Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][O:6][C:7](=[O:34])[C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH:9]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.C(NCC)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:4]=1[CH2:5][O:6][C:7](=[O:34])[C@H:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[NH2:9]
Reactant: COc1ccc(COC(=O)[C@H](Cc2ccccc2)NC(=O)OCC2c3ccccc3-c3ccccc32)c(OC)c1
Solvent: CCNCC
Solvent: ClCCl
Product: COc1ccc(COC(=O)[C@@H](N)Cc2ccccc2)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 500-mL round-bottom flask was charged with Fmoc-L-phenylalanine-2,4-dimethoxybenzyl ester (26.00 g, 48.3 mmol), CH2Cl2 (150 mL) and diethylamine (75 mL, Acros). Mixture was stirred at room temperature and the completion monitored by HPLC. After 4 h, the mixture was concentrated (bath temp<30° C.). The residue was resuspended in CH2Cl2 (200 mL) and concentrated. This was repeated once. To the residue was added MeOH (20 mL), which caused the formation of a gel. This residue was diluted with CH2Cl2 (200 mL), concentrated and the cloudy oil left under vacuum overnight. The residue was suspended in CH2Cl2 (100 mL), then toluene (120 mL) was added. The mixture was concentrated and the residue left under vacuum overnight.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[C:10](=[O:21])[C:9](Br)=[CH:8]2)=[O:4].[C:24]1([Sn](CCCC)(CCCC)CCCC)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:23])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[C:10](=[O:21])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2nccs2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2nccs2)c1O
Temperature: 120 °C
Yield: 56.5 %

Procedure:
A mixture of 3-bromo-5-hydroxy-2-oxo-1-thiazol-2-ylmethyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (29 mg, 0.072 mmol), PhSnBu3 (0.030 mL, 0.087 mmol), and PdCl2(PPh3)2 (10 mg, 0.014 mmol) in DMF (3 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine and EtOAc were added. 1 M HCl was added with stirring until pH was about 4. The aqueous layer was extracted with EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH) to give 16 mg of the title compound. MS: (+) m/z 394.25 (M+1).
Reaction SMILES: C([C:3]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])([CH2:10][CH3:11])[CH2:4][CH2:5][C:6]([O:8]C)=[O:7])=O.O=O>>[CH2:10]([C:3]1([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[O:8][C:6](=[O:7])[CH2:5][CH2:4]1)[CH3:11]
Reactant: CCC(C=O)(CCC(=O)OC)CCC(=O)OC
Agent: O=O
Product: CCC1(CCC(=O)OC)CCC(=O)O1
Yield: 56 %

Procedure:
Using a method similar to Example 1, a mixture of 244 parts of methyl 4-formyl-4-(β-methoxycarbonylethyl)-hexanoate and 2.4 parts of CoCl2.6H2O is reacted with 100 parts of oxygen in the course of 5 hours. The batch is then washed with water, dried with anhydrous magnesium sulfate and subjected to fractional distillation. 113 parts (56% of theory) of γ-ethyl-γ-(β'-methoxycarbonylethyl)-γ-butyrolactone (boiling point 125° C./0.5 mbar) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:10][CH3:11])[C:7]=1[CH2:8]O.[Br:12]P(Br)Br>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:6]([CH2:10][CH3:11])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: BrP(Br)Br
Reactant: CCc1cncc(Cl)c1CO
Solvent: ClC(Cl)Cl
Product: CCc1cncc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3-chloro-5-ethylpyridin-4-yl)methanol (1.83 g, 10.66 mmol) in anhydrous chloroform (40 mL) was added dropwise tribromophosphane (2.91 g, 1.01 mL, 10.75 mmol) at 0° C. The reaction mixture was allowed to stir overnight at room temperature. The solvent was then evaporated to provide crude 4-(bromomethyl)-3-chloro-5-ethylpyridine, which was used for the next step without any further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: COC(=O)c1ccc(-n2cnc(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cn(-c2ccc(C(=O)O)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution (5 ml) of methyl 4-(4-methyl-1H-imidazol-1-yl)benzoate (137 mg, 0.635 mmol) in methanol was added 1M sodium hydroxide (5 ml), and the mixture was stirred at room temperature for 3 hrs. 1M Hydrochloric acid (5 ml) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was used for the next reaction without purification.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](OB(O)O)=[CH:24][CH:23]=1>O1CCOCC1.CO>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)/C=C/c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
173 mg (0.15 mmol) of tetrakistriphenylphosphine palladium and 4.4 mL (8.8 mmol) of a 2M sodium carbonate solution is added at ambient temperature to a solution of 1.124 g (4.04 mmol) of ethyl (E)-3-(4-bromophenyl)acrylate in 50 mL of dioxane. 0.689 g (4.404 mmol) of 4-chlorophenylboric acid dissolved in 10 mL of methanol is added to this reaction mixture and refluxed for 5 hours. The reaction mixture is evaporated down, the residue is taken up in dichloromethane, and extracted with water. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether/ethyl acetate (9:1)). Yield: 0.94 g (74.4% of theory); C17H15ClO2 (M=286.76); calc.: molecular ion peak (M+H)+: 287/289; found: molecular ion peak (M+H)+: 287/289; Rf value: 0.44 (silica gel, petroleum ether/ethyl acetate (40:10)).
Reaction SMILES: [N+:1]([O-:31])([O:3][C@@H:4]1[CH:21]2[C@:16]([CH3:22])([CH2:17][CH2:18][CH2:19][CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10]24OCCO[C:9]2(OCC[O:23]4)[CH2:8]3)[CH2:5]1)=[O:2].CC1C=CC(S(O)(=O)=[O:40])=CC=1.O.C([O-])(O)=O.[Na+]>CC(C)=O>[N+:1]([O-:31])([O:3][C@@H:4]1[CH:21]2[C@:16]([CH3:22])([CH2:17][CH2:18][C:19](=[O:40])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:23])[CH2:9][CH2:8]3)[CH2:5]1)=[O:2]
Reactant: C[C@]12CCCCC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CCC(=O)CC1[C@@H](O[N+](=O)[O-])C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12

