Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]1([C:14]([O:16]C)=[O:15])[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([OH:13])=[CH:8][CH:9]=2)[O:4]1)[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][C:20]=1[O:31][CH2:32][CH2:33][CH2:34]Br>>[Cl:18][C:19]1[CH:24]=[C:23]([CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:22]=[CH:21][C:20]=1[O:31][CH2:32][CH2:33][CH2:34][O:13][C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][CH2:12][C@:3]([CH2:1][CH3:2])([C:14]([OH:16])=[O:15])[O:4]2)=[CH:9][CH:8]=1
Reactant: CC[C@]1(C(=O)OC)CCc2ccc(O)cc2O1
Reactant: Clc1cc(C2CCOCC2)ccc1OCCCBr
Product: CC[C@]1(C(=O)O)CCc2ccc(OCCCOc3ccc(C4CCOCC4)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the procedure described in Example 5, Steps D-E employing (2R)-methyl 2-ethyl-7-hydroxychromane-2-carboxylate (Example 13, Step E) instead of ethyl 7-hydroxychromane-2-carboxylate, and 3-bromopropyl 2-chloro-4-(4-tetrahydropyranyl)phenyl ether instead of 3-bromopropyl 2-chloro-4-(2,2,2-trifluoroethoxy)phenyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[F:13][C:14]([F:18])([F:17])[CH2:15][NH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:16]([CH2:15][C:14]([F:18])([F:17])[F:13])[CH2:11]2
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Reactant: NCC(F)(F)F
Product: O=C1c2ccc(Br)cc2CN1CC(F)(F)F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate and 2,2,2-trifluoroethylamine (Aldrich Cat No. 269042). LCMS (M+H)+=294.0/296.0.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22](O)=[O:23].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:20])([F:19])[F:21])=[CH:13][CH:12]=2)=[O:9])[N:4]=[C:3]1[C:22]([N:56]1[CH2:57][CH2:58][N:53]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][N:47]=2)[CH2:54][CH2:55]1)=[O:23]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1.50 g (4.36 mmol) of the compound of Example 4A is dissolved in 30 ml of DMF and mixed with 1.82 g (5.66 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) and 266 mg (2.18 mmol) of 4-dimethylaminopyridine. After adding 925 mg (5.66 mmol) of 1-(pyridin-2-yl)-piperazine, it is allowed to stir for 4 hours at room temperature. The reaction mixture is purified by RP-HPLC.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1.I[C:40]1[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[CH:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][C@@:9]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:14][C:13](=[O:15])[N:12]([C@H:16]([C:18]3[CH:19]=[CH:20][C:21]([C:40]4[CH:45]=[CH:44][N:43]([CH3:46])[C:42](=[O:47])[CH:41]=4)=[CH:22][CH:23]=3)[CH3:17])[CH2:11][CH2:10]2)=[N:4][N:3]=1
Reactant: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)C(=O)O2)o1
Reactant: Cn1ccc(I)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nnc(CC[C@]2(c3ccccc3)CCN([C@@H](C)c3ccc(-c4ccn(C)c(=O)c4)cc3)C(=O)O2)o1
Yield: 41.8 %

Procedure:
To a solution of (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.12 mmol) and 4-iodo-1-methylpyridin-2(1H)-one (33 mg, 0.14 mmol) in dry 1,4-dioxane (15 mL) were added Cs2CO3 (2M, 1 mL) and Pd(PPh3)Cl2 (7.7 mg, 0.01 mmol). The mixture was heated at reflux for 2 h under N2 atmosphere, the solid was filtered off, and the mixture was diluted with water (30 mL) and EtOAc (30 mL). The combined organic layers was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by prep TLC to afford (R)-6-(2-(5-methyl-1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (25 mg, yield: 41.8%). LC-MS Method 2 tR=0.984 min, m/z=499.1; 1H NMR (CDCl3): δ1.48-1.50 (m, 3H), 2.16-2.20 (m, 1H), 2.23-2.26 (m, 1H),2.27-2.32 (m, 2H), 2.39 (s, 3H), 2.40-2.47 (m, 1H), 2.49-2.54 (m, 1H), 2.87-2.90 (m, 1H), 2.98-3.01 (m, 1H), 3.58 (s, 3H), 5.62-5.64 (m, 1H), 6.45-6.48 (m, 1H), 6.87 (s, 1H), 6.92-6.94 (d, 2H), 7.20-7.24 (m, 4H), 7.25-7.35 (m, 4H).
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:16]([Mg]Br)[CH3:17]>[Co](Cl)Cl>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH:2]([CH:2]([C:17]2[CH:16]=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:13]=[CH:12][CH:11]=1
Reactant: CC[Mg]Br
Reactant: CCCCCC(Cl)c1cccc(OC)c1
Agent: Cl[Co]Cl
Product: CCCCCC(c1cccc(OC)c1)C(CCCCC)c1cccc(OC)c1

