Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[CH3:33][N:34]1[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)/[C:13]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH3:33])[N:35]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Reactant: Cn1ccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ccc(NC(=O)/C(=N/OC2CCCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (112 mg, 0.31 mmol), N,N-diisopropylethylamine (163 μL, 0.94 mmol) and 1-methyl-1H-pyrazol-3-ylamine (30 μL, 0.31 mmol) were combined in methylene chloride (1.5 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the cooling bath was removed. After stirring 16 h, the reaction mixture was diluted with chloroform (2 mL) and washed with saturated aqueous sodium bicarbonate solution (1.5 mL). The aqueous phase was extracted with chloroform (1.5 mL) and the combined organic phases were filtered through sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (110 mg, 81%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C19H23ClN4O4S [M+] 438.11, found 439 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.24-1.61 (m, 6H, 3×CH2), 1.71 (m, 2H, 2×CH of CH2), 1.96 (m, 2H, 2×CH of CH2), 3.29 (s, 3 H, SO2CH3), 3.85 (s, 3 H, NCH3), 4.29 (m, 1 H, OCH), 6.69 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.60 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.71 (d, Jm=1.5 Hz, 1 H, Ar), 8.20 (d, Jo=8.2 Hz, 1 H, Ar), 9.15 (s, 1 H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH2:5][CH:6]([CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[NH:7]2.CS(O)(=O)=O.C(OCC)(=O)C.[Cl-].[Na+]>O>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:19])[CH2:5][CH:6]1[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[N:7]12
Reactant: O=C(O)CCCC1CC(=O)c2c(O)cc(O)cc2N1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CC2CCCC(=O)N2c2cc(O)cc(O)c21
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A mixture of 26 g. (0.098 mole) 4-[2,3-dihydro-5,7-dihydroxy-(1H)-quinolin-4-one-2-yl]butyric acid and 260 ml. methanesulfonic acid was heated under a nitrogen atmosphere at 140° C. for two hours. The reaction mixture was cooled to room temperature and poured onto 1000 ml. ice. To this was added 4 liters ethyl acetate, 1 liter water, 250 g. sodium chloride and the resulting mixture stirred at room temperature overnight. The layers were separated, the aqueous phase extracted with 4×500 ml. ethyl acetate and the combined organic layers washed with saturated sodium bicarbonate solution until the pH was 7 and no effervescence was observed. The extract was then washed with water (1000 ml.), brine (1000 ml.) and dried (MgSO4). The solvent was evaporated in vacuo, the residue redissolved in a small amount of hot ethyl acetate, diluted with ethyl ether and cooled to 0° C. The precipitated solid was collected by filtration and dried in vacuo to afford 9.4 g. (38.8%) of the title compound, M.P. 259°-268° C. (decomp.). 1H-NMR [(CD3)2SO] ppm (delta): 1.75-3.25 (m, 11H), 6.1 and 6.95 (2H, split doublets, meta aryl). Mass spectrum (m/e): 247 M+.
