Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15](Cl)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.O.O.O.O.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([F:19])=[C:15]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH:16]=2)[C:11](=[O:20])[C:10]([C:21]([OH:23])=[O:22])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2cc(Cl)c(F)cc2c1=O
Reactant: C1CNCCN1
Solvent: O
Product: O=C(O)c1cn(Cc2ccccc2)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 79.1 %

Procedure:
A mixture of 1-benzyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid 1.1 g and piperazine hexahydrate 10 g was heated in a sealed tube at 125°-135° C. (inner temperature) for 22 hours. After cooling, the reaction mixture was evaporated under vacuum. The residue was dissolved in warm acetic acid and the insoluble matters was filtered off. The filtrate was neutralized with an aqueous solution of NaOH, and the precipitated crystals were collected by filtration, washed with water and dried. Recrystallizing the crystals from dimethylformamide, 1.0 g (79%) of 1-benzyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid was obtained. Colorless powders.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=S)[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1.[NH3:19]>>[NH2:19][C:8]1[CH:7]2[CH2:14][CH2:15][CH2:16][CH:6]2[C:5]2[CH:4]=[C:3]([C:2]([F:18])([F:17])[F:1])[CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: FC(F)(F)c1ccc2c(c1)C1CCCC1C(=S)N2
Reactant: N
Product: NC1=Nc2ccc(C(F)(F)F)cc2C2CCCC12
Yield: 76 %

Procedure:
Analogously to Example 4, 8-(trifluoromethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (93 mg, 0.34 mmol) in 7N methanolic ammonia solution (20 ml) is reacted to form 66 mg (76%) of product.
Reaction SMILES: C(OP([CH:9]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[O:10][CH3:11])(=O)OCC)C.[H-].[Na+].[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[N:27]1[CH:32]2[CH2:33][CH2:34][CH:28]1[CH2:29][C:30](=O)[CH2:31]2>COCCOC>[Br:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]([O:10][CH3:11])=[C:30]2[CH2:31][CH:32]3[N:27]([C:22]4[N:21]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH:28]([CH2:34][CH2:33]3)[CH2:29]2)=[CH:17][CH:16]=1
Reactant: CCOP(=O)(OCC)C(OC)c1ccc(Br)cc1
Reactant: O=C1CC2CCC(C1)N2c1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=C1CC2CCC(C1)N2c1ncccn1)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 15.8 %

Procedure:
To a solution of [(4-bromo-phenyl)-methoxy-methyl]-phosphonic acid diethyl ester (4.58 g, 13.5 mmol) in 1,2-dimethoxy-ethane (60 ml), was added NaH (540 mg, 13.5 mmol, 60% in mineral oil) in one portion. The mixture was stirred at 50° C. for 1.5 hrs before it was added by 8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octan-3-one (2.0 g, 9.85 mmol) in 1,2-dimethoxy-ethane (5 ml). The mixture was stirred at 50° C. over the weekend. The resulting mixture was concentrated down and purified by ISCO to afford 3-[(4-bromo-phenyl)-methoxy-methylene]-8-pyrimidin-2-yl-8-aza-bicyclo[3.2.1]octane (600 mg, 30%). The white solid product was used as it was. MS (M+1)=386.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)/[C:4]([NH:6][CH3:7])=[O:5].[C:22](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.O>CC(C)=O>[CH3:22][O:1]/[N:2]=[C:3](\[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)/[C:4]([NH:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)/C(=N/O)c1ccccc1Oc1ccc(C)cc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(C)cc1
Yield: 91.9 %

