Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:19](I)[CH:20]=[CH2:21]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[N:7]([CH2:21][CH:20]=[CH2:19])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCI
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of (3,4-difluorophenyl)-carbamic acid-tert-butyl ester (2.42 g, 10.55 mmol) in DMF (80 mL) at 0° C. under Ar was added NaH (60% dispersion in mineral oil, 0.805 g, 21 mmol, 2 eq.). The mixture was stirred at 0° C. for 30 min and then allyl iodide (6.42 mL, 53 mmol, 5 eq.) was added over 5 min. The mixture was warmed to room temperature and stirred for 2 h. The mixture was then diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (100 mL). The aqueous phase was washed with EtOAc (3×60 mL) and the combined organic extracts were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to give a brown oil which was purified by flash column chromatography by eluting with 10% EtOAc/hexanes to give allyl-(3,4-difluorophenyl)-carbamic acid-tert-butyl ester as a clear oil (2.238 g, 75%).). 1H NMR (300 MHz, CDCl3): δ 7.18 (m, 3H), 6.00 (m, 1H), 5.30 (m, 2H), 4.30 (m, 2H), 1.59 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:49]=[N+:50]=[N-:51].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][N:49]=[N+:50]=[N-:51])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCN=[N+]=[N-])C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 98.0 mg of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 18b) in N,N-dimethylformamide are added 94 mg of sodium azide and the resulting mixture is stirred for 24 hours at room temperature. The reaction mixture is diluted with water, extracted with tert-butyl methyl ether, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.47 (EtOAc-heptane 1:1); Rt=5.65.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]([CH3:19])([CH3:18])[CH2:6][CH:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)=[O:4].C(N(CC)CC)C>C(O)C.[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]([CH3:19])([CH3:18])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)=[O:4]
Reactant: COC(=O)C(C)(C)CC=Cc1ccc(C(=O)O)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)CCCc1ccc(C(=O)O)cc1
Reaction time: 20 h
Yield: 84.9 %

Procedure:
4-(4-Methoxycarbonyl-4-methyl-pent-1-enyl)-benzoic acid (900 mg, 3.4 mmol, 1 eq.) was dissolved in ethanol (13 ml) and triethylamine (568 μl, 4.1 mmol, 1.2 eq.) and palladium on carbon (90 mg, 10% Pd/C) were then added. The mixture was stirred under hydrogen atmosphere for 20 h. Reaction mixture was filtered over celite and washed with ethanol. The filtrate was evaporated to yield a yellow oil. This oil was dissolved in ethyl acetate and washed with a 1N aqueous hydrochloric acid solution. The aqueous layer was removed and the organic layer was washed with water, and brine, then dried over magnesium sulfate, filtered and concentrated to give 4-(4-methoxycarbonyl-4-methyl-pentyl)-benzoic acid (763 mg, 85%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][CH:13]=[CH2:14])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].C(N(CC)CC)C>O.C(Cl)(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][N:2]([CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:16]1[CH:22]=[CH:21][CH:20]=[C:18]([NH2:19])[CH:17]=1)[C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(I)c1
Reactant: C=CCCN(C)C(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CN(CC/C=C/c1cccc(N)c1)C(=O)c1ccccc1
Temperature: 107.5 °C
Yield: 112.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of N-methyl-N-(3-buten-1-yl)benzamide (2.15 g, 11.36 mmol), 3-iodoaniline (2.49 g, 11.36 mmol, Aldrich Chemical Company), palladium(II) acetate (25.5 mg, 0.11 mmol), and triethylamine (2.30 g, 22.70 mmol) was stirred and heated under reflux at 105-110° C. (oil bath temperature) for 52 h. The dark-brown solution was allowed to cool to ambient temperature and was diluted with water (20 mL) and CHCl3 (40 mL). The water layer was separated and extracted with CHCl3 (2×10 mL). The combined CHCl3 extracts were washed with saturated NaCl solution (10 mL), dried (CHCl3), filtered, and concentrated by rotary evaporation. Further drying under high vacuum (0.3 mm Hg) for 15 h produced a viscous, brown oil (3.59 g). The crude material was purified by column chromatography on silica gel (155.5 g, 4.0 cm i.d.×60.5 cm column) eluting with EtOAc (25→67%, v/v) in CHCl3. Fractions containing the product (Rf 0.34 in EtOAc-CHCl3, 1:1, v/v) were combined, concentrated by rotary evaporation, and vacuum dried at 45° C. for 15 h to give 1.60 g (50.2%) of an amber oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[N:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.[B:15]1(B2OCC(C)(C)CO2)[O:20]CC(C)(C)C[O:16]1>>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[C:8]1[N:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: Fc1ccc(Br)cc1-c1cccnn1
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Product: OB(O)c1ccc(F)c(-c2cccnn2)c1