Procedure:
A solution of 3,3:17,17-bis(ethylendioxy)androstane-6α-yl nitrate (2.50 g) and pTSA.H2O (6.05 g) in acetone (150 mL) was stirred at room temperature for 1.5 h. The solution was neutralized by addition of 5% aqueous NaHCO3, and acetone was evaporated. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/acetone/CH2Cl2 70/15/15) to give the title compound II-aa as a white solid (1.66 g, 75%). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.09 (ddd, 1H), 2.60-0.95 (m, 17H), 1.25 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)[CH:16]=[CH:17][N:18](C)C)=[N:9]1.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]2[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[N:9]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccccc2Cl)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: O=c1ccn(-c2ccccc2Cl)nc1-c1ccnn1-c1ccccc1
Yield: 8.2 %

Procedure:
To a solution of 1-(2-chlorophenyl)-3-[3-(dimethylamino)prop-2-enoyl]pyridazin-4(1H)-one (crude, 636 mg, 2.10 mmol) in 20 mL of methanol was added phenylhydrazine (907 mg, 8.40 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(2-chlorophenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (60 mg, 8% for two steps) as a red gel.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].OS(O)(=O)=O.[CH3:21]O>>[CH3:21][O:7][C:6](=[O:8])[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: COC(CCC(=O)O)c1ccccc1C
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(OC)c1ccccc1C
Reaction time: 12 h

Procedure:
To a solution of the 4-methoxy-4-o-tolyl-butyric acid obtained above in 6 mL methanol was added 60 μL concentrated H2SO4 at room temperature. After stirring for 12 h the reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2×10 mL) and dried over Na2SO4. The product was isolated by flash column chromatography eluting with 0% to 10% ethyl acetate/hexane to give 229 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]([O:7]C)=[O:6].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:28][CH3:29])[C:20]=1[O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:16]=O.[OH-].[K+]>O1CCCC1>[CH3:1][O:2][CH2:3][C:4](=[CH:16][C:15]1[CH:14]=[C:13]([O:12][CH3:11])[C:20]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:19]([O:28][CH3:29])[CH:18]=1)[C:5]([OH:7])=[O:6]
Reactant: COCCC(=O)OC
Reactant: COCCOCOc1c(OC)cc(C=O)cc1OC
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1c(OC)cc(C=C(COC)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 637.7 %

