Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])=[CH:7][CH:6]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CC(C)=O>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:6][CH:7]=1)=[O:20]
Reactant: C1CCNCC1
Reactant: O=C(Cc1ccccc1Cl)c1ccc(OCCCl)cc1
Solvent: CC(C)=O
Product: O=C(Cc1ccccc1Cl)c1ccc(OCCN2CCCCC2)cc1

Procedure:
The mixture of 1-[4-(2-chloroethoxy)phenyl]-2-(2-chlorophenyl)ethanone (4 g, 13 mmol) and piperidine (5.8 g, 68 mmol) in 80% aqueous acetone (50 ml) is refluxed for 12 h. Additional portions of 0.3 g of piperidine are added three times in 4 h intervals to the mixture. The solvents are evaporated. Diethyl ether is added and the precipitated piperidine hydrochloride is filtered off. Diethyl ether is evaporated and the residual product is purified by flash chromatography (eluent toluene:triethylamine 9:1). The yield is 4.1 g, 89%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].N1CCCC1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25](=O)[CH3:26])[CH:23]=2)[CH:18]=[N:17]1>C1(C)C=CC=CC=1>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22](/[C:25](=[C:3]3/[C:2](=[O:10])[NH:1][C:9]4[C:4]/3=[CH:5][CH:6]=[CH:7][CH:8]=4)/[CH3:26])[CH:23]=2)[CH:18]=[N:17]1
Reactant: CC(=O)c1ccc2cn[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: C/C(=C1\C(=O)Nc2ccccc21)c1ccc2cn[nH]c2c1
Temperature: 50 °C
Reaction time: 72 h
Yield: 15.1 %

Procedure:
A solution of oxindole (16 mg, 0.12 mmol), pyrrolidine (10 μL, 0.12 mmol) and 1-(1H-indazol-6-yl)ethanone (20 mg, 0.12 mmol) in toluene was refluxed in a Dean-Stark trap for 2 h. The solution was then stirred at 50° C. for 72 h. Two equivalents of pyrrolidine were added and the solution was heated to reflux for 48 h. The solution was concentrated and the red residue was purified by preparatory HPLC to give the title compound as an orange solid (5 mg, 16%). 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.78 (s, 1H), 7.70 (d, 1H, J=8.5 Hz), 7.34 (d, 1H, J=8.5 Hz), 7.03 (t, 1H, J=7.6 Hz), 6.81 (d, 1H, J=7.7 Hz), 6.50 (t, 1H, J=7.6 Hz), 6.05 (d, 1H, J=7.7 Hz), 2.82 (s, 3H); MS ESI [M+H]+, calcd for [C17H13N3O+H]+ 276.1; found m/z 276.0.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[N:3]=1.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N:12]([CH3:14])[CH3:13])[CH:10]=3)[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[N:3]=2)=[CH:27][CH:26]=1
Reactant: COc1cccc(-c2cc3ccc(N(C)C)cc3c(Cl)n2)c1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(-c3cccc(OC)c3)cc3ccc(N(C)C)cc23)cc1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A mixture of 1-chloroimine isoquinoline II (500 mg, 1.6 mmol), 4-methoxy benzylamine (877 mg, 6.4 mmol), and potassium carbonate (2 g, 15 mmol) in DMF was refluxed overnight. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The combined organic extracts were washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel with n-hexane-ethyl acetate (3:1) to afford compound III (310 mg, 47%). 1H NMR (300 MHz, CDCl3) δ: 7.74-7.62 (m, 3H), 7.45-7.33 (m, 4H), 7.22 (m, 1H), 6.92 (m, 3H), 6.66 (m, 1H), 5.24 (s, 1H), 4.91 (d, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.09 (s, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=O)[O:10]C2C=CC=CC=2)[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)[CH3:2].[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CS(C)=O.C(OCC)(=O)C>[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][N:30]=[C:29]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:9]([NH:8][C:6]2[N:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=2)=[O:10])[CH:43]=[CH:44][CH:45]=1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCc1cc(NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Temperature: 70 °C
Yield: 31.3 %

