Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Ca+2].[H-].[CH3:4][NH:5][CH2:6][C:7]1[N:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[S:10][CH:11]=1.[O:15]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=O)C1C=CC=CC=1>C1COCC1>[CH3:4][N:5]([C:22]([NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:15])[CH2:6][C:7]1[N:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[S:10][CH:11]=1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Reactant: CNCc1csc(C(C)C)n1
Agent: [Ca+2]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a suspension of calcium hydride (o.98 g, 23.2 mmol) in THF (25 mL) at 0° C. to 5° C. was added 3.94 g (23.1 mmol) of N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine. To this was added a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) in 20 mL of THF. Following a 5 mL THF rinse, 4.0 mL of water was added, and the reaction mixture was allowed to warm to 20° C. with stirring. After 2 hours, HPLC analysis (t=12.6 min; HPLC conditions: 65% 0.03M KH2PO4 buffer/35% acetonitrile; pH=4; 5μ nucleosil; 4.6×250 mm; 1 mL/min; 205 nm) indicated that the reaction was complete and the desired product had been formed.
Reaction SMILES: [In].Br[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C[Si](Cl)(C)C.[CH2:19]([CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH:24]=[CH:23]1)[CH:20]=[CH2:21]>C1COCC1>[CH2:19]([CH:22]1[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH:23]1[CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:20]=[CH2:21]
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: C=CCC1C=CC(=O)CC1
Agent: C[Si](C)(C)Cl
Agent: [In]
Solvent: C1CCOC1
Product: C=CCC1CCC(=O)CC1C(C(=O)OCC)C(=O)OCC
Reaction time: 0.5 h

Procedure:
Indium (114.8 mg, 1.0 mmol), diethyl bromomalonate (359.0 mg, 1.5 mmol), and TMSCl (0.6 mL, 5.0 mmol) were added to (±)-4-(2-propenyl)-2-cyclohexen-1-one (0.120 mg, 1.0 mmol) in anhydrous THF (1 mL) at room temperature under nitrogen atmosphere. After 30 minutes of stirring the reaction was quenched with saturated NaHCO3. The aqueous layer was extracted with diethyl ether and the combined organics were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was identified by mass spectrometry, (ESI, Pos) m/z 391 (M+23).
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][S:33]([CH:30]2[CH2:32][CH2:31]2)(=[O:35])=[O:34])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg) and triethylamine (0.193 mmol, 0.027 mL, 19.50 mg) in DCM (0.9 mL) was added cyclopropanesulfonyl chloride (0.096 mmol, 13.55 mg) and the whole stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give the desired product as a clear film (12.0 mg, 0.029 mmol, 30%). MS (ESI): m/z [M+H]− 417.0.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:20][N:19]=1)=[O:23])([CH3:29])[CH3:28]
Reactant: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)O)nc1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NC(C)(C)CO)nc1
Yield: 84 %

Procedure:
As described for example 7, 5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyridine-2-carboxylic acid (81.6 mg, 0.26 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (84 mg, 84%), which was obtained as a white solid. MS: m/e=383.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[N+:13]([CH:15](S(C1C=CC(C)=CC=1)(=O)=O)[CH3:16])#[C-:14].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:14]=[N:13][C:15]=2[CH3:16])=[CH:6][CH:5]=1
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccc(-c2ocnc2C)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-formyl-benzoic acid methyl ester (2.50 g), 1-(1-isocyano-ethanesulfonyl)-4-methyl-benzene (3.19 g), and potassium carbonate (2.76 g) in methanol (50 mL) is heated to reflux for 2 h. After cooling to room temperature, the mixture is poured onto water and extracted with dichloromethane. The organic phase is washed with water, dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 40:1) to afford the title compound. LC (method 6): tR=2.68 min; Mass spectrum (ESI+): m/z=218 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[N:28]1([CH2:34][CH2:35][O:36][C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[C:42](=O)[O:41][CH2:40]3)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.Cl.[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[C:42]1[C:43]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:45][CH:44]=2)[CH2:40][O:41]1
Reactant: O=C1OCc2cc(OCCN3CCOCC3)ccc21
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=C1OCc3cc(OCCN4CCOCC4)ccc31)C(=O)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.6 %