Procedure:
E-2-hydroxyimino-N-methyl-2-[2-(4-methylphenoxy) phenyl]acetoamide (1.00 g, 0.0035 mole) was dissolved in dried acetone (7 ml), and potassium carbonate (0.63 g, 0.0046 mole) and dimethylsulfate (0.53 g, 0.0042 mole) were added to the mixture, which was reacted at room temperature for 22 hours. After completion of the reaction, water was added to the reaction mixture, which was extracted twice with methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain E-2-methoxyimino-N-methyl-2-[2-(4-methylphenoxy)phenyl]-acetamide as colorless crystals (0.96 g, yield: 92.3%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[C:13]([O:19][CH2:20]Cl)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>O1CCCC1>[C:13]([O:19][CH2:20][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[CH:10]=[CH:9]1)(=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Clc1ncnc2[nH]ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.651 mmol) was dissolved in tetrahydrofuran (5 mL). After cooling to 0° C., the reaction mixture was added to sodium hydride (60% in mineral oil, 52 mg, 1.30 mmol). 10 minutes later, chloromethyl pivalate (0.19 mL, 1.30 mmol) was added at 0° C. After stirring for 1.5 hours at room temperature, the reaction mixture was added to saturated ammonium chloride aqueous solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, EA:Hx=1:4) yielded (4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (170 mg, 0.635 mmol) as white solid.
Reaction SMILES: [CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH3:11])[C:6](=[O:19])[CH2:5]1)[CH:2]=[CH2:3].B.C1C[O:31]CC1>C1COCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C@@H:10]([N:7]2[CH2:8][CH2:9][C@@:4]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:1][CH2:2][CH2:3][OH:31])[CH2:5][C:6]2=[O:19])[CH3:11])=[CH:13][CH:14]=1
Reactant: C1CCOC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)C1
Agent: B
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)CC1=O
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of (S)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)piperidin-2-one (70 mg, 0.169 mmol) in THF (5 mL) was added BH3/THF (0.6 mL, 1 M) at 0° C. under nitrogen atmosphere. The mixture was stirred for 2 h, and the reaction was quenched with water. Aqueous NaOH solution (1 M, 2 mL) and H2O2 (1 mL□30%) were added to the above mixture, and the resulting mixture was stirred for 1 h. The mixture was extracted with EtOAc, and the combined organic phase was concentrated to give the crude product, which was purified by preparative HPLC to give (S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-4-(3-hydroxypropyl)piperidin-2-one (30 mg, 41%). 1H NMR (CDCl3): δ 1.36 (m, 1H), 1.52 (m, 1H), 1.72 (m, 2H), 1.89 (m, 1H), 1.98 (m, 1H), 2.21 (m, 1H), 2.44 (m, 1H), 2.92 (m, 1H), 3.01 (m, 1H), 3.44 (m, 2H), 5.92 (m, 2H), 6.73 (m, 2H), 6.91 (m, 2H), 7.14 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]=[C:34]=[O:35]>C1COCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:1][C:34]([NH:33][C:27]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=3[F:25])=[O:35])=[CH:3][C:4](=[O:14])[O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(=O)Nc3ccc(F)cc3F)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (671 mg, 3.62 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 2,4-difluoro-1-isocyanato-benzene (224 mg) was added into the reaction mixture and the reaction mixture was then stirred for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(2,4-difluoro-phenyl)-acetamide as a yellow solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8](=[O:22])C2C=C(C)C=CC=2C2C=NN(C)C=2)[C@@H:3]1[CH2:23][N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].[Br:35][C:36]1[C:37](C(O)=O)=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1>>[Br:35][C:36]1[C:37]([C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]2[CH2:23][N:24]2[C:25](=[O:34])[C:26]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:32]2=[O:33])=[O:22])=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)c1
Reactant: Cc1ccc(Br)c(C(=O)O)n1
Product: Cc1ccc(Br)c(C(=O)N2CCC[C@@H](C)[C@H]2CN2C(=O)c3ccccc3C2=O)n1

Procedure:
The title compound was prepared following the same general protocol as described for 2-(((2S,3R)-3-methyl-1-(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoyl)piperidin-2-yl)methyl)isoindoline-1,3-dione in Example A1, using 3-bromo-6-methylpicolinic acid. ESI-MS (m/z): 456, 458 [M]+[M+2]+.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1>>[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CNCCc1ccc(N)cc1
Product: CNCCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 by reacting 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-methylamino-ethyl)-aniline.
Reaction SMILES: [OH-].[Li+].[CH2:3]([S:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([CH2:19][C:20]([O:22]C)=[O:21])[CH2:14]2)[CH:10]=[CH:9][C:8]=1[C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:4][CH3:5].Cl>O.CO.C1COCC1.CCOC(C)=O>[CH2:3]([S:6][C:7]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][C@@H:15]([CH2:19][C:20]([OH:22])=[O:21])[CH2:14]2)[CH:10]=[CH:9][C:8]=1[C:24](=[O:32])[NH:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:4][CH3:5]
Reactant: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)NC1CCOCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)O)C2)ccc1C(=O)NC1CCOCC1
Temperature: 18 °C
Reaction time: 20 h
Yield: 105.4 %