Procedure:
A stirred mixture of phenyl 3-ethyl-1-phenyl-1H-pyrazol-5-ylcarbamate (0.15 g, 0.50 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (0.15 g, 0.50 mmol) in DMSO (2 mL) was heated at 70° C. for 15 h. After cooling to rt, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to afford an oil. Purification via preparative silica gel thin-layer chromatography (eluting with a mixture of 8% methanol in dichloromethane containing 0.5% ammonia) followed by recrystallization from diethyl ether afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-ethyl-1-phenyl-1H-pyrazol-5-yl)urea (80 mg, 32%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6) 89.21 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 7.52-7.55 (m, 6H), 7.34-7.42 (m, 3H), 7.18 (m, 1H), 6.92 (m, 1H), 6.30 (s, 1H), 3.99 (s, 3H), 3.98 (s, 3H), 2.56 (m, 2H), 1.19 (m, 3H); LC-MS (ESI) m/z 511 (M+H)+.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[C:8]([O:12][C:13]([N:15]1[CH2:22][C@@H:21]([OH:23])[CH2:20][C@@H:16]1[C:17]([OH:19])=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl.CO>[OH:23][C@@H:21]1[CH2:22][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])[C@@H:16]([C:17]([O:19][CH3:1])=[O:18])[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@H]1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Yield: 97 %

Procedure:
(Trimethylsilyl)diazomethane (2N solution in hexane, 2.9 ml) was added dropwise over 5 minutes to a stirred solution of (4S)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline (1.0 g) in DCM (20 ml) and methanol (5 ml) at room temperature until a permanent faint yellow colour persisted. The reaction mixture was concentrated in vacuo and purified by column chromatography, using 0-50% ethyl acetate in hexane as eluent, to give 1-tert-butyl 2-methyl (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate as a clear oil (1.03 g, 97%); NMR spectrum (CDCl3) 4.90-4.37 (m, 2H), 3.73 (s, 3H), 3.64 (dd, 1H), 3.53-3.43 (m, 1H), 2.34-2.27 (m, 1H), 2.12-1.97 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:21]=[CH2:22]
Reactant: Cc1cc2ccccc2c(Cl)c1OS(=O)(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: C=Cc1c(C)cc2ccccc2c1Cl
Temperature: 50 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 1-chloro-3-methyl-naphthalen-2-yl ester (14.75 g, 45.43 mmol), tributyl(vinyl)tin (14.59 mL, 49.97 mmol) and lithium chloride (5.78 g, 136.29 mmol) was added dichlorobis(triphenylphosphine) palladium(II) under argon. The reaction mixture was heated at 50° C. for 20 h, then heated at 90° C. for 8 h. The reaction mixture was than cooled to room temperature, diluted with ethyl acetate, washed with 5% lithium chloride solution (3×), brine and dried (MgSO4), filtered and then concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1-chloro-3-methyl-2-vinyl-naphthalene contaminated by organotin. The residue was dissolved in dichloromethane and stirred with 10% KF solution overnight. The resulting white mixture was filtered through a pad of Celite and extracted with dichloromethane (2×). The organic layer was concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give 1-chloro-3-methyl-2-vinyl-naphthalene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH:13]3[O:14][CH2:15][CH:16]([OH:17])[CH:12]3[O:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]1.CCN(C(C)C)C(C)C>CCCCO>[CH3:18][N:19]1[CH:23]=[C:22]([NH:24][C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH:13]4[O:14][CH2:15][CH:16]([OH:17])[CH:12]4[O:11][CH2:10]3)[CH:5]=[CH:4][N:3]=2)[CH:21]=[N:20]1
Reactant: Cn1cc(N)cn1
Reactant: OC1COC2C(Nc3ccnc(Cl)n3)COC12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cn1cc(Nc2nccc(NC3COC4C(O)COC34)n2)cn1
Temperature: 150 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a suspension of 6-((2-chloropyrimidin-4-yl)amino)hexahydrofuro[3,2-b]furan-3-ol (354 mg, 1.37 mmol) in n-BuOH (3 mL) were added 1-methyl-1H-pyrazol-4-amine (220 mg, 1.65 mmol) and DIPEA (531 mg, 4.11 mmol). Then the mixture was stirred under nitrogen atmosphere at 150° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=30/1) to give the title compound as a yellow solid (120 mg, 22%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:8])[CH2:6][NH2:7].O[CH:15]=[CH:16][C:17]#[N:18].[Na]>C(O)C>[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:8])[CH2:6][NH:7][CH:15]=[CH:16][C:17]#[N:18]
Reactant: N#CC=CO
Reactant: NCC(=O)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC=CNCC(=O)c1cccc(Cl)c1Cl