Procedure:
A solution of 2.6 g (22.0 mmol) of methyl 3-methoxy-propionate in 5 ml of tetrahydrofuran was added to a solution of 666 mg of sodium hydride in 15 ml of tetrahydrofuran solution with ice cooling, subsequently to the resulting solution was added a solution of 3 g (1.1 mmol) of 3,5-dimethoxy-4-(β-methoxyethoxy)methoxybenzaldehyde in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature for 17 hours. The mixture was extracted with 60 ml of ethyl acetate after adding ice to the solution. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily product thus obtained was dissolved in 20 ml of tetrahydrofuran. An aqueous potassium hydroxide solution (740 mg/5 ml) was added to the solution. The mixture was stirred at room temperature for 21 hours. The solution was evaporated under reduced pressure. A 40 ml of water was added to the residue, and the aqueous solution was washed with 30 ml of ethyl acetate. The aqueous layer was neutralized with acetic acid and extracted with 60 ml of methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to give 2.5 g (yield 63.2%) of a desired α-methoxymethyl-3,5-dimethoxy-4-(β-methoxyethoxy)-methoxycinnamic acid.
Reaction SMILES: C([Li])CCC.C(NC1CCCCC1)(C)C.C[Si]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(C)C.[F:26][C:27]([F:53])([F:52])[C:28]1[CH:29]=[C:30]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:40][C:41](=O)[CH2:42][CH3:43]>CCCCCC.O1CCCC1>[F:26][C:27]([F:52])([F:53])[C:28]1[CH:29]=[C:30]([CH:45]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:47]=1)[CH2:31][O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:40][C:41]([CH2:42][CH3:43])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: CCC(=O)C=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C=C(C=CCCCCCCOCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (4.99 mmol) in hexane was added to N-isopropyl cyclohexylamine (0.69 g, 4.88 mmol, Aldrich Chem Co.) in dry tetrahydrofuran (20 ml) at -78° under nitrogen. After 15 mins, ethyl trimethylsilylacetate (0.78 g, 4.88 mmol, Fluka Chem. Co.) was added. After a further 10 mins, 11-(3',5'-bistrifluoromethylbenzyloxy) undeca-4-ene-3-one (1 g, 2.44 mmol) was added and the temperature was allowed to reach room temperature. After conventional work-up and chromatography on silica, ethyl 11-(3',5'-bistrifluoromethylbenzyloxy)-3-ethyl-undeca-2, 4- dienoate was obtained as a mixture of two isomers.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:25])[CH2:23][N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(CCl)Nc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(2,4-difluorophenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 37.3 mg (74.8%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.52 (t, J=4 Hz, 4H), 3.23 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.08 (t, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.92 (m, 1H), 8.12 (d, J=5 Hz, 1H), 9.60 (s, 1H); MS (ESI/APCI+) m/e 333 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6](=[CH:11][O:12][CH3:13])[C:7]([O:9][CH3:10])=[O:8].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6](=[CH:11][O:12][CH3:13])[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC=C(Oc1cccc(C)c1)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(Oc1cccc(CBr)c1)C(=O)OC
Yield: 50 %

Procedure:
A mixture of 9.6 g of methyl 2-(3-methylphenoxy)-3-methoxyacrylate, 8.0 g of N-bromosuccinimide and a catalytic amount of azobisisobutyronitrile was heated at reflux in carbon tetrachloride for 4 hours. After cooling, the solid was filtered, the filtrate evaporated, and purified by silica gel column chromatography to give methyl 2-(3-bromomethylphenoxy)-3-methoxyacrylate (6.5 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[NH3:14]>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: N
Reactant: Fc1ccc(C(F)(F)F)c(F)c1F
Solvent: C1CCOC1
Product: Nc1ccc(C(F)(F)F)c(F)c1F
Temperature: 130 °C
Reaction time: 6 h