Procedure:
A solution of lithium hydroxide (0.055 g, 1.29 mmol) in water (1 mL) was added dropwise to a stirred solution of methyl {(3S)-1-[6-(propylthio)-5-(tetrahydro-2H-pyran-4-ylcarbamoyl)pyridin-2-yl]piperidin-3-yl}acetate (188 mg, 0.43 mmol) in MeOH (3 mL) and THF (2 mL) at 18° C., over a period of 1 minute. The resulting solution was stirred at 18° C. for 20 hours. The reaction mixture was adjusted to pH 4.5 with 2M HCl and the reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford {(3S)-1-[6-(propylthio)-5-(tetrahydro-2H-pyran-4-ylcarbamoyl)pyridin-2-yl]piperidin-3-yl}acetic acid (191 mg, 100%), as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[O:9][CH2:10][CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1(c2ccc(Br)cc2)OCCO1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1(c2ccc(Br)cc2)OCCO1
Temperature: 23 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
73.5 g 2-(4-Bromophenyl)-1,3-dioxolane-2-methanol are dissolved in 800 ml N,N-dimethylformamide. 38.6 g imidazole and 51.3 g tert-butyldimethylchlorosilane were added. It was stirred for 12 hours at 23° C. Afterwards, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. It was stirred for another 30 min. Then it was extracted with ethyl acetate twice. The combined organic layers were washed with brine and dried over sodium sulphate. The crude product was purified by column chromatography. 103.21 g product was obtained (97.5% of theory).
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][C:29]([C:33]([O:35]C(C)(C)C)=[O:34])=[C:30]([CH3:32])[N:31]=2)[CH2:13][CH2:12]1)=[O:9]>Cl.O1CCOCC1>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][N:19]([CH3:41])[C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][C:29]([C:33]([OH:35])=[O:34])=[C:30]([CH3:32])[N:31]=2)[CH2:15][CH2:16]1)=[O:9]
Reactant: Cc1nc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(NCCCCCC(=O)N(C)CCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.3 %

Procedure:
A 4 N hydrochloric acid-dioxane solution (10 mL) was added to the compound (66 mg, 0.099 mmol) obtained in Example 105a, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness to give crude 2-({6-[(2-{4-[(biphenyl-2-ylcarbamoyl)oxy]piperidin-1-yl}ethyl)(methyl)amino]-6-oxohexyl}amino)-4-methyl-1,3-thiazole-5-carboxylic acid (70 mg). The resulting crude carboxylic acid (70 mg) and the compound (98 mg, 0.126 mmol) obtained in Example 1k were dissolved in dichloromethane (4 mL), and triethylamine (30 μL, 0.218 mmol) was added. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (38 mg, 0.198 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated sodium chloride solution. The organic layer was dried with anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure, and the resulting residue was purified by NH silica gel chromatography (ethyl acetate:methanol, 100:0→90:10, v/v) and by reverse phase preparative chromatography (Waters Corporation; XBridge Prep C18 OBD column, 30 mm ID×150 mm, 5 μm; 0.1% [w/v] aqueous ammonium formate solution:acetonitrile, 50:50->30:70) to give a free form (56 mg; yield, 41%) of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[NH2:12]OS(O)(=O)=O.O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([OH:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>O.C(Cl)(Cl)Cl>[C:19]1([CH3:29])[CH:20]=[CH:21][C:22]([S:25]([OH:28])(=[O:26])=[O:27])=[CH:23][CH:24]=1.[NH2:12][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: c1c[nH]cn1
Reactant: NOS(=O)(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nn1ccnc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In 50 ml of water was dissolved 2.76 g (20 mmol) of potassium carbonate and 1.36 g (20 mmol) of imidazole was added thereto. 2.26 g (20 mmol) of hydroxylamine-O-sulfonic acid was added thereto and the mixture was stirred at room temperature for 6 hours. The resulting precipitate was filtered off and the filtrate was concentrated under the reduced pressure. To the concentrate were slowly added 10 ml of chloroform and a solution of 3.8 g (20 mmol) of p-toluenesulfonic acid monohydrate in 10 ml of chloroform. Stirring for 30 min, filtration and drying of the mixture gave 1.74 g of the desired compound(34%).
Reaction SMILES: CCCCCC[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21]C(O)[C@H]1OC[C@H](O)[C@H]1O)=[O:19].CC(=CCCC(=CC=[O:41])C)C.C(N)COP(O)(O)=O>O>[CH3:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH:12]1[C:13](=[O:41])[CH2:14][CH2:15][CH:16]1[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(O)[C@H]1OC[C@H](O)[C@H]1O
Reactant: CC(C)=CCCC(C)=CC=O
Agent: NCCOP(=O)(O)O
Solvent: O
Product: CC/C=C\CC1C(=O)CCC1CC(=O)OC