Procedure:
The preparation was effected in analogy to example 1(c) from 1-chlor-1-(3'-methoxyphenyl)-hexane and ethyl magnesium bromide activated with cobalt - (II) - chloride.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][O:7][C:6]1=[O:10]>CO>[O:2]1[CH2:3][CH2:4][CH:5]([C:6]([O:7][CH3:8])=[O:10])[CH2:9][CH2:1]1.[CH2:4]1[C:5]2([CH2:9][CH2:8][O:7][CH2:6]2)[C:3]1=[O:2]
Reactant: COCCC1CCOC1=O
Solvent: CO
Product: COC(=O)C1CCOCC1
Product: O=C1CC12CCOC2

Procedure:
During an experimental period of 36 h a total of 900 g of a solution consisting of 53 wt % of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone and 47 wt % of methanol was evaporated and the vapors were passed over 90 g of aluminum oxide catalyst (diameter 1.5 ram) at a temperature of 250° C. in a tubular reactor. Following condensation of the gaseous effluent, analysis was effected using gas chromatography. The conversion of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone was 53%. 46 mol % of methyl tetrahydropyran-4-carboxylate and 7 mol % of 5-oxaspiro-[2.4 ]heptan-2-one were formed.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)=O.[CH3:18]C(C)=O.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[Li].CI>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][C:11]([O:14][CH3:18])([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(C)=O
Reactant: [Li]c1cccs1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CI
Product: COC1(c2cccs2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 100 %

Procedure:
To a solution of N-Boc-4-piperidone (Boc-29.155) (201 mg, 1.01 mmol) in THF (5 mL), cooled by dry ice/acetone, was added 2-thienyllithium (1M in THF, 1.5 mL, 1.5 mmol). After 50 min, the cooling bath was removed; after additional 1 h, methyl iodide (125 μL, 2.01 mmol) was added, and the solution was stirred at ambient temperature overnight. The solvent was evaporated, water was added, and the mixture was extracted with EtOAc (4×15 mL). The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude material (acc. to 1H NMR mixture of methyl ether and the alcohol in a 1:2 ratio) was methylated according to the general procedure, yielding 300 mg (1.01 mmol, 100% yield) of the title compound as yellow oil. 1H NMR (CDCl3, 200 MHz): δ=1.46 (s, 9H), 1.93 (brdt, J=4.3, 12.6 Hz, 2H), 2.00 (brd, J=12.8 Hz, 2H), 3.05 (s, 3H), 3.16 (brt, J=11.0 Hz, 2H), 3.84 (brd, J=12.2 Hz, 2H), 6.93-7.00 (m, 2H), 7.25-7.31 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1.C[Si](C=[N+]=[N-])(C)C.C[OH:28].C1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:17][C:16](=[O:28])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 93 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamine)-6-chloro-nicotinic acid methyl ester: To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid (5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N2 was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise until the bubbling caused by gas evolution ceased. Solids precipitated out of solution. The reaction was allowed to stir for 1 hour. Excess (trimethylsilyl)diazomethane was quenched by the dropwise addition of glacial acetic acid. The precipitated solids were filtered and washed with methanol. The filtrate was concentrated to a smaller volume and additional solids precipitated out of solution that were filtered and washed with methanol. The solids were combined and dried under vacuum to yield 4.82 g (93%) of pure desired product as a dark pink solid.
Reaction SMILES: [CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12]OCC)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].[CH2:23]([NH2:25])[CH3:24]>>[CH3:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[CH:17]=[C:16]([F:22])[C:3]=1[C:4]([C:6](=[CH:12][NH:25][CH2:23][CH3:24])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C
Reactant: CCN
Product: CCNC=C(C(=O)OCC)C(=O)c1c(F)cc(F)c(F)c1C