Procedure:
3-(5-Bromo-2-fluorophenyl)pyridazine (304 mg, 1.20 mmol) was reacted with bis(neopentyl glycolato)diboron (298 mg, 1.32 mmol) using the method of Example 20 to give 4-fluoro-3-(pyridazin-3-yl)phenylboronic acid as a white solid: MS (ES+) m/z 219 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=[CH:20]2.C(O)(C(F)(F)F)=O.[OH-].[Na+]>O.C(O)(C)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=[CH:20]2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COC(=O)c1cccc2cc(N)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1cccc2cc(Nc3ncnc4cc(OC)c(OC)cc34)ccc12
Temperature: 90 °C

Procedure:
The following reagents were combined in a flask and placed in a RT oil bath that was then heated to 90° C.: 4-Chloro-6,7-dimethoxyquinazoline (954 mg, 4.24 mmol), methyl 6-amino-1-naphthoate (857 mg, 4.24 mmol), TFA (098 mL, 12.7 mmol), and isopropanol (12 mL). The reaction was done before the bath reached the desired temperature. The mixture was diluted with water and made pH basic with 6N NaOH. The solid was filtered and rinsed with water and Et2O. The title compound was obtained as a pink solid.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[O:20].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][C@H:14]([C:22]([OH:24])=[O:23])[CH2:15][CH2:16][CH2:17][NH:18][C:19]([NH2:21])=[O:20]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NC(=O)NCCC[C@H](N)C(=O)O
Agent: [Ni]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: NC(=O)NCCC[C@H](NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The product was made from D-glucose and L-(+)-citrulline using Raney nickel or palladium/activated carbon as a catalyst and heating for 2 hours to 50° C. and 4 hours to 70° C. A product was obtained which had a melting point of 176° C. and an RF -value of 0.7 (determined on DC-finished plates of silica gel G (Merck) with a transporting liquid made up of 50 parts by volume of methanol and 50 parts by volume of water).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17](=[N:21]O)C(O)=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>C(OC(=O)C)(=O)C>[C:1]1([C:7]2[C:15]([CH2:16][C:17]#[N:21])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(Cc1c(-c2ccccc2)nn2ccccc12)=NO
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: N#CCc1c(-c2ccccc2)nn2ccccc12
Yield: 63.3 %

Procedure:
A solution of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-hydroxyiminopropionic acid (0.20 g) in acetic anhydride (1 ml) was stirred for an hour at 80° C. After cooling to the mixture was added water (10 ml). The resulting precipitates were collected by filtration to give 2-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)acetonitrile (0.10 g).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[CH:11]1(B(O)O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+].N1C=CC=CC=1C1C=CC=CN=1.[NH4+].[Cl-]>C(Cl)Cl.O>[CH:11]1([N:8]2[C:6]3=[N:7][C:2]([F:1])=[CH:3][CH:4]=[C:5]3[CH:10]=[CH:9]2)[CH2:13][CH2:12]1
Reactant: OB(O)C1CC1
Reactant: Fc1ccc2cc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: Fc1ccc2ccn(C3CC3)c2n1
Temperature: 50 °C
Yield: 25.3 %

