2-(2-butyl-1-benzofuran-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetate (295 mg, 0.647 mmol), prepared in the previous step, and 1N NaOH (1.3 mL, 1.3 mmol) in 35 mL of THF and 20 mL of H2O was stirred under nitrogen at room temperature for 14 h (overnight). The reaction was acidified by the addition of 1.4 mL of 1N HCl and then concentrated under reduced pressure to remove the THF. The yellow solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (237 mg, 93%) as a yellow solid, mp 214-216° C. Elemental Analysis for C27H23NO5 Calc'd: C, 73.46; H, 5.25; N, 3.17. Found: C, 73.00; H, 5.49; N, 3.02.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[C:27]([CH3:34])=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[C:27]([CH3:34])=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(F)cccc1NN
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: Cc1c(F)cccc1-n1nccc1-c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-fluoro-2-methyl-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=425.2 (M+H)+
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][C:19]=1[O:32][CH3:33])[OH:17])C1C=CC=CC=1.[CH3:38][O-:39].[Na+]>CO>[CH3:38][O:39][C:14](=[O:37])[C@@H:15]([O:34][CH2:35][CH3:36])[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:20][C:19]=1[O:32][CH3:33])[OH:17]
Reactant: C[O-]
Reactant: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1OC
Agent: [Na+]
Solvent: CO
Product: CCO[C@H](C(=O)OC)[C@H](O)c1ccc(OCc2ccccc2)cc1OC

Procedure:
In analogy to the procedure described in example 1 b], (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one was treated with sodium methoxide in methanol to give (2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionic acid methyl ester as colorless liquid. According to 1H-NMR spectroscopy, one single diastereomer was obtained.