Procedure:
To a stirred solution of 5-methoxyoxindole (197 mg, 1.21 mmol) in anhydrous THF (10 ml) under nitrogen was added 1.0M LiHMDS/THF solution (2.8 ml, 2.8 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-(2-morpholin-4-yl-ethoxy)-3H-isobenzofuran-1-one (200 mg, 0.76 mmol) was added. After stirred at room temperature for 3.0 hours, the mixture was poured into a mixture of THF (5 ml) and 2M HCl aqueous solution (10 ml), and heated at 60° C. for 40 minutes. The mixture was cooled to room temperature, basified with 5M NaOH aqueous solution, and then poured into water (150 ml). The resulting solid was separated, rinsed with water, and dried to give 5-methoxy-3-[5-(2-morpholin-4-yl-ethoxy)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (275 mg, 89%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25]CC)=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([OH:25])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1)[CH:16]=2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc3cc(NC(=O)OCc4ccccc4)c(C(=O)O)nc3c2)CC1
Temperature: 100 °C

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (300 mg, 0.7 mmol), 1-methylpiperazine (200 mg, 2 mmol), Pd(OAc)2 (20 mg), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (49 mg, 0.10 mmol), and K3PO4 (580 mg, 2.8 mmol) in tert-butyl alcohol (10 mL) was purged with N2 prior and then heated at 100° C. in a sealed vial for 2 h. The mixture was allowed to cool, diluted with EtOAc, and then filtered through a diatomaceous earth plug. The filtrate was concentrated under reduced pressure. To the resulting residue, 10 mL of dioxane and 4 mL of 2.5 M NaOH were added.
Reaction SMILES: FF.[C:3]([OH:8])(=[O:7])[C:4]([CH3:6])=[CH2:5].[F:9][C:10](=[C:15]([F:17])[F:16])[CH2:11][CH2:12][CH2:13]O>>[C:3]([O:8][CH2:13][CH2:12][CH2:11][C:10]([F:9])=[C:15]([F:17])[F:16])(=[O:7])[C:4]([CH3:6])=[CH2:5]
Reactant: OCCCC(F)=C(F)F
Reactant: C=C(C)C(=O)O
Agent: FF
Product: C=C(C)C(=O)OCCCC(F)=C(F)F
Yield: 43 %

Procedure:
A fluorine based polymer was also tested to provide a plasma reactive functionality. The fluorine based monomer used to form the polymer was synthesized by the reaction of methacrylic acid and 4,5,5-trifluoropent-4-en-1-ol to yield 4,5,5-trifluoropent-4-enyl methacrylate. This yield was about 43%. The chemical structure of 4,5,5-trifluoropent-4-enyl methacrylate is shown in Formula (IV):
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.Cl.[NH2:17]O.O>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:12]3[CH2:14][CH2:13]3)[O:11][N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C1CC1)c1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: O
Product: Brc1ccc(-c2cc(C3CC3)on2)cc1
Yield: 40.5 %