Procedure:
To a solution of 6-fluoro-1H-pyrrolo[2,3-b]pyridine (6.2 g, 45.55 mmol) in dry DCM (250 mL) is added cyclopropylboronic acid (7.82 g, 91.09 mmol), followed by cupric acetate (8.36 g, 45.55 mmol), sodium carbonate (9.65 g, 91.09 mmol) and 2,2′-bipyridine (7.11 g, 45.55 mmol). The resulting mixture is stirred and heated at 50° C. for 15 h. The mixture is cooled to room temperature and further cupric acetate (4.18 g, 22.77 mmol) and sodium carbonate (2.41 g, 22.77 mmol) are added, followed by cyclopropylboronic acid (1.96 g, 22.77 mmol). The mixture is stirred and heated at 50° C. for a further 15 h when further cupric acetate (1.5 g, 8.25 mmol) and cyclopropylboronic acid (1.49 g, 17.34 mmol) are added. The mixture is stirred at room temperature for 4 days and then poured onto sat. aq. NH4Cl, diluted with water and extracted with DCM. The organic layers are combined, washed with brine, dried (magnesium sulphate) and concentrated in vacuo to give a green oil, which is purified by column chromatography on silica, eluting with DCM, to give the title compound (2.03 g, 11.52 mmol). MS (m/z): 177 (M+1). Unreacted 6-fluoro-1H-pyrrolo[2,3-b]pyridine is also recovered (3.012 g, 22.1 mmol). MS (m/z): 137 (M+1).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10]C)=O.[NH3:12]>CO>[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([NH2:12])=[O:10]
Reactant: COC(=O)C1COCCN1
Reactant: N
Agent: Cl
Solvent: CO
Product: NC(=O)C1COCCN1
Yield: 99 %

Procedure:
A mixture of methyl morpholine-3-carboxylate hydrochloride (0.55 g, 3.0 mmol) and a solution of NH3 in methanol (7 mol/L, 20 mL) was stirred at 50° C. for 24 hours in a sealed tube. The mixture was concentrated in vacuo to give the title compound as glutinous semisolid (0.39 g, 99%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:28])C=1>O>[OH:28][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Yield: 52.9 %

Procedure:
A mixture of 2.2 g of ethyl 2-(4-formylphenoxy)propionate, 10 ml of methylene chloride and 2.6 g of m-chloroperbenzoic acid, were reacted for 2 hours under reflux, and after an addition of 0.5 g of water, further refluxed for 1 hour. After cooling, the reaction mixture was washed twice with 20 g of a 5% sodium hydrogen carbonate aqueous solution, then with 10 g of a 5% sodium hydrogen sulfite aqueous solution and further with 10 g of water. The mixture was concentrated by distilling off methylene chloride, and then subjected to distillation under reduced pressure, whereby 1.1 g of ethyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][C:14]1[C:15]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:24]2[CH2:25][CH2:26][N:21]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[CH:17][N:16]=3)[CH2:22][CH2:23]2)=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: COc1cc(Br)ccc1C(=O)O
Product: COc1cc(Br)ccc1C(=O)N1CCN(c2ncc(C)cc2C)CC1
Yield: 94.4 %

Procedure:
Using 4-bromo-2-methoxybenzoic acid (2.31 g) and 1-(3,5-dimethylpyridin-2-yl)piperazine (1.91 g) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.81 g) was obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:10][C:9]2=[CH:11][C:12]3[CH:16]=[C:15]([Sn](CCCC)(CCCC)CCCC)[S:14][C:13]=3[CH:30]=[C:8]2[CH:7]=1)CCC.C(OC([N:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[N:52](COCC[Si](C)(C)C)[CH:53]=[C:54](Br)[N:55]=1)=O)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:46]1[CH2:50][CH2:49][CH2:48][CH:47]1[C:51]1[NH:55][C:54]([C:15]2[S:14][C:13]3[CH:30]=[C:8]4[CH:7]=[C:6]([C:54]5[NH:55][C:51]([CH:47]6[CH2:48][CH2:49][CH2:50][NH:46]6)=[N:52][CH:53]=5)[S:10][C:9]4=[CH:11][C:12]=3[CH:16]=2)=[CH:53][N:52]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cc3sc([Sn](CCCC)(CCCC)CCCC)cc3cc2s1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)cn1COCC[Si](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1nc(C2CCCN2)[nH]c1-c1cc2cc3sc(-c4cnc(C5CCCN5)[nH]4)cc3cc2s1
Temperature: 25 °C