Reaction SMILES: F[B-](F)(F)F.C[N+:7](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[N:36]([CH2:37][C:38](O)=[O:39])[C:35](=[O:41])[N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[C:33]3[CH2:52][CH2:53][C:54](=[O:55])[C:32]2=3)=[CH:27][CH:26]=1)#[N:24].C(N(CC)C(C)C)(C)C.N>CN(C)C=O>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH:31]2[N:36]([CH2:37][C:38]([NH2:7])=[O:39])[C:35](=[O:41])[N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:49])([F:51])[F:50])[CH:43]=3)[C:33]3[CH2:52][CH2:53][C:54](=[O:55])[C:32]2=3)=[CH:29][CH:30]=1)#[N:24]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Agent: F[B-](F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (43 mg, 0.13 mmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoro-methyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetic acid (example 4, 60 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 μL, 0.29 mmol) in N,N-dimethylformamide (0.5 mL). After 20 min aqueous ammonia (32%, 8 μL, 0.13 mmol) added and the mixture is stirred at room temperature for 1 h. The mixture is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 36 mg; ESI mass spectrum [M+H]+=455; Retention time HPLC: 0.50 min (X012_S01).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:10][OH:11])[CH2:8][CH2:7][C:6](=[CH2:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>ClCCl>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][C:3]2([CH2:10][OH:11])[CH2:8][CH2:7][C:6](=[CH2:9])[CH2:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C1CCC(CO)(CO)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=C1CCC(CO)(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of Compound 100b (0.25 g, 1.6 mmol) and pyridine (0.40 mL) in dichloromethane was added at 0° C. a solution of para-toluenesulphonyl chloride (0.336 g, 1.76 mmol) in 1 mL of dichloromethane. The reaction mixture was stirred at 0° C. for 30 min., then at r.t. for 3.5 h. Dilution with dichloromethane, washing with 1M aqueous NaHSO4 and brine, drying with Na2SO4, afforded, after evaporation, a crude which was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient Dichloromethane-Methanol from 1:0 to 95:5) to give the title
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:14]2[CH:10]3[CH:11]([CH:16]([C:17](Cl)=[O:18])[CH:8]1[CH2:9]3)[C:12](=[O:15])[O:13]2)(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][OH:23].[C:29]1([S+:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:20][C:21]([F:28])([S:24]([O-:27])(=[O:26])=[O:25])[CH2:22][O:23][C:17]([CH:16]1[CH:11]2[CH:10]3[CH:14]([CH:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[CH:8]1[CH2:9]3)[O:13][C:12]2=[O:15])=[O:18].[C:42]1([S+:35]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=S(=O)([O-])C(F)(F)CO
Reactant: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)Cl
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OCC(F)(F)S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To 2.8 g (10 mmol) of the 2-methacryloyloxy-5-oxo-4-oxa-tricyclo[4.2.1.03,7]-non-9-ylcarbonyl chloride were added 4.2 g (10 mmol) of triphenylsulfonium 1,1-difluoro-2-hydroxy-ethanesulfonate in Synthesis Example 1-13 and 20 g of methylene chloride. To the mixture under ice cooling, a solution containing 1.0 g (10 mmol) of triethylamine and 0.25 g (2 mmol) of N,N-dimethylaminopyridine in 5 g of methylene chloride was added at a temperature below 5° C., and the resulting mixture was stirred for 2 hours at room temperature. Thereafter, 11 g of 5% dilute hydrochloric acid was added to the reaction mixture. The organic layer was taken out and washed with water, from which methylene chloride was distilled off in vacuum. 30 g of methyl isobutyl ketone was added to the residue, from which the residual water was distilled off in vacuum together with methyl isobutyl ketone. The resulting residue was purified by silica gel chromatography, obtaining the target compound, triphenylsulfonium 1,1-difluoro-2-(9-methacryloyloxy-4-oxo-5-oxatricyclo[4.2.1.03,7]-non-2-ylcarbonyloxy)-ethane-1-sulfonate. Colorless solids, 4.0 g (yield 61%). The compound has the following structure.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@:14]([OH:16])([CH3:15])[C@@H:13]([OH:17])[C@@H:12]([CH3:18])[O:11][C@H:10]2[O:19][C:20]2[C:25]3[C:26]4[O:36][C:34](=[O:35])[C:33]5[C:28]6=[C:29]([O:38][C:39]([C:41](=[C:42]([OH:43])[C:24]=3[CH:23]=[CH:22][CH:21]=2)[C:27]=46)=[O:40])[CH:30]=[CH:31][C:32]=5[CH3:37])[C@H:5]([NH2:44])[C@@H:4]([O:45][CH3:46])[C@H:3]1[OH:47].