Procedure:
To a solution of 1-(4-bromophenyl)-3-cyclopropyl-1,3-propanedione (2.60 g, 9.73 mmol) in anhydrous MeOH (80 ml) was added hydroxylamine hydrochloride (2.71 g, 39.00 mmol). The mixture was heated to reflux for 14 h. Upon cooling, the solution was poured into water, and extracted with CH2Cl2 (3×200 ml). The combined organic phases were dried with MgSO4 and concentrated in vacuo. The regioisomers were separated by flash chromatography (CH2Cl2/hexanes, 10:90 to 40:60) to yield the title compound as a white solid (1.04 g, 40%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:7][C:8]([CH3:15])=[CH:9][C:10](OCC)=[O:11].F>>[CH3:7][C:8]1([CH3:15])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[C:10](=[O:11])[CH2:9]1
Reactant: c1ccccc1
Reactant: CCOC(=O)C=C(C)C
Agent: F
Product: CC1(C)CC(=O)c2ccccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
7.81 g (100 mmol) of benzene and 14.4 g (112 mmol) of ethyl 3,3-dimethylacrylate were reacted analogously with 100 g (5 mol) of liquid hydrogen fluoride and the mixture was stirred at 70° C. for 1 hour. The work-up was carried out analogously to Example A, giving 15.5 g of the compound (3) in a purity of 96% (GC). (Yield: 93.1% of theory). 1H-NMR spectra (100 MHz, CDCl3): 3:7.77-7.25 (m,4H), 2.57 (s,2H), 1.37 (s,6H).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:6](C(O)=O)[C:5]=1[OH:16])([CH3:3])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O>[CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[CH:6][C:5]=1[OH:16])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(C(=O)O)c(O)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC(C)c1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
A mixture of 3,5-diisopropylsalicylic acid (Intermediate 9, 25 g, 0.11 mol, available from Aldrich) and quinoline (50 mL) was refluxed for 4 h. The mixture was cooled to room temperature, diluted with EtOAc (200 mL), washed with 1M HCl (2×200 mL) until acidic, then with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5% then 10% EtOAc-hexanes) to yield the title compound as a yellow oil (20 g, ˜100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1C(OC)=O)[CH3:2].C(COC1C=CC=CC=1C(O)=O)(O)=[O:19].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>>[C:1]([O:3][C:4]1[C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[O:6][CH:5]=1)(=[O:19])[CH3:2]
Reactant: O=C(O)COc1ccccc1C(=O)O
Reactant: CCOC(=O)COc1ccccc1C(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Oc1coc2ccccc12

Procedure:
Another synthesis of (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13) is illustrated in Scheme 2B. According to the synthesis, methyl salicylate reacts with ethyl chloroacetate in the presence of potassium carbonate to give methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6). Hydrolysis of methyl 2-(2-ethoxy-2-oxoethoxy)benzoate (6) followed by a consecutive cyclization of 2-(carboxymethoxy)benzoic acid (7) with acetic anhydride in the presence of sodium acetate gives benzofuran-3-yl acetate (8) which is converted to benzofuran-3(2H)-one (9) by methanolysis. Treatment of benzofuran-3(2H)-one (9) with O-methylhydroxylamine and sodium acetate affords benzofuran-3(2H)-one O-methyl oxime (10) which is oxidized with tert-butyl nitrate in hydrochloric acid to yield exclusively or predominantly (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A). In the presence of potassium hydroxide and 2-haloethanol, the (3E)-benzofuran-2,3-dione O3-methyl dioxime (11A) may form (3E)-benzofuran-2,3-dione O2-(2-hydroxyethyl) O3-methyl dioxime (12A), which may undergo potassium hydroxide-catalyzed cyclization to provide (E)-(5,6-dihydro-1,4,2-dioxazin-3-yl)(2-hydroxyphenyl)methanone O-methyl oxime (13).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH3:19])=[N:5][CH:4]=[C:3]1[C:20]([O:22]CC)=[O:21].O=C1NC(C2C=CC=CC=2OCCCC)=NC=C1C(O)=O>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=2[O:16][CH2:17][CH2:18][CH3:19])=[N:5][CH:4]=[C:3]1[C:20]([OH:22])=[O:21]
Reactant: CCCOc1ccc(OC)cc1-c1ncc(C(=O)OCC)c(=O)[nH]1
Agent: CCCCOc1ccccc1-c1ncc(C(=O)O)c(=O)[nH]1
Product: CCCOc1ccc(OC)cc1-c1ncc(C(=O)O)c(=O)[nH]1

Procedure:
The title compound was prepared from ethyl 1,6-dihydro-6-oxo-2-(5-methoxy-2-n-propoxyphenyl)pyrimidine-5-carboxylate in a manner similar to that described for the preparation of 1,6-dihydro-6-oxo-2-(2-n-butoxyphenyl)pyrimidine-5-carboxylic acid in Example 23. The product had m.p. 185°-187°.
Reaction SMILES: Br.[N:2]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=2)[S:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.NN>C(O)C.CCOCC>[N:2]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=2)[S:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1cccc(CN2CCCCC2)c1
Agent: Br
Agent: NN
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: NCCCSc1cccc(CN2CCCCC2)c1
Yield: 44.4 %