Procedure:
200 g of 2,3,4-trifluorobenzotrifluoride in 500 ml of tetrahydrofuran are introduced in an autoclave, and 60 ml of liquid ammonia are forced in. The mixture is stirred at 130° C. for 6 hours (maximum pressure 18 bar), cooled, and released. By distillation, 72 g of 2-amino-3,4-difluoro-benzotrifluoride are obtained at a boiling point of 60° to 64° C. at 26 mbar and 92 g of 2,3-difluoro-4-amino-benzotrifluoride are obtained at a boiling point of 92° to 93° C. at 26 mbar.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH:40]([CH3:46])[C:41]([O:43]CC)=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH:40]([C:41]([OH:43])=[O:42])[CH3:46])[N:28]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(C)Br
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC(C)C(=O)O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1.50 g 4-{(S)-4-tert-butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 12 ml DMF were added 670 μl ethyl 2-bromopropionate and 3.2 g cesium carbonate. After stirring at RT for 24 h the solution was diluted with ethyl acetate and extracted with aqueous LiCl (4 w/w). The crude product obtained after evaporation of the solvent was dissolved in THF and treated with 1 N NaOH. When conversion was complete (4 h) Amberlite IR-120®was added, the suspension filtrated and the filtrate evaporated to give the crude product (1.56 g)
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>[Cu](I)I.C(OCC)(=O)C>[CH3:1][CH2:2][C:3]([N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: CCC(=O)Nc1ccccc1
Reactant: Ic1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)N(c1ccccc1)c1ccccc1
Temperature: 150 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 2-methylacetanilide (4.5 g), iodobenzene (6.8 ml), potassium carbonate (8.3 g), and copper iodide (574 mg) was stirred overnight at 150° C. After the mixture was allowed to cool, water and ethyl acetate were added thereto, and the mixture was further stirred. The mixture was then filtered with celite. Filtrate was collected, and an aqueous phase was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over sodium sulfate. The resulting solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:2.5) to obtain 2-methyl-N-phenylacetanilide (4.96 g; yield, 73%) as a light brown oil.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:32][CH2:33][N:34]([CH:37]3[CH2:40][O:39][CH2:38]3)[C:35](=[O:36])[C:10]=12)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:32][CH2:33][N:34]([CH:37]3[CH2:38][O:39][CH2:40]3)[C:35](=[O:36])[C:10]=12
Reactant: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1COC1
Agent: [Pd]
Solvent: CCO
Product: O=C1c2c(O)c(=O)nc(CC3(c4cccc5ccccc45)CCCC3)n2CCN1C1COC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 31.2 %

Procedure:
A solution of 9-benzyloxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-2-oxetan-3-yl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (364) (125 mg, 0.23 mmol) in ethanol (60 mL) was degassed under nitrogen, followed by the addition of Pd—C (10%) (40 mg) and again degassed under nitrogen. The reaction mixture was then stirred under a hydrogen atmosphere of balloon pressure for 25 min at room temperature. The reaction mixture was the filtered through a celite bed and the filtrate was concentrated in vacuo to get a crude sticky mass which was purified by preparative TLC plate using as developing solvent 3% methanol in dichloromethane to get pure 9-hydroxy-6-(1-naphthalen-1-yl-cyclopentylmethyl)-2-oxetan-3-yl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (365) (32 mg, 31%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([O:10]CC)=O.[NH2:22][CH2:23][C:24]([OH:26])=[O:25].[O-]CC.[Na+].Cl>CN(C=O)C.O.CCOC(C)=O>[OH:1][C:2]1[C:3]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[C:4]=2[CH:5]=[N:6][C:7]=1[C:8]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:10]
Reactant: CCOC(=O)c1ncc2c(-c3ccncc3)noc2c1O
Reactant: NCC(=O)O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CNC(=O)c1ncc2c(-c3ccncc3)noc2c1O
Temperature: 25 °C
Yield: 28.9 %

Procedure:
Ethyl 7-hydroxy-3-(pyridin-4-yl)isoxazolo[4,5-c]pyridine-6-carboxylate (95 mg, 0.33 mmol) was dissolved in 10 mL of DMF. Glycine (500 mg, 6.67 mmol) and sodium ethoxide (340 mg, 5.0 mmol) were added and the mixture was refluxed for 2 h. The mixture was cooled to room temperature and diluted with 50 mL of water. Concentrated hydrochloric acid was added dropwise until pH was 3. EtOAc (50 mL) was added to the resulting suspension, and the mixture was transferred to a separatory funnel. The aqueous layer was removed, and the organic layer, which contained an insoluble solid, was filtered. The solid was dried under vacuum to give 30 mg of the title compound. MS: (+) m/z 315.34 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[OH:23])[CH:18]=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[O:6][C:7]=1[CH3:8])[CH:18]=[O:19]
Reactant: Cc1oc(-c2ccco2)nc1CCl
Reactant: O=Cc1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cc1Br
Temperature: 90 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of 4-chloromethyl-2-(2-furyl)-5-methyl-1,3-oxazole (4.62 g), 3-bromo-4-hydroxybenzaldehyde (4.28 g), potassium carbonate (2.94 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 4 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give 3-bromo-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzaldehyde as pale-brown crystals (5.20 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-147° C.