Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH:6]([OH:8])[CH:5]2[O:9][CH2:10][CH:11]([OH:12])[CH:4]12.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([O:8][CH:6]1[CH:5]2[O:9][CH2:10][CH:11]([OH:12])[CH:4]2[O:3][CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OC1COC2C(O)COC12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC1COC2C(OCc3ccccc3)COC12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of sodium hydride (3.24 g, 81.0 mmol) in anhydrous DMF (20 mL) was added hexahydrofuro[3,2-b]furan-3,6-diol (10.1 g, 69.1 mmol) at 0° C. and the mixture was stirred for 1 h at 0° C. To the mixture was added bromomethylbenzene (11.73 g, 68.58 mmol) and the resulting mixture was stirred at rt for 4.5 h, and then quenched with H2O 2O (50 mL). The separated water layer was extracted with EtOAc (250 mL×3). The combined organic layers were washed with H2O (50 mL×6), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as light yellow oil (8.1 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([N:26](COCC[Si](C)(C)C)[S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:9][CH3:10])=[CH:4][CH:3]=1.Cl>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:11][CH2:12][C:13]([F:16])([F:14])[F:15])[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: CCC(CCC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: Cl
Solvent: CCO
Product: CCC(CCC(F)(F)F)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 50 °C

Procedure:
A mixture of the product from step C (20 mg, 0.034 mmol, enantiomer A), 2 M HCl (1 mL) and EtOH (2 mL) was heated to 50° C. for 3 h. The volatile was removed under reduced pressure. The residue was purified by Combiflash (mobile phase: MeOH/water (0.08% of NH4HCO3)) to give the title compound. LC/MS m/z=458.7 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=3.6 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.10 (d, J=7.6 Hz, 1H), 7.05 (d, J=8.8 Hz, 2H), 6.86 (t, J=8.1 Hz, 1H), 6.59-6.58 (m, 2H), 6.40 (d, J=8.4 Hz, 1H), 3.03 (s, 3H), 2.74-2.67 (m, 1H), 2.55-2.45 (m, 2H), 2.26-2.16 (m, 1H), 1.89-1.86 (m, 1H), 1.45-1.38 (m, 1H), 0.67 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:37])[C:18]([N:20]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:28]3[S:32][CH:31]=[N:30][CH:29]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:38][CH3:39].[OH-].[K+]>O1CCOCC1.O.Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:37])[C:18]([N:20]([C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]#[C:27][C:28]3[S:32][CH:31]=[N:30][CH:29]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:38][CH3:39]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCCOCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCCOCC#Cc1cncs1)C(C)(C)C)CC2
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 293 mg of 8c in 3 ml of dioxane was mixed with a solution of 100 mg of KOH in 1 ml of water and stirred at 55° C. for 1 hr. After this period all ester had disappeared according to TLC. The reaction mixture was cooled, diluted with 10 ml of water and cold 0.5N HCl was added until pH 3. The product was extracted into ethyl acetate. The combined organic layers were once washed with water, dried and concentrated. The amorphous product 8d thus obtained was used without further purification in the next step.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzotrifluoride (1a, 1.0 g, 4.78 mmol), methyl 4-hydroxyphenylacetate (1b, 795 mg, 4.78 mmol) and potassium carbonate (661 mg, 4.78 mmol) in 10 mL of DMSO was allowed to stir at 60° C. for 24 h. Upon completion, the mixture was cooled to room temperature and 50 mL of water was added. The resulting mixture was extracted with ethyl acetate (3×30 mL). The combined extracts were washed with water (2×30 mL) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using 20% EtOAc/hexane as the eluent to give 1.31 g of [4-(2-nitro-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester. 1H NMR (CDCl3): δ 8.22 (d, J=2.00 Hz, 1H), 7.70 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (d, J=8.36 Hz, 2H), 7.08 9s, 1H), 7.07 (d, J=8.48 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.CC(C1C=CC(Cl)=CC=1)=O.ClC1C=CC([C@@H](O)C)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Cl)cc1
Agent: CC(=O)c1ccc(Cl)cc1
Agent: C[C@H](O)c1ccc(Cl)cc1
Product: C[C@@H](O)c1ccc(Cl)cc1
Reaction time: 72 h
Yield: 51 %