Procedure:
2 g of 2,3-dichlorophenacylamine hydrochloride, 1 g of 3-hydroxyacrylonitrile, sodium salt, and 20 ml of ethanol are heated for 2 hours under reflux. The reaction mixture is concentrated by evaporation and the oily residue is purified by column chromatography (silica gel; elution with a 4:1 mixture of toluene/ethyl acetate), affording 3-(2,3-dichlorophenacylamino)acrylonitrile in the cis/trans ratio of 5:1. Melting point: 122°-125° C.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N:14]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[C:22]([OH:24])=[O:23])=O>C1COCC1>[NH:14]1[N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]2[C:22](=[O:23])[O:24]1
Reactant: O=NN1CCCCC1C(=O)O
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C1ONN2CCCCC12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic anhydride (1.93 g) was added to the THF (92 mL) solution of crude (2RS)-1-nitrosopiperidine-2-carboxylic acid under a nitrogen atmosphere at 0° C. and stirred for 5 h at 0° C. and for 2 h at room temperature. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (1/1–0/1). The titled compound was obtained as colorless crystals (1.10 g, 33%).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:21]([CH3:23])[CH3:22])[C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[CH:7]=O)([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2.N1CCCC1.Cl>C(O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[C:28]2=[CH:7][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:10]([CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1OCCN1CCOCC1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: Cl
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)c1cc(C=C2C(=O)Nc3ccc(Cl)cc32)cc(C(C)C)c1OCCN1CCOCC1
Reaction time: 12 h
Yield: 10.2 %

Procedure:
A mixture of 3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzaldehyde (0.4 g, 1.26 mmol), 5-chloro-2-oxindole (0.21 g, 1.26 mmol) and pyrrolidine (0.5 ml, 6.3 mmol) in ethanol (2 ml) was held in sealed tube at 100° C. for 12 hours. The mixture was then poured into 1N hydrochloric acid (100 ml) and the solid which remained were filtered and washed with more water (50 ml). The solid was then dissolved in ethyl acetate (200 ml), the solution dried over magnesium sulfate, filtered and then concentrated. The solid which remained was chromatographed (silica, 4/4/1 dichloromethane/hexanes/methanol) to give 60 mg (10%) of 5-chloro-3-[3,5-diisopropyl-4-(2-morpholin-4-ylethoxy)-benzylidene]-1,3-dihydroindol-2-one as a brownish-orange solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=S)[CH:8]3[CH2:15][CH2:16][CH2:17][CH:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[NH3:18]>>[NH2:18][C:9]1[CH:8]2[CH2:15][CH2:16][CH2:17][CH:7]2[C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C1CCCC1C(=S)N2
Reactant: N
Product: NC1=Nc2ccc([N+](=O)[O-])cc2C2CCCC12
Yield: 76 %

Procedure:
As described for Example 4, 8-nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (100 mg, 0.40 mmol) is reacted with 7N methanolic ammonia solution (15 ml) to form 70 mg (76%) of product.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29]([OH:31])=O)[CH:24]=4)/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN.[CH:38]([N:41](C(C)C)CC)(C)C>>[N:1]1([CH2:7][C:8]2[CH:34]=[CH:33][C:11]([NH:12]/[C:13](=[C:20]3\[C:21](=[O:32])[NH:22][C:23]4[C:28]\3=[CH:27][CH:26]=[C:25]([C:29](=[O:31])[NH:41][CH3:38])[CH:24]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1Nc2cc(C(=O)O)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1
Agent: CN
Agent: Cl
Product: CNC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone and methylamine hydrochloride/diisopropylethylamine Rf value: 0.3 (aluminium oxide, methylene chloride/ethanol=20:1) C29H30N4O2
Reaction SMILES: [NH2:1][C:2](=[N:24]O)[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:23]=[CH:22][C:12]([O:13][CH2:14][C:15]([CH3:21])([CH3:20])[C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[C:16]([OH:18])(=[O:17])[CH3:15].[NH2:24][C:2](=[NH:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([CH3:20])([CH3:21])[C:16]([O:18][CH3:19])=[O:17])=[CH:22][CH:23]=2)=[N:7][CH:8]=1
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(N)=NO)cn2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(=N)N)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 186.7 %