[C:48](OC(=O)C)(=[O:50])[CH3:49].O>CO>[CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@:14]([OH:16])([CH3:15])[C@@H:13]([OH:17])[C@@H:12]([CH3:18])[O:11][C@H:10]2[O:19][C:20]2[C:25]3[C:26]4[O:36][C:34](=[O:35])[C:33]5[C:28]6=[C:29]([O:38][C:39]([C:41](=[C:42]([OH:43])[C:24]=3[CH:23]=[CH:22][CH:21]=2)[C:27]=46)=[O:40])[CH:30]=[CH:31][C:32]=5[CH3:37])[C@H:5]([NH:44][C:48]([CH3:49])=[O:50])[C@@H:4]([O:45][CH3:46])[C@H:3]1[OH:47]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@@H]1[C@@H](N)[C@@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)O[C@H](C)[C@@H]1O
Solvent: CO
Solvent: O
Product: CO[C@H]1[C@@H](O)[C@@H](C)O[C@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)[C@@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of elsamicin A (65.4 mg) and acetic anhydride (0.1 ml) in dry methanol (2 ml) was stirred at room temperature for 1 hour. Water (1 ml) was added and the mixture was evaporated in vacuo to give a yellow oil, which was purified by column chromatography on silica gel to give 70.5 mg (100%) of the desired product.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]([CH:36]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:37]([OH:39])=[O:38])[CH3:35])=[CH:30][CH:29]=1.[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([N:34]([C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)[CH3:35])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:47]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CN(c1ccc(F)cc1)C(C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN(c1ccc(F)cc1)C(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
PS-DCC (1.02 g, 1.35 mmol, loading: 1.33 mmol/g) is suspended in dry THF (13.5 mL). Then HOBT (0.21 g, 1.35 mmol), [(4-fluoro-phenyl)-methyl-amino]-phenyl-acetic acid hydrochloride (I71) (0.20 g, 0.68 mmol) and (R)-quinuclidin-3-ol (0.26 g, 2.03 mmol) are added. The mixture is shaken at RT overnight. PS-DCC is filtered off, washed with EtOAc and THF. The solution is evaporated and the residue is portioned between EtOAc and water. The organic phase is washed with sat. NaHCO3, dried (Na2SO4) and evaporated. The crude is purified by flash chromatography (DCM/MeOH=95/5) to afford the title compound as a colorless oil (209 mg, 84% yield, mixture of diastereoisomers).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][C:5](=NOCC(O)=O)[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.[OH-].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=[O:21].[K+].[K+]>O>[CH3:17][C:2]1([CH3:1])[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:21])[CH2:4][CH2:3]1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: CC(C)CCC(=NOCC(=O)O)c1ccsc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(=O)c2ccsc21
Reaction time: 2 h
Yield: 12.8 %

Procedure:
(4-Methyl-1-thiophen-3-yl-pentylideneaminooxy)-acetic acid (2.17 g, 8.5 mmol) was added to a 0.1 M sodium hydroxide solution (93.5 ml) and heated to reflux. A solution of potassium persulfate (3.45 g, 12.75 mmol) in water (10 ml) was added dropwise and heating continued. After 2 hours, the reaction mixture was extracted with dry diethyl ether (100 ml). The organic layer was then washed with saturate sodium bicarbonate, water and brine, dried (Na2SO4) and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to afford the title compound as a colourless oil (196 mg, 13%). MS (ES+) 18. δH (d6DMSO): 1.42 (6H, s), 2.03 (2H, t), 2.60 (2H, t), 7.22 (1H, d), 7.42 (1H, d).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH2:11].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[NH:11][C:20](=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(=O)Cl
Reactant: COC(=O)c1ccc(C)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc(C)ccc1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
To a 0° C. solution of 2-amino-4-methyl-benzoic acid methyl ester (1.5 g, 9.0 mmol) and triethylamine (1.4 g, 13.5 mmol) in methylene chloride (30.0 mL) is added butyryl chloride (1.2 g, 10.8 mmol) dropwise. The mixture is stirred at 0° C. for 30 min and is quenched with saturated sodium bicarbonate (10 mL). The organic phase is washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as syrup (2.2 g, 100%). LC-ES/MS m/e 236.3 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[OH:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1>CN(C)C(=O)C>[OH:30][CH2:31][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1