Procedure:
As shown here, the biochemical conversion reaction of immobilized soy bean protein for the substrate (±)-1-(4-chlorophenyl)ethanol (200 mg) requires 3 days by going through bioconversion to 4-chloroacetophenone accompanying sterically selective oxidation of (S)-1-(4-chlorophenyl)ethanol to obtain 102 mg of (R)-1-(4-chlorophenyl)ethanol at a yield of 51%. Optical purity was obtained at 96% e.e.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].[N+:12]([C:15]1[CH:16]=[C:17]([S:22](Cl)(=[O:24])=[O:23])[CH:18]=[CH:19][C:20]=1[Cl:21])([O-:14])=[O:13]>O.C(#N)C>[CH2:3]([N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[S:22]([C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=1)(=[O:23])=[O:24])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNCCCC
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCCCN(CCCC)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
150 g of sodium hydroxide was dissolved in 200 ml of water, and the solution was cooled. To this solution was added 600 ml of dibutylamine, and the solution was cooled to 0° C. A solution of 954 g of 3-nitro-4-chlorobenzenesulfonyl chloride in 950 ml of acetonitrile was dropwise added thereto under vigorous stirring while keeping the solution temperature at not higher than 10° C. After completion of the dropwise addition, the reaction mixture was stirred for 1 hour at 10° C., and the crystals which precipitated were collected by filtration, washed wellwith a dilute hydrochloric acid aqueous solution (1N), and dried.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:20][CH:19]=[C:18]([CH3:21])[N:9]2[C:10](=[O:17])[C:11]=1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:20][CH:19]=[C:18]([CH3:21])[N:9]2[C:10](=[O:17])[C:11]=1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3nccs3)c(=O)n12
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc2nc(C(C)N)c(-c3nccs3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.030 g, 0.094 mmol) in tetrahydrofuran (0.3 mL) and water (0.068 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.11 mL, 0.11 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step. LCMS calculated for C12H13N4OS2 (M+H)+: m/z=293.1. Found: 293.0.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[C:3](O)=[O:4].C([O:24][N:25]1C2C(=CC=CC=2)[C@H](C)[C@H](NC(=O)OC(C)(C)C)C1=O)C1C=CC=CC=1.C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>B(Cl)(Cl)Cl>[NH2:1][CH:2]1[CH2:6][C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[N:25]([OH:24])[C:3]1=[O:4]
Reactant: C[C@H]1c2ccccc2N(OCc2ccccc2)C(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: NC(Cc1cccc2ccccc12)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: NC1Cc2c(ccc3ccccc23)N(O)C1=O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 10 %

Procedure:
Benzyl[4-(benzyloxy)-3-oxo-1,2,3,4-tetrahydrobenzo[t]quinolin-2-yl]carbamate (54, prepared from 2-amino-3-(1-naphthyl)propanoic acid according to the general procedure for synthesis of tert-butyl (3S,4S)-1-(benzyloxy)-4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (33) in Example 7) (35 mg, 0.077 mmol) was dissolved in a solution of boron trichloride in DCM (1.0 M, 5.00 mL, 5.00 mmol), and the reaction was heated at 50° C. for 1 h. After being quenched with MeOH (10 mL), the reaction was stirred for 15 min, then treated with silica gel impregnated with p-toluenesulfonic acid (0.68 mEq/g, 2 g, 1.36 mmol). After 1.5 hours, the silica was filtered off and rinsed with MeOH; the silica was then slurried with a 2N solution of ammonia in MeOH for 20 minutes, and filtered. The solids were rinsed with MeOH and the combined filtrates were concentrated in vacuo to afford a solid, which was triturated with Et2O to provide the product as a solid (2 mg, 10%). LCMS m/z 229.0 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.07 (dd, J=15, 15 Hz, 1H), 3.82 (dd, J=16, 6.5 Hz, 1H), 4.00 (dd, J=14, 6 Hz, 1H), 7.45 (dd, J=7, 7 Hz, 1H), 7.58 (dd, J=8, 8 Hz, 1H), 7.67 (d, J=9 Hz, 1H), 7.88 (m, 2H), 8.01 (d, J=9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C(O)(C(F)(F)F)=O>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=4)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: Nc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)Nc4ccc(O)cc4)cc3)cc12