Procedure:
In acetic acid (60 mL) was dissolved methyl 3-(4-{5-[amino(hydroxyimino)methyl]-pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (5.8 g), acetic anhydride (4 mL) was added to the solution and the mixture was stirred at room temperature for 2 hours. To the residue obtained by concentrating the mixture under reduced pressure were added methanol (300 mL) and tetrahydrofuran (70 mL), and 10% palladium carbon (1.2 g) was added to the mixture under nitrogen atmosphere. The atmosphere of the reaction mixture was made hydrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. After replacing the atmosphere with nitrogen, the mixture was filtered using Celite. The filtrate was concentrated under reduced pressure, ether was added to the obtained residue to pulverize the solid, and the solid was collected by filtration and dried to obtain methyl 3-(4-{5-[amino(imino)methyl]pyridin-2-yl}-phenoxy)-2,2-dimethylpropanoate acetate (6.11 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH:8]=C)[N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=1.[O:14]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.ClCCl>[CH:8]([C:6]1[N:5]=[C:4]([NH:10][C:11](=[O:13])[CH3:12])[CH:3]=[C:2]([CH3:1])[CH:7]=1)=[O:14]
Reactant: C=Cc1cc(C)cc(NC(C)=O)n1
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)Nc1cc(C)cc(C=O)n1
Temperature: -80 °C
Reaction time: 0.08 h

Procedure:
5.0 g N-(4-methyl-6-vinyl-pyridin-2-yl)-acetamide (compound F5) are dissolved in a mixture of each 200 ml methanol and dichloromethane and cooled to −80° C. Subsequently, ozone is passed into the solution (flow 20-25 l/h ozone). After 5 min ozone treatment is stopped. Thereafter, nitrogen is applied for 5 min and 7.44 g of triphenylphosphane are added while stirring is continued. The solution is allowed to warm up to r.t. Subsequently, the volatile components are removed in vacuo and the residue is purified by chromatography on silica gel (eluent cyclohexane/ethyl acetate 3:1) to afford 2.72 g of the title compound as colourless solid. M.p. 202° C. GC-MS: 178.2 (M+). TLC: Rf=0.50 (cyclohexane/ethyl acetate 1:1). [Remark: Occasionally remaining traces of triphenylphosphine oxide can be removed by dissolving crude product in ethyl acetate followed by cooling to precipitate triphenylphosphine oxide.]
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:7](=O)[C:6]=2[CH:19]=1.C>O1CCOCC1.C(O)C.S(=O)(=O)(O)O.[Pd]>[OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[CH2:7][C:6]=2[CH:19]=1
Reactant: O=c1c(-c2ccc(F)cc2)coc2cc(O)c(O)cc12
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: C1COCCO1
Product: Oc1cc2c(cc1O)OCC(c1ccc(F)cc1)C2

Procedure:
6,7-Dihydroxy-3-(4-fluorophenyl)-4H-1-benzopyran-4-one (1.2 g), dissolved in a mixture of dioxan/ethanol 4:6 (40 ml), is hydrogenated for 24 h at room temperature over palladium 5% on active charcoal (0.48 g) in the presence of a few drops of conc. sulphuric acid. After filtration of the catalyst, the filtrate is evaporated to dryness under vacuum. An oil is obtained which crystallizes to give 3,4-dihydro-6,7-dihydroxy-3-(4-fluorophenyl)-2H-1-benzopyran, m.p. 135°-137°.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:16][C@H:15]([OH:17])[C@:14]([OH:21])([C:18]#[C:19][CH3:20])[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([C:22](O)=[O:23])[CH:6]=[CH:5][C:4]2=1)[CH3:2].C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][C:56]1[C:61]([CH2:62][NH2:63])=[CH:60][CH:59]=[CH:58][N:57]=1>O1CCCC1>[CH3:55][C:56]1[C:61]([CH2:62][NH:63][C:22]([C:7]2[CH:6]=[CH:5][C:4]3[C@@:3]4([CH2:1][CH3:2])[C@@H:12]([CH2:13][C@@:14]([OH:21])([C:18]#[C:19][CH3:20])[C@@H:15]([OH:17])[CH2:16]4)[CH2:11][CH2:10][C:9]=3[CH:8]=2)=[O:23])=[CH:60][CH:59]=[CH:58][N:57]=1
Reactant: Cc1ncccc1CN
Reactant: CC#C[C@]1(O)C[C@H]2CCc3cc(C(=O)O)ccc3[C@]2(CC)C[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@]1(O)C[C@H]2CCc3cc(C(=O)NCc4cccnc4C)ccc3[C@]2(CC)C[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.9 %