Procedure:
Pd(PPh3)4 (61 mg, 0.053 mmol) was added to a degassed solution of 2,6-bis(tri-n-butylstannyl)-benzo[1,2-b:4,5-b′]dithiophene (202 mg, 0.26 mmol) and 2-[4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (260 mg, 0.58 mmol) in toluene (4 mL). The reaction was refluxed for 24 hours, then cooled to room temperature and filtered through CELITE and a palladium scavenging column (Stratospheres™ PL-Guanidine MP SPE+, Part #: PL3514-CM89). The solids were rinsed twice with toluene. The filtrate was concentrated and the crude product purified by flash chromatography to yield the desired, fully protected product (100 mg, 41%). LCMS-ESI+: calculated for C46H68N6O6S2Si2: 920.42; observed [M+1]+: 921.45.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])/[C:5](OC)=[O:6].[CH3:25][NH2:26]>>[CH3:1][O:2]/[N:3]=[C:4](\[C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])/[C:5]([NH:26][CH3:25])=[O:6]
Reactant: CN
Reactant: CO/N=C(/C(=O)OC)c1c(C)cccc1COc1ccccc1C
Product: CNC(=O)/C(=N/OC)c1c(C)cccc1COc1ccccc1C

Procedure:
methyl E-2-((2-methylphenyl)oxymethyl)-6-methylphenylglyoxylate O-methyl oxime prepared in the step 1 is reacted with methylamine (NH2Me) to give N-methyl E-2-((2-methylphenyl)oxymethyl)-6-methylphenylglyoxylamide O-methyl oxime of the present invention (step 2).
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[C:24]([CH3:26])[CH:25]=1.C1C(=O)N([Br:38])C(=O)C1>ClCCl>[Br:38][CH2:26][C:24]1[CH:23]=[C:22]([CH2:27][C:28]([OH:30])=[O:29])[CH:21]=[C:20]([F:19])[CH:25]=1
Reactant: Cc1cc(F)cc(CC(=O)O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(O)Cc1cc(F)cc(CBr)c1
Temperature: 25 °C

Procedure:
Benzoyl peroxide (0.5 g) was added to a stirred mixture of 2-(3-fluoro-5-methylphenyl)acetic acid (5.19 g) and NBS (6.04 g) in dichloromethane (100 mL). The resultant mixture was heated at reflux for 5 hours. The reaction mixture was cooled to room temperature and then washed twice with water, the organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% acetic acid and 17% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 4.3 g.
Reaction SMILES: [Na].C([C:4]1([CH2:12][CH3:13])[O:8][C@@H:7]([CH2:9]CI)[CH2:6][O:5]1)C.C(OCC)(=O)CC(OCC)=[O:17].CCOCC>C(O)C.O>[OH:5][CH2:6][C@H:7]1[O:8][C:4](=[O:17])[CH2:12][CH2:13][CH2:9]1
Reactant: CCC1(CC)OC[C@H](CCI)O1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: O=C1CCC[C@@H](CO)O1
Yield: 25.5 %

Procedure:
To a solution of 0.55 g of sodium in 20 ml of absolute ethanol were added 6 g of (S)-2,2-diethyl-4-(2-iodoethyl)-1,3-dioxolane synthesized in Example 1 and 3.7 g of diethyl malonate, and the mixture was refluxed for 2 hr. Then, 50 ml of an ether and 50 ml of water were successively added to the resultant solution, and the ether phase was collected. The resultant ether solution was washed with a saturated saline solution, dried over magnesium sulfate, the solvent was removed from the dried ether solution by distillation, and the resultant residue was purified by a silica gel column chromatography through the use of hexane-ethyl acetate as a developing solvent. The purified product was dissolved in an ether, and 2N sodium hydroxide was added thereto. The mixture was refluxed for hydrolysis and decarboxylation, the pH was adjusted to 5 with 1N hydrochloric acid, and the reaction product was extracted with ethyl acetate. The solvent was removed from the extract, the resultant residue was dissolved in THF, a few drops of sulfuric acid was added thereto, the solution was concentrated, and the solute was purified from the concentrate by a silica gel column chromatography through the use of a mixed solution comprising hexane and ethyl acetate as a developing solution to obtain 0.7 g of (S)-5-hydroxymethyl-valerolactone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH:10]([CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[Br-].[Li+]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]([CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: CCOC(=O)C(Br)C(C)C
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Product: CCOC(=O)C(C(C)C)n1ccc(Br)cc1=O