Procedure:
4-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethylamino)phenol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and 4-aminophenol following the procedures described for Example 187, except that in this case, acetic acid was used instead of triethylamine (28%). 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.73 (s, 1H), 8.33 (d, 1H), 7.44 (s, 1H), 7.40 (d, 2H), 7.36 (d, 1H), 7.24 (d, 2H), 7.10 (d, 2H), 6.76 (d, 2H), 4.72 (m, 1H) 3.27 (t, 2H), 3.12 (t, 2H), 2.50 (s, 3H), 2.06 (d, 3H). LRMS [M+H]=449.2
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][NH2:8])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19]>C(Cl)Cl>[CH2:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][NH:8][C:17](=[O:21])[C:18]([CH3:20])=[CH2:19])[CH:2]=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: C=CCOCC(O)CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOCC(O)CNC(=O)C(=C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Allyloxy-2-hydroxy-propylamine made in Example 8 (110 g, 0.84 mol), triethylamine (85.6 g, 0.84 mol), and methylene chloride (300 mL) were mixed in a two-liter, two-neck flask, which was placed in an ice bath. To the above mixture, methacryloyl chloride (90.36 g, 84 mol) was added dropwise through an additional funnel at 0° C. After completion of the addition of methacryloyl chloride, the whole mixture was allowed to warm up to room temperature and stirred at ambient temperature overnight (˜15 hours). The reaction suspension was diluted with 250 mL of methylene chloride and washed with 5% aqueous sodium chloride solution, saturated aqueous sodium bicarbonate solution, 5% aqueous sodium chloride solution and then followed by washing with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulfate (100 g). After the removal of sodium sulfate by filtration, 4-methoxyphenol (0.5 g) was added to the filtrate. The solution was concentrated under vacuum using a rotovap to give about 122 g of crude N-(3-allyloxy-2-hydroxy-propyl)-2-methyl acrylamide. N-(3-Allyloxy-2-hydroxy-propyl)-2-methyl acrylamide was purified by distilling the raw material inhibited with 1% of 4-methoxyphenol under vacuum at 168° C.-170° C. (7-8 mbar) using Kugelrohr distillation equipment.
Reaction SMILES: S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20]S(C1C=CC(C)=CC=1)(=O)=O)(C1C=CC(C)=CC=1)(=O)=O>C(OCC)(=O)C>[CH2:12]([OH:11])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Product: OCCOCCOCCO
Temperature: 25 °C
Yield: 89 %