Procedure:
To a solution of (6S,7R,4bR,8aR)-4b-ethyl-6,7-dihydroxy-7-prop-1-ynyl-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-2-carboxylic acid (20 mg, 0.061 mmol) in tetrahydrofuran (2 mL) was added sequentially diisopropylethylamine (0.042 mL, 0.24 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (14 mg, 0.073 mmol), 1-hydroxybenzotriazole (9 mg, 0.064 mmol) and C-(2-methylpyridin-3-yl)-methylamine (0.025 mL, approximately 0.2 mmol). The mixture was stirred at room temperature for 1 day and was then quenched with saturated aqueous ammonium chloride solution. After extracting twice with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4) and concentrated under vacuum. The title compound (10 mg, 38%) was isolated by flash chromatography eluting with 50% acetone in methylene chloride. Mass spectrum: m/e 433 (M+1).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].N1C=CC=CC=1.Cl[C:16]([O:18][CH:19]=[CH2:20])=[O:17]>O1CCCC1>[CH:19]([O:18][C:16]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:17])=[CH2:20]
Reactant: C=COC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=COC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a 500 mL 3-neck round bottom flask fitted with a mechanical stirrer, condenser, nitrogen blanket, dropping funnel, ice-saltwater bath, and thermometer were added 10.0 (87.0 mmol) of N-hydroxy succinimide, 6.9 g (87.0 mmol) of pyridine, and 100 mL tetrahydrofuran was added. To the reaction mixture 9.25 g (87.0 mmol) of vinyl chloroformate was added so that the temperature remained below 10° C. After stirring at room temperature for 18 hours the reaction mixture was washed with 100 mL 2N HCl, and 100 mL 2N NaOH. The organic phase was dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the resulting liquid chromatographed (silica gel, chloroform) to yield 10.0 g (54.0 mmol, 62.1% yield) of an oil. FTIR (neat, capillary) 3516.50, 3132.04, 3099.40, 3003.94, 2960.21, 1830.80, 1823.25, 1792.36, 1734.05, 1671.98, 1653.62, 1646.30, 1429.97, 1380.77, 1368.60, 1306.35, 1260.89, 1241.83, 1201.12, 1162.09, 1154.49, 1134.29, 1087.59, 1049.93, 1005.21, 990.18, 948.77, 941.86, 908.06, 897.29, 892.42, 812.37, 769.04, 756.85, 724.90, 707 81. NMR (CDCl3) 6.73-7.09 (1H,q), 4.61-5.24 (2H,m), 2.78 (4H,S). ##STR16##
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.[ClH:26]>CCOCC.O1CCOCC1>[ClH:17].[Cl:26][C:19]1[CH:20]=[C:21]([N:24]2[C:14](=[O:16])[CH2:13][CH:3]3[CH2:4][CH2:5][CH2:6][C:7]4[CH:12]=[CH:11][N:10]=[CH:9][C:8]=4[C:2]3=[N:25]2)[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: O=C(O)CC1CCCc2ccncc2C1=O
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C1CC2CCCc3ccncc3C2=NN1c1ccc(Cl)c(Cl)c1

Procedure:
Prepared according to the method described in Example 1 from 9-oxo-6,7,8,9-tetrahydro-5H-cyclohepta[c]pyridine-8-acetic acid and 4-chlorophenylhydrazine, the compound being dissolved in ether and hydrogen chloride in dioxan added to precipitate the hydrochloride salt.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1([OH:10])[CH2:9][O:8][CH2:7]1)([CH3:5])[CH3:4].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18](=O)[O:19]C1C=CC=CN=1>C1COCC1.CCOC(C)=O>[C:18](=[O:19])([O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)[O:10][C:6]1([CH:3]([CH3:5])[CH3:4])[CH2:9][O:8][CH2:7]1
Reactant: CC(C)C1(O)COC1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C1(OC(=O)Oc2ccccn2)COC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
To a suspension of sodium hydride, 60% in mineral oil (331 mg, 8.26 mmol) in THF (25 mL) was added 3-isopropyloxetan-3-ol (800 mg, 6.89 mmol) at 0° C. After stirring 30 min, the solution was transferred to a solution of di(pyridin-2-yl)carbonate (1489 mg, 6.89 mmol) in THF (25 mL) through a cannula. The formed slurry was stirred at 0° C. for 30 min. The slurry was warmed to rt and stirred for 2 h. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated to give a residue that was purified by Biotage eluting with 20% EtOAc in hexanes to afford the desired product 3-isopropyloxetan-3-yl pyridin-2-yl carbonate (320 mg, 20.2% yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) d 8.47-8.39 (m, 1H), 7.86-7.78 (m, 1H), 7.31-7.24 (m, 1H), 7.15 (d, J=8.0 Hz, 1H), 4.89 (d, J=8.5 Hz, 2H), 4.67 (d, J=8.5 Hz, 2H), 2.53 (dt, J=13.7, 7.0 Hz, 1H), 1.13 (s, 3H), 1.12 (s, 3H).