Procedure:
Poly(ε-caprolactone) having average Mw 65.000, Sorbitan monostearate (Span®60), and Polysorbate 80 (Tween®80) were obtained from Sigma-Aldrich (St. Louis, USA). All organic solvents used for were HPLC grade purchased from J. T. Baker (Ecatepec, Mexico). Ultrapure water was produced in-house by Milli-Q System (18 MΩ) (Millipore Corporation, Bedford, Mass., USA). Nanoparticles containing citral (3,7-dimethyl-2,6-octadienal), phosphorylethanolamine and/or methyl jasmonate were obtained as follows. First, an oil/water (O/W) emulsion was made by vigorous stirring of oil (10.0 g) and the active compounds, alone or in mixture ranging from 0.05 to 0.50 g, (internal constituents) in water (400 mL) by using a Ultra-Turrax homogenizer (IKA T10 basic Ultra-turrax®, Ika-Werke, Staufen, Germany) at 15,000 rpm by 1 min. In a second step, an organic solution which was prepared by dissolving a polymer (between 0.2 and 2.0 g) in acetone (400 mL) was poured under moderate magnetic stirring, into emulsion phase using a peristaltic pump at 10% (PumpPro TPM 600 55 RPM, Waton-Marlow, Wilmington, UK). After 10 min of stirring, an aqueous solution prepared by dissolving 1.0 g of Tween®80 in water (200 mL) was also poured under moderate magnetic stirring into the emulsion. Again, a peristaltic pump at 10% was used. After complete addition, the reaction mixture was further stirred for 10 min. In the last step, the organic solvent was removed and the volume of nanoparticle dispersion was concentrated to 500 mL under reduced pressure (R-21, Büchi, Switzerland). The O/W emulsion made in the first step was stable even without the polymer. Several different nanoemulsions were prepared and analyzed.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1)CC.OCC(C)(CO)C.CC(C)=O>CC(O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([C:7]2[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCc1ccc(B(O)O)cc1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(CO)CO
Solvent: CC(C)=O
Solvent: CC(C)O
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Yield: 89 %