Reactant: OC[C@@H]1CCCN1
Reactant: CN(C[C@H]1CC[C@H](COCCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COCCCCN2CCC[C@H]2CO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-butoxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with (S)-2-hydroxymethyl-pyrrolidine in N,N-dimethylacetamide at room temperature to yield trans-N-{4-[4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-butoxymethyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as colorless solid, MS: 521 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][C:8]([CH2:10][CH:3]1[CH2:4][CH2:5]2)=[O:9].ClC(O[CH2:15][CH2:16]Cl)=O.O>C(Cl)(Cl)Cl>[CH2:1]([N:2]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH2:10][C:8](=[O:9])[CH2:7]2)[C:16]1[CH:15]=[CH:5][CH:4]=[CH:3][CH:10]=1
Reactant: O=C(Cl)OCCCl
Reactant: CN1C2CCC1CC(=O)C2
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
25 g of tropinone was dissolved in 100 mL of chloroform, and 50 mL of chloroethyl chloroformate was added thereto and stirred at room temperature for 6 hours. The reaction liquid was concentrated, 100 mL of methanol was added thereto, and heated overnight under reflux. The reaction liquid was cooled to room temperature and concentrated, and the resulting crude product was dissolved in 80 mL of N-methylpyrrolidone. 43 mL of benzyl bromide and 99 g of potassium carbonate were added thereto and stirred overnight at room temperature. The reaction liquid was poured into water, and extracted three times with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure to obtain 29.5 g of the entitled compound as a pale yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([OH:18])=O)=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:28].[OH-]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]([NH2:28])=[O:18])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: [NH4+]
Reactant: CCn1cc(C(=O)O)c2ccc(C(=O)OC)cc21
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C(N)=O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
1-Ethyl-1H-indole-3,6-dicarboxylic acid 6-methyl ester (600 mg, 2.43 mmol) was suspended in a solution of CH2Cl2 (27 ml) and DMF (20 μL). Oxalyl chloride (470 μL, 5.38 mmol) was added, and the reaction mixture was stirred for 1 hour at room temperature. This mixture was then slowly poured into a rapidly stirring solution of concentrated NH4OH (10 mL). This was then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer was triturated with acetone to yield 6-methoxycarbonyl-1-ethyl-1H-indole-3-carboxamide (511 mg, 85%) as a white solid.
Reaction SMILES: [CH:1](OC(Cl)(Cl)Cl)=[O:2].[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([NH:29][NH2:30])=[O:28])[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.O>O1CCOCC1>[F:8][C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH2:23][C:24]3[CH:33]=[CH:32][CH:31]=[C:26]([C:27]4[O:28][C:1](=[O:2])[NH:30][N:29]=4)[CH:25]=3)[N:17]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: O=COC(Cl)(Cl)Cl
Reactant: NNC(=O)c1cccc(Cn2nc(-c3cc(F)cc(F)c3)ccc2=O)c1
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)o1

Procedure:
7.2 A solution of 131 mg (0.65 mmol) of trichloromethyl formate in 3 ml of dioxane is added to a suspension of 178 mg (0.50 mmol) of 3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]benzohydrazide in 1 ml of dioxane, and the mixture is heated at the boil for 4 hours. The reaction mixture is allowed to cool, and water is added. The resultant precipitate is filtered off with suction, washed with water and dried. The residue is chromatographed on a silica gel column with dichloromethane/methanol, giving 6-(3,5-difluorophenyl)-2-[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)benzyl]-2H-pyridazin-3-one (“A15”) as colourless crystals; ESI 383;
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23](Cl)=[O:24]>C(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[F:29])[C:23]([NH:9][CH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:24]