Procedure:
Employing ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethoxyacrylate (1.0 g) and 70% aqueous ethylamine solution (0.24 ml), the procedure of Reference Example 8 is repeated to give ethyl 2-(2-methyl-3,4,6-trifluorobenzoyl)-3-ethylaminoacrylate, which is then treated with 60 % sodium hydride (0.15 g) as in Reference Example 9 to give ethyl 1-ethyl-5-methyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (0.6 g), as white crystals, m.p. 157°-159° C.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.Cl[CH2:7][CH2:8][N:9]([CH2:32][CH2:33]Cl)[C:10]1[CH:30]=[C:29]([Cl:31])[C:13]2[O:14][C:15]3[C:24]([CH3:25])=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][C:16]=3[S:17](=[O:20])(=[O:19])[CH2:18][C:12]=2[CH:11]=1.[CH3:35]O>>[CH3:35][O:28][C:26]([C:22]1[CH:23]=[C:24]([CH3:25])[C:15]2[O:14][C:13]3[C:29]([Cl:31])=[CH:30][C:10]([N:9]4[CH2:8][CH2:7][N:5]([CH:1]5[CH2:4][CH2:3][CH2:2]5)[CH2:33][CH2:32]4)=[CH:11][C:12]=3[CH2:18][S:17](=[O:20])(=[O:19])[C:16]=2[CH:21]=1)=[O:27]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: NC1CCC1
Reactant: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(C4CCC4)CC3)cc(Cl)c1O2
Temperature: 70 °C

Procedure:
Cyclobutylamine (1 mL, excess) was added to a solution of Example 102j (0.6 g, 1.25 mmol) in methanol (10 mL), followed by the addition of n-tetrabutylammonium iodide (0.01 g, 0.027 mmol) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 110° C. for 6 h. It was brought to room temperature, concentrated, treated with methanolic HCl solution, and refluxed at 70° C. for 6 h. The reaction mixture was concentrated, treated with water, aqueous sodium bicarbonate solution to neutral pH and the solid that separated was washed with water dried, and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.410 g, (25%); 1H NMR (DMSO-d6): δ 1.60-2.10 (m, 6H, 3CH2), 2.40-2.50 (m, 4H, 2CH2), 2.80 (m, 1H, CH), 3.20-3.30 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 4.70 (s, 2H, CH2), 6.80 (s, 1H, Ar), 6.90 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.50 (s, 1H, Ar); MS: m/e (CI+) 491 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]([NH:17]C(=O)C(F)(F)F)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:25]=[CH:24][C:16]([NH2:17])=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(CCOCOCc2ccccc2)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Nc1ccc(CCOCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
To a solution of 4′-[2-(benzyloxymethoxy)ethyl]-2,2,2-trifluoroacetanilide (9.7 g) in methanol (50 ml) were added water (30 ml) and potassium carbonate (3.3 g), and the mixture was stirred for 24 hours at room temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure gave 4-[2-(benzyloxymethoxy)ethyl]aniline (6.2 g).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[C:8]([CH3:18])=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.ClCCl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[C:4]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][N:9]=[C:8]([CH3:18])[C:7]=2[N:6]=1
Reactant: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccccc1F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1n[nH]c2c1nc(-c1ccccc1F)c1ccccc12
Reaction time: 4 h