Procedure:
To a solution of N-{3-[3-(piperidinomethyl)thiophenoxy]propyl}phthalimide hydrobromide (58.0 g, 0.12 mole) [prepared in Step A] in 1650 mL of 95% ethanol was added hydrazine hydrate (26.9 g, 0.54 mole) and the reaction mixture was heated at 45° for 4.5 hours. The mixture was diluted with 500 mL of ether, filtered and the filtrate evaporated to dryness to give the title compound as an amber oil (14.1 g). An aliquot was distilled to a colorless oil, b.p. 154°-155°/0.15 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:18](=[O:20])[CH3:19]
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1NC(C)=O
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(N)c(C(F)(F)F)cc1NC(C)=O
Yield: 103.1 %

Procedure:
A solution of 1.7 g (5.55 mmol) of 2-acetylamino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester in 29 ml of methanol is treated with 250 mg of Pd/C (10%) and the mixture stirred under 5 bars of hydrogen for 20 minutes. The mixture is filtered and the filtrate concentrated in vacuo to give 1.58 g (quantitative) of 2-acetylamino-5-amino-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 143-152° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C=CC=CC=1.[CH2:25]([O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:3][P:4]([C:9]([F:11])([F:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:46]([C:43]1[CH:42]=[CH:41][C:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:35][CH:36]=2)=[CH:45][CH:44]=1)=[O:47])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccccc1N
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Nc3ccccc3C(F)(F)P(=O)(OCC)OCC)cc2)cc1
Reaction time: 0.25 h

Procedure:
Tto a solution of [(2-amino-phenyl)-difluoro-methyl]-phosphonic acid diethyl ester NVP-VAV664 in CH2Cl2 are added 5 equivalents of pyridine followed by 1 equivalent of 4′-octyloxy-biphenyl-4-carbonylchloride at rt and the mixture obtained is stirred for ca. 10 to 20 minutes. To the mixture obtained EtOAc is added and and the mixture obtained is extracted with NaHCO3. From the organic phase obtained solvent is evaporated and the evaporation residue is subjected to column chromatography. (Difluoro-{2-[(4′-octyloxy-biphenyl-4-carbonyl)-amino]-phenyl}-methyl)-phosphonic acid diethyl ester is obtained in the form of a colourless powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:14][C:15]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=1)[CH3:13]>C(Cl)Cl>[CH2:12]([S:14]([C:15]1[N:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:17][CH:16]=1)=[O:9])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(SCC)nc1C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(S(=O)CC)nc1C(F)(F)F