Procedure:
500 mg (2.9 mmol) of 4-bromopyridin-2(1H)-one and 841 mg (4.02 mmol) of ethyl 2-bromo-3-methylbutanoate (racemate) in the presence of 1.15 eq. of sodium hydride and 2.3 eq. of lithium bromide were reacted according to General Method 4C. Yield: 260 mg (purity 92%, 28% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>C(#N)C>[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][O:9][C:8]1[CH:10]=[CH:11][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: Fc1ccccc1CBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: 52.5 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Methylparaben (8.85 g, 58.19 mmol) and K2CO3 (16.1 g, 116.38 mmol) were stirred in acetonitrile (100 mL) for 5 minutes and then 2-fluorobenzyl bromide (10 g, 52.9 mmol) was added. The suspension was heated to 50-55° C. and held for 2 hours. The mixture was then cooled to 20-25° C., filtered, and the filtrate solution concentrated to a thick residue. The residue was then dissolved in CH2Cl2, washed with a 1 M Na2CO3 solution, dried over Na2SO4, and concentrated to a solid. The solid was then stirred vigorously for 1 hour in just enough hexanes to allow for agitation (˜40 mL) and then cooled to 0-5° C. After 15 minutes, the product was isolated by filtration and washed with ˜25 mL of hexanes. After drying under vacuum, 1 was isolated as a white solid (13.1 g, 87% yield).
Reaction SMILES: [CH:1]1([C:6]2([C:11]3[CH:16]=[C:15]([O:17]C)[CH:14]=[C:13]([O:19]C)[CH:12]=3)[S:10][CH2:9][CH2:8][S:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)(=O)C>[CH:1]1([C:6]2([C:11]3[CH:12]=[C:13]([OH:19])[CH:14]=[C:15]([OH:17])[CH:16]=3)[S:7][CH2:8][CH2:9][S:10]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(OC)cc(C2(C3CCCC3)SCCS2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Oc1cc(O)cc(C2(C3CCCC3)SCCS2)c1

Procedure:
Compound 17 was prepared from Compound 10 using the same procedure as described above for Compound 16. Yield 0.67 g (74.1%) as a waxy solid. Rf=0.28 (hexane:ethyl acetate 8:2); 1H NMR δ 6.89 (d, J=2.4 Hz, 2H), 6.23 (t, J=2.1 Hz, 1H), 5.68 (br s, 2H), 3.34–3.07 (m, 4H), 2.78–2.67 (m, 1H), 1.71–1.38 (m, 8H); 13C NMR δ 156.26, 150.31, 108.13, 101.59, 79.28, 52.27, 39.02, 31.39, 25.94; MS: (ESI, Pos.) m/z 305 ([M+23]+).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:19][S@](C(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])(C(C)(C)C)(C)C.[ClH:26].O1CCOCC1>CO>[ClH:26].[NH2:19][C@H:10]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH2:9][OH:8]
Reactant: CC(C)(C)[S@](=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](CO)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a mixture of (S)—N—((R)-2-(tert-butyldimethylsilyloxy)-1-(2,4-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (1.08 g, 2.76 mmol) in MeOH (8 mL) was added 4N HCl in dioxane (6.9 mL, 28 mmol) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 4 hours. The solvents were evaporated in vacuo to give (R)-2-amino-2-(2,4-difluorophenyl)ethanol hydrochloride (0.58 g, 100%) as a white solid, which was used in the next step without further purification.
Reaction SMILES: [ClH:1].[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)(=O)[CH3:3].Cl.[CH3:14][O:15][NH2:16]>CO>[ClH:1].[CH3:14][O:15][N:16]=[C:2]([CH:5]1[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1)[CH3:3]
Reactant: CON
Reactant: CC(=O)C1CN2CCC1CC2
Agent: Cl
Solvent: CO
Product: CON=C(C)C1CN2CCC1CC2
Yield: 67.9 %

Procedure:
2.3 g of 3-acetyl quinuclidine hydrochloride (Helv. Chim. Acta (1963) 229, 2658) and 1.02 g of O-methylhydroxylamine hydrochloride are heated for 20 minutes to reflux in 30 cm3 of methanol. The solvent is evaporated and the residue is chromatographed on silica (eluant: chloroform-methanol 7-3). After crystallization from ethanol and from ether, 1.8 g of expected product is obtained. M.p.=186°-188° C.