Procedure:
The preparation took place in analogy to example 34 (D) using 182 mg of 2-fluoro-N-(3-methyl-5-phenyl-1H-pyrazol-4-yl)-benzamide, except 10.7 ml of phosphorous oxychloride was used and the reaction was stirred for 4 hrs. Trituration of the residue with ethyl acetate/dichloromethane (1/1) gave the title compound as a cream solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:11][C:10]([CH2:18]CS([O-])(=O)=O)([CH2:12]CS([O-])(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[NH:29][N:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)[C:26]=1[C:43]#[N:44].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:9][C:10]2([CH2:12][N:29]3[N:28]=[C:27]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:32][CH:31]=4)[C:26]([C:43]#[N:44])=[C:25]3[NH:24][CH2:18]2)[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O=S(=O)([O-])CCC1(CCS(=O)(=O)[O-])CN(Cc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC1(CN(Cc3ccccc3)C1)C2
Temperature: 80 °C
Reaction time: 16 h
Yield: 8.1 %

Procedure:
To a solution of (1-benzylazetidine-3,3-diyl)bis(methylene)dimethanesulfonate (300 mg, 0.83 mmol) in DMF (10 mL) was added 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (230 mg, 0.83 mmol) and K2CO3 (230 mg, 1.66 mmol). The mixture was stirred at 80° C. under N2 for 16 hr. The mixture was concentrated. The residue was washed with H2O (100 mL×2), dried and purified by pre-TLC (DCM/CH3OH=10/1) to afford 30 mg (10%) of desired product as a yellow liquid. MS (ESI) m/e [M+1]+ 447.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])[CH:5]=[C:6]([Cl:25])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH:16](O)[C:17](Cl)([Cl:22])[C:18]([F:21])([F:20])[F:19].N1C=CC=CC=1.C(OC(=O)C)(=O)C.Cl>CN(C1C=CN=CC=1)C.[Zn].CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:26][CH2:27][CH:28]=[C:29]([Cl:31])[Cl:30])[CH:5]=[C:6]([Cl:25])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15]/[CH:16]=[C:17](\[Cl:22])/[C:18]([F:21])([F:20])[F:19]
Reactant: OC(CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(Cl)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: FC(F)(F)/C(Cl)=C/CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
A mixture of 0.57 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(4,4-dichloro-5,5,5-trifluoro-3-hydroxypentyloxy)butyloxy)benzene, 0.16 g of pyridine, 0.12 g of acetic anhydride, 10 mg of N,N-dimethyl-4-aminopyridine and 20 ml of N,N-dimethylformamide was stirred at room temperature for 30 minutes, to which 0.078 g of zinc dust was added. The reaction mixture was further stirred at room temperature for 1 hour, poured into 20 ml of diluted hydrochloric acid and extracted twice with 50 ml of diethyl ether. The diethyl ether layers were combined, washed with water, dried over magnesium sulfate and then evaporated to give a crude product. The crude product was subjected to silica gel chromatography, which afforded 0.41 g of (Z)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(4-(4-chloro-5,5,5-trifluoro-3-pentenyloxy)butyloxy)benzene [the integrated CF3 signal ratio of Z/E=93/7 as determined by 19F-NMR (CDCl3 /CFCl3)] (yield, 79%), nD30.0 1.5057.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][C@H:8]([CH:22]([CH3:24])[CH3:23])[CH2:9][C@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C@@H:11]2[CH2:13][O:12]2)=[CH:5][C:4]=1[O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32].[NH2:33][CH2:34][CH2:35][CH2:36][C:37]([OH:39])=O.[OH-].[Na+].Cl>C(O)(C)C>[OH:12][C@H:11]([C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])[CH2:9][C@H:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:5]=1)[CH:22]([CH3:23])[CH3:24])[CH2:13][N:33]1[CH2:34][CH2:35][CH2:36][C:37]1=[O:39]
Reactant: NCCCC(=O)O
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H]2CO2)C(C)C)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN2CCCC2=O)C(C)C)ccc1OC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of 0.025 g of tert-butyl {3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methyl-1(S)-(R)-oxiranylpentyl}carbamate (Example 1b) in 0.50 ml of isopropanol is admixed successively with 0.027 g of 4-aminobutyric acid and 0.13 ml of 1M NaOH and stirred at 60° C. over 3 hours. The reaction mixture is cooled to 0° C. and admixed with 0.13 ml of 1M HCl and concentrated by evaporation to dryness. The residue is dissolved in 2.5 ml of dichloromethane, admixed successively with 0.016 g of N,N-dicyclohexylcarbodiimide and 0.012 mg of 1-hydroxybenzotriazole, and stirred at room temperature over 18 hours. The reaction solution is admixed with 1M sodium hydrogen carbonate solution and extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.32 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=4.51 (gradient I).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O[C:21](=[O:34])[C:22](=[O:33])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)C>C(O)C>[OH:33][C:22]1[C:21](=[O:34])[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:23]=1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Solvent: CCO
Product: O=C1C(O)=C(c2c[nH]c3ccccc23)C(c2ccccc2)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and Benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(1H-Indol-3-yl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[C:8]([CH3:14])=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:5][O:6][C:7]1[C:8]([CH3:14])=[N+:9]([O-:13])[CH:10]=[CH:11][C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: COc1ccc[n+]([O-])c1C
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reaction time: 8 h