Procedure:
A solution of (2 mmol) of 8, (2.2 mmol) of 4-propylphenylboronic acid, 250 mg (2.40 mmol) of neopentyl glycol, 1:53 g (4.84 mmol) of Ba(OH)2. 8H2O, 1.35 ml (0.103 mmol, 5 mol %) of a 76 mM acetone solution of Pd(OAc)2 in 20 ml of 95% i-PrOH is stirred at 80° for 12 hours. The solvent is subsequently removed under reduced pressure. 5 ml of 2 M HCl are added to the residue, and the mixture is extracted with dichloromethane (3×5 ml). The combined organic phases are dried over MgSO4 and filtered through SiO2. The solvent is removed under reduced pressure, and the residue is converted into 10 (yield: 89%).
Reaction SMILES: [CH3:1][N:2]([S:13]([CH3:16])(=[O:15])=[O:14])[C:3]1[O:4][CH:5]=[C:6]([C:8]([O:10]CC)=[O:9])[N:7]=1.[OH-].[Li+].O1CCCC1.Cl>O>[CH3:1][N:2]([S:13]([CH3:16])(=[O:15])=[O:14])[C:3]1[O:4][CH:5]=[C:6]([C:8]([OH:10])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1coc(N(C)S(C)(=O)=O)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1nc(C(=O)O)co1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a 50 ml round bottom flask was added (61 mg, 0.2457 mmoles) ethyl 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylate, (51.5 mg, 1.2274 mmoles, 5.0 eq.) lithium hydroxide, (2.5 ml) tetrahydrofuran and (1.5 ml) water. The reaction was agitated at ambient temperature for ˜2 hours. The reaction was complete by electrospray mass spec. The reaction was worked up by adding (5 ml) 1N HCl and then extracting with ethyl acetate. The organic layer was washed with water and brine and then dried with magnesium sulfate. The solution was then evaporated to dryness, leaving (44.6 mg) of 2-[methyl(methylsulfonyl)amino]-1,3-oxazole-4-carboxylic acid.
Reaction SMILES: [F:1][CH:2]([F:21])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19][CH3:20].C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C1C=C(Cl)C=C(C(O)=O)C=1>>[F:21][CH:2]([F:1])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([CH3:18])[C:4]=1[S:19]([CH3:20])=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(SC)c1C
Agent: O=C(O)c1cccc(Cl)c1
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(S(C)=O)c1C

Procedure:
Prepared from product of Example 1 (5.75 g, 17.5 mmol) and MCPBA (3.4 g of an 85% mixture with MCBA; 17.5 mmol) as described above. Recrystallization (ether) afforded the product as a white solid (5.23 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([Cl:12])[N:3]=1.O.[NH2:14][NH2:15]>C(O)C>[Cl:12][C:4]1[N:3]=[C:2]([NH:14][NH2:15])[CH:7]=[CH:6][C:5]=1[C:8]([F:11])([F:10])[F:9]
Reactant: NN
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Solvent: CCO
Solvent: O
Product: NNc1ccc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To the solution of 2,6-Dichloro-5-trifluoromethyl-pyridine (18, 2 g, 9.26 mmol) in ethanol (30 mL) was added hydrazine hydrate (2.9 g, 46 mmol). The reaction mixture was stirred for 4 h at room temperature, then concentrated to remove the solvent, and added ethyl acetate, washed with water. The organic layer was dried over anhydrous Na2SO4. Column chromatography (Silica, petroleum ether/ethyl acetate=4/1˜3/1) afforded compound 19 as white solid (yield: 56%) and another isomer 20 (yield: 18%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=1[O:19][CH3:20])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:11]=1[CH:7]1[CH2:8][CH2:9][CH2:10][CH:6]1[CH2:4][OH:3]
Reactant: CCOC(=O)C1CCCC1c1cc(OC)ccc1OC
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(OC)c(C2CCCC2CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Dissolve 2-(2,5-dimethoxy-phenyl)-cyclopentanecarboxylic acid ethyl ester (4.5 g, 16 mmol) in tetrahydrofuran (80 ml), add a 1.0M solution of lithium aluminum hydride in tetrahydrofuran (49 ml, 49 mmol), and stir at room temperature for 1 hour. Pour slowly into a mixture of ether and aqueous Rochelle's Salt, stir over night, separate layers, wash organic with brine, dry and concentrate to give the title compound (3.6 g, 94%): 1H NMR (CDCl3) δ 6.82-6.70 (m, 3H), 3.82 (s, 3H), 3.77 (s,−3H), 3.66-3.60 (m, 1H), 3.30-3.23 (m, 1H), 3.07-3.01 (m, 1H), 2.53-2.43 (m, 1H), 2.14-2.11 (m, 1H), 2.03-1.98 (m, 1H), 1.94-1.89 (m, 2H), 1.81-1.71 (m, 2H), 1.43-1.38 (m, 1H).