Procedure:
To a 25 mL schlenk flask with Kontes valve and stirbar under argon 1 (1.67 mmol, 0.423 g) was added and the flask evacuated and backfilled with argon 3×. Anhydrous DMF (12.2 mL) was added via syringe and the solution stirred at rt. Next, anhydrous CsCO3 (3.52 mmol, 1.15 g) was added followed by triethylene glycol ditosylate (0.808 mmol, 0.371 g) and the mixture stirred at rt. The vessel was closed, stirred and heated to 70° C. for ca. 12 h. The reaction was allowed to cool to rt then diluted with ethyl acetate (10 mL), filtered and the solid washed with ethyl acetate (3×100 mL) and filtered. The organic extracts combined and washed with saturated NH4Cl(aq) (25 mL) then washed with brine (3×25 mL) dried over Na2SO4, filtered and the solvent removed by rotovaporation to afford the crude product. Purification by silica plug (ethyl acetate) afforded a white solid (0.464 g; 89% yield). IR (cm−1) 2947, 2884, 1683, 1601, 1476, 1397, 1110; 1H NMR (400 MHz, CDCl3) δ 7.38 (s, 4 H, ArH), 6.13 (s, 4 H, ArCHO2), 4.18 (m, 4 H, ArOCH2—), 4.02 (m, 16 H, OCH2CH2O), 3.84 (m, 4 H, ArOCH2CH2—), 3.78 (s, 4 H, ArOCH2CH2OCH2CH2OCH2CH2OAr), 2.33 (s, 6 H, ArCH3); {1H} 13C NMR (100 MHz, CDCl3) 154.5, 134.2, 130.8, 129.0, 99.1, 76.0, 70.9, 70.5, 65.5, 21.2.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1.Cl.[CH3:17][N:18]([CH2:20][CH2:21]Cl)[CH3:19]>C(O)C>[CH3:17][N:18]([CH3:19])[CH2:20][CH2:21][N:4]1[CH:5]=[CH:6][C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][C:3]1=[O:2]
Reactant: CCOC(=O)CCc1ccnc(O)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCc1ccn(CCN(C)C)c(=O)c1
Yield: 64.1 %

Procedure:
To a cooled solution of sodium (7.50 g) in ethanol (150 ml) was added a solution of ethyl β-(2-hydroxy-4-pyridyl)propionate (29.07 g) in ethanol (175 ml). After the solution was stirred for 40 minutes a solution of dimethylaminoethyl chloride hydrochloride (21.78 g) in ethanol (175 ml) was added and the reaction mixture was stirred under reflux for 6 hours and then was allowed to cool overnight. The reaction mixture was filtered and evaporated under reduced pressure to remove most of the solvent. Water (150 ml) was added and the solution was extracted with ethyl acetate (3×200 ml). The combined ethyl acetate extracts were dried over MgSO4 and evaporated under reduced pressure to yield an oil which was subjected to medium pressure column chromatography (using Kieselgel 60 silica gel 70-230 mesh-pre column and 230-400 mesh-main column) with gradient elution (dichloromethane→10% methanolic dichloromethane). The fractions containing the desired product were combined and evaporated under reduced pressure to yield ethyl β-[N-(2 -dimethylaminoethyl)-2-oxo-4-pyridyl]propionate (25.43 g) as an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13].[NH:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[Cl:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:14]1[CH2:15][CH2:16][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:18][CH2:19]1
Reactant: Fc1ccc(OCCCCl)c(Cl)c1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2n1C1CCN(CCCOc2ccc(F)cc2Cl)CC1

Procedure:
A mixture of 3.3 g of 2-(3-chloropropoxy)-5-fluorochlorobenzene, 3.3 g of 1-(4-piperidinyl)-2-oxobenzimidazoline, 0.9 g of sodium carbonate and 80 ml of dimethylformamide was heated at 80° - 90° C for 15 hours. After cooling, the reaction mixture was poured into water and extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was triturated with ether, cooled and filtered to give 1-{3-(2-chloro-4-fluorophenoxy)propyl}-4-(2-oxo-1-benzimidazolinyl)piperidine, m.p. 130° - 132° C; recrystallized from benzenecyclohexane, m.p. 149° - 149.5° C.
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][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and phenylhydrazine according to the method described for example 43. MS: M=393.1 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:48]([C:50]1[O:54][N:53]=[C:52](O)[C:51]=1[F:56])[CH3:49]>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][C:52]4[C:51]([F:56])=[C:50]([CH2:48][CH3:49])[O:54][N:53]=4)[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Reactant: CCc1onc(O)c1F
Product: CCc1onc(OCCCc2csc(C3=C(C(=O)N(Cc4cccc(Cl)c4Cl)C4CC4)C4CN(C(=O)OC(C)(C)C)CC(C3)N4C(=O)OC(C)(C)C)n2)c1F