Procedure:
8 ml of concentrated nitric acid are added in four portions of 2 ml each to 5.4 g of 3-methoxy-2-methylpyridine 1-oxide in 12 ml of glacial acetic acid at 80° C. in the course of 6 hours, the mixture is stirred at the same temperature overnight, a further 8 ml of nitric acid are added in three portions in the course of 6 hours and the mixture is stirred for a further 15 hours. After cooling, the mixture is poured onto ice (40 g) and brought to pH 6 with 10N sodium hydroxide solution, the byproduct (3-methoxy-2-methyl-4-nitropyridine) which has precipitated out is filtered off and the filtrate is extracted four times with 50 ml of methylene chloride. After drying, the combined organic phases are concentrated completely and the residue is recrystallized from a little methylene chloride/petroleum ether. 4.2 g (57% of theory) of the title compound are obtained in the form of yellow crystals of m.p. 103°-104° C.
Reaction SMILES: C([O-])(=O)C.[CH:5]1[N:10]=[C:9]([NH2:11])[C:8]2[N:12]=[CH:13][N:14]([C@@H:15]3[O:19][C@H:18]([CH2:20][O:21][P:22]([OH:25])([OH:24])=[O:23])[C@@H:17]([OH:26])[C@H:16]3[OH:27])[C:7]=2[N:6]=1.C(SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)C[O:43][P:44]([OH:73])(=[O:72])[O:45][P:46](O)(=[O:70])[O:47]C[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)(=O)C>>[P:22]([O:21][CH2:20][C@H:18]1[O:19][C@@H:15]([N:14]2[C:7]3[N:6]=[CH:5][N:10]=[C:9]([NH2:11])[C:8]=3[N:12]=[CH:13]2)[C@H:16]([OH:27])[C@@H:17]1[OH:26])([O:25][P:46]([O:45][P:44]([OH:73])([OH:72])=[O:43])([OH:70])=[O:47])(=[O:24])[OH:23]
Reactant: CC(=O)SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: CC(=O)[O-]
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
A column (inside diameter: 1.8 cm, length: 12 cm) was packed with 2,000 units of immobilized acetate kinase, 200 units of immobilized adenylate kinase and 10 units of immobilized acetyl CoA synthetase which were obtained by the same methods as in Example 11, and 4 mM of AMP, 1.0 mM of ATP (25% based on the concentration of AMP), 25 mM of acetyl phosphate, 2.5 mM of potassium acetate and 2.5 mM of reduction type CoA lithium salt which were dissolved in a 100 mM imidazole hydrochloride buffer solution containing 10 mM magnesium chloride were fed thereto at a flow rate of 50 ml/hour. The reaction temperature in the column was kept at 37° C. AMP was separated from the solution eluted from the column by the same method as in Example 1 and it was sent back to the inlet for substrates. After 40 minutes from the initiation of the reaction, the formed acetyl CoA became 1.6 mM, and thereafter a stabilized state was kept over 15 hours.