Reactant: NCCc1ccccc1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccc(F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of phenethylamine (1.01 mL, 7.95 mmol) and DIEA (1.38 mL, 7.95 mmol) in 20 mL of DCM, 3,4-difluorobenzoyl chloride (1.00 mL, 7.95 mmol) was added dropwise. The clear solution was stirred for 1 h. The reaction mixture was concentrated and the crude product was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.57 (ddd, J=10.63, 7.56, 2.12 Hz, 1H) 7.31-7.44 (m, 3H) 7.15-7.31 (m, 4H) 6.02 (br. s., 1H) 3.67-3.78 (m, 2H) 2.94 (t, J=6.87 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:13])=[O:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:13][C:4]1[CH:5]=[C:6]([CH2:8][CH2:9][C:10]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)=[O:12])[NH:7][C:3]=1[CH:1]=[O:2]
Reactant: CN1CCNCC1
Reactant: Cc1cc(CCC(=O)O)[nH]c1C=O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(CCC(=O)N2CCN(C)CC2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 3-(5-formyl-4-methyl-1H-pyrrol-2-yl)-propionic acid (271.8 mg, 1.5 mmol) in DMF (4mL) was added HOBt (243.2 mg, 1.8 mmol), EDC (345.1 mg, 1.8 mmol) and then 1-methylpiperazine (0.2 mL, 1.8 mmol). The mixture was stirred at room temperature under nitrogen for overnight. The reaction was poured into sat. sodium bicarbonate (50 mL) and extracted with ethyl acetate. The combined organic layer was dried, concentrated and column chromatographed (MeOH/DCM) to give 325.2 mg (82%) of 3-methyl-5-[3-(4-methyl-piperazin-1-yl)-3-oxo-propyl]-1H-pyrrole-2-carbaldehyde as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH:18]=1)[OH:17])[CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2].[C:20]([CH:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][C:24]1=O)(=O)[CH3:21]>>[CH2:1]([CH:3]([C:12]1[CH:18]=[C:16]([OH:17])[C:15]2[CH:20]([CH3:21])[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][C:24]=3[O:19][C:14]=2[CH:13]=1)[CH:4]([CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CC(=O)C1CCC(C)CC1=O
Reactant: CCCCCC(CC)C(CC)c1cc(O)cc(O)c1
Product: CCCCCC(CC)C(CC)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
Condensation of 5-(1,2-diethylheptyl)resorcinol and 2-acetyl-5-methylcyclohexanone as described in the procedure of Example 1 gives the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[O:8][CH2:9][O:10][C:3]=12.C([Li])CCC.C[O:17][B:18](OC)[O:19]C>C1COCC1>[F:1][C:2]1([B:18]([OH:19])[OH:17])[CH:7]=[CH:6][CH:5]=[C:4]2[O:8][CH2:9][O:10][CH:3]12
Reactant: Fc1cccc2c1OCO2
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)C1(F)C=CC=C2OCOC21
Temperature: -65 °C
Yield: 21.3 %

Procedure:
1-Fluoro-2,3-methylenedioxybenzene (5.0 g, 35.7 mmol) was dissolved in THF (70 mL) and the solution was cooled to −65° C. in a dry ice acetone bath. n-Butyl lithium (2.5 g, 15.7 mL, 39.3 mmol) was added to the solution via syringe with stirring. The reaction was allowed to warm to −35° C. over 1 hour, then cooled to −65° C. and treated with trimethylborate (4.1 g, 39.3 mmol) via syringe. The reaction was allowed to warm slowly to room temperature, quenched with 1N HCl (50 mL), stirred for 15 minutes, and then extracted with ether. The organic phase was then extracted with 1N sodium hydroxide and this aqueous extract was then acidified with 1N hydrochloric acid. The acidic aqueous solution was then extracted with two portions of ether and these combined ether extracts were dried and concentrated to an oily solid that was triturated with methylene chloride. The resulting solid was collected by filtration, washed with methylene chloride, and dried to give 1-fluoro-2,3-methylenedioxyphenylboronic acid (1.4 g, 7.6 mmol) as a tan solid: 1H NMR (DMSO-d6): δ 8.05 (br s, 2H), 7.08 (dd, 1H, J=7.8, 5.1 Hz), 6.76 (d, 1H, J=7.8 Hz), 6.08 (s, 2H).
Reaction SMILES: [CH2:1]([C:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15].C[O-].[Na+]>>[CH2:1]([CH:6]1[C:7](=[O:11])[CH2:8][CH2:9][CH:10]1[CH:13]([C:12]([O:19][CH3:20])=[O:18])[C:14]([O:16][CH3:17])=[O:15])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC1=CCCC1=O
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: CCCCCC1C(=O)CCC1C(C(=O)OC)C(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
The reaction product was refined to obtain 95 g (0.6 mol) of 2-pentyl-2-cyclopentenone. Moreover, 95 g (0.6 mol) of 2-pentyl-2-cyclopentenone was dropped to a solution, prepared by dissolving 118 g (0.9 mol) of dimethyl malonate in 38 g of methanol anhydride in a nitrogen atmosphere, cooling the mixture to 0° C. and adding 6.5 g (0.036 mol) of sodium methoxide (30% methanol solution), at 0° C. over 2 hours. After the addition was finished, unreacted dimethyl malonate was vacuum-distilled to obtain 160 g of dimethyl 2-pentyl-3-oxo-cyclopentylmalonate.