Procedure:
This compound is prepared from compound E4 and 5-ethyl-4-fluoroisoxazol-3-ol, according to the above-described procedure A. LC-MS: tR=1.24 min, ES+: 820.35.
Reaction SMILES: [C:1]([CH:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[H-].[Na+].[Br:26]Br>O1CCCC1.ClCCl>[C:1]([C:4]([Br:26])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(CCCCCCCOC1CCCCO1)C(C)=O
Reactant: BrBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C(Br)(CCCCCCCOC1CCCCO1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-acetyl-9-tetrahydropyranyloxy-nonanoate (20 g) in dry tetrahydrofuran (100 ml) was added dropwise to a stirred suspension of sodium hydride (2.01 g of 80% oil dispersion) in dry tetrahydrofuran (50 ml), under nitrogen. The mixture was warmed to reflux for 10 minutes. The clear solution was allowed to cool to room temperature then a solution of bromine (3.15 ml) in dry dichloromethane (50 mls) was added rapidly. After stirring for 30 minutes, during which time a yellow precipitate was formed, the mixture was partitioned between water and ether. The ether solution was washed with brine, dried and evaporated in vacuo at low temperature (<30° C.). The ethyl 2-acetyl-2-bromo-9-tetrahydropyranyloxy-nonanoate was obtained as a dark yellow oil (27.1 g.) which still contained a small amount of solvent.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][C:5]1[N:9]2[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38]C(Cl)=O.Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC(O)=O>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([C:5]([CH2:4][C:3](=[O:22])[CH2:38][C:34]3[S:33][CH:37]=[CH:36][CH:35]=3)=[C:6]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[N:7]=2)[CH:10]=1
Reactant: COC(=O)Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Reactant: O=C(Cl)Cc1cccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)Cc2cccs2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 4.8 %

Procedure:
(6-methyl-2-p-tolyl-imidazo[1,2,a]pyridin-3-yl)-acetic acid methyl ester 35a (440 mg, 1.5 mmol) was dissolved in anhydrous THF (15 mL) and cooled to −78° C. Potassium hexamethyldisilazide (0.5M in toluene, 3.0 mL, 1.5 mmol) was added slowly and the resulting bright orange solution was stirred at −78° C. for 10 minutes. Thiophen-2-yl-acetyl chloride (92 μL, 0.75 mmol) dissolved in anhydrous THF (8 mL) was added dropwise to the enolate solution. The resulting yellow solution was stirred for 2 h at −78° C. and quenched with H2O (30 mL). After the solution warmed to room temperature, it was washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. The crude material was flushed through a pad of silica gel equilibrated with 10% MeOH/CH2Cl2 and concentrated. The crude keto-ester (0.75 mmol) was dissolved in concentrated AcOH (4.5 mL) and concentrated HCl (4.5 mL). A reflux condenser was attached and the yellow solution was heated at 120° C. for 16 h. The solution was cooled to room temperature and saturated aqueous K2CO3 was added slowly until pH=6. The suspension was poured into saturated aqueous K2CO3 and washed with EtOAc (3×50 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated. Purification was affected via silica gel column chromatography with 0–10% MeOH/CH2Cl2, then semi preparative reverse phase HPLC. Conditions: 20 mL/min flow rate, gradient of 40–70% CH3CN/H2O over 20 minutes, monitoring at 254 nm. Product eluted at 13.3 minutes. Product fractions were collected and concentrated to remove CH3CN, then washed with EtOAc (3×30 mL). The combined organic washes were dried (Na2SO4), filtered and concentrated to give the title compound (13 mg, 5%) as an off-white solid. 1H NMR (400 MHz, CDCl3) 7.85 (d, J=9.17 Hz, 1H), 7.63 (s, 1H), 7.55 (d, J=9.17 Hz, 1H), 7.26–7.18 (m, 5H), 6.98–6.94 (m, 2H), 4.26 (s, 2H), 4.06 (s, 2H), 2.32 (s, 6H). Mass spectrum (m/e) 361 (M+1)+.