Procedure:
Under an atmosphere of nitrogen and with stirring and cooling, a solution of 2.5 g of m-chloroperbenzoic acid in 40 ml of methylene chloride is added dropwise at a temperature of −20° C. to a solution of 2.8 g of ethyl 6-ethylthio-2-trifluoromethylpyridin-3-ylcarboxylate, which had been charged initially, and the mixture is stirred at a temperature of +5° C. for 20 hours. The mixture is then evaporated gently and purified over silica gel (hexanelethyl acetate 7:3). This gives 2.48 g (84%) of 6-ethylsulfinyl-2-trifluoromethylpyridin-3-yl-ethyl ester. 1H NMR (CDCl3, ppm): 8.38 (d, 1H); 8.30 (d, 1H); 4.45 (q, 2H); 3.26-3.00 (m, 2H); 1.43 (t, 3H); 1.26 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15](C)[C:16](=O)OCC3C=CC=CC=3)[CH2:11][CH2:10]2)[CH:6]=[C:5]([CH3:27])[N:4]=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH:15][CH3:16])[CH2:11][CH2:10]2)[CH:6]=[C:5]([CH3:27])[N:4]=1
Reactant: COc1nc(C)cc(N2CCC(N(C)C(=O)OCc3ccccc3)CC2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC1CCN(c2cc(C)nc(OC)n2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
A solution of benzyl 1-(2-methoxy-6-methylpyrimidin-4-yl)piperidin-4-yl(methyl)carbamate (400 mg, 1.0810 mmol, 1 eq) in methanol (6 ml) was degassed for 20 min with argon, and then Pd(OH)2 (200 mg) was added. The reaction mixture was stirred for 3 h at room temperature under a hydrogen atmosphere (balloon), and then the catalyst was filtered off. The filtrate was concentrated under reduced pressure. The crude product so obtained was in the form of a colourless liquid, which was used in the next stage without being purified further. Yield: 94% (240 mg, 1.0169 mmol)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([O:16]CC)=[O:15])[N:3]=1.FC(F)(F)C([O-])=O.[Cl:26][C:27]1[C:31]([Cl:32])=[C:30]([CH3:33])[NH:29][C:28]=1[C:34]([NH:36][CH:37]1[CH2:42][CH2:41][NH2+:40][CH2:39][CH2:38]1)=[O:35].C([O-])([O-])=O.[K+].[K+]>C(O)(C)(C)C>[Cl:26][C:27]1[C:31]([Cl:32])=[C:30]([CH3:33])[NH:29][C:28]=1[C:34]([NH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([O:12][CH3:13])=[C:4]([C:14]([OH:16])=[O:15])[N:3]=2)[CH2:39][CH2:38]1)=[O:35]
Reactant: Cc1[nH]c(C(=O)NC2CC[NH2+]CC2)c(Cl)c1Cl
Reactant: CCOC(=O)c1nc(Cl)c2ccccc2c1OC
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COc1c(C(=O)O)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c2ccccc12
Temperature: 170 °C
Reaction time: 8 h
Yield: 1.8 %

Procedure:
In a sealed high pressure container with a Teflon lining was combined ethyl 1-chloro-4-methoxyisoquinoline-3-carboxylate (EP 650961 A1; 390 mg, 1.55 mmol), 4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidinium trifluoroacetate (Intermediate 86; 1.7 g, 4.4 mmol), and K2CO3 (2.2 g) in 20 ml tert-butanol. The container was heated at 170° C. with stirring for 8 hours. The solution was concentrated by rotary evaporation and reconstituted with EtOAc. The organic layer was washed 4× with H2O, and dried over MgSO4. Crude ethyl 1-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-methoxyisoquinoline-3-carboxylate was purified by reverse phase Si yielding 20 mg of the intermediate ester. The ethyl ester was then hydrolyzed as in Example 262 to yield 13.5 mg white solid final product.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH3:9][NH:10][C:11](SC)=[CH:12][N+:13]([O-:15])=[O:14]>C(O)C>[OH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:11]([NH:10][CH3:9])=[CH:12][N+:13]([O-:15])=[O:14]
Reactant: NCCCCCCO
Reactant: CNC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])CCCCCCO

Procedure:
A mixture of 6-aminohexan-1-ol and 1-methylamino-1-methylthio-2-nitroethylene in ethanol is heated on a steam-bath to give 1-(6-hydroxyhexyl)-1-methylamino-2-nitroethylene. Substitution of 1-(6-hydroxyhexyl)-1-methylamino-2-nitroethylene for N-cyano-N'-(5-hydroxypentyl)-N"-methylguanidine in the procedure of Example 5 (ii and iii) leads to the production of S-[6-((1-methylamino-2-nitrovinyl)amino)hexyl]isothiourea.
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].CN(C)C=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[OH:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:6]
Reactant: BrCc1ccccc1
Reactant: CC(O)CCC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.2 %

Procedure:
80 g (0.57 mol) of sodium 4-hydroxypentanoate and 184.1 g (0.57 mol) of tetrabutylammonium bromide are suspended in 1.2 liters of abs. dimethyl formamide and the suspension is stirred for 15 minutes at room temperature. Then 67.8 ml (0.57 mol) of benzyl bromide are added dropwise and the reaction mixture is stirred for 15 hours at room temperature. The solution so obtained is diluted with water and extracted three times with ether. The organic phases are washed once with water and once with brine. The combined organic phases are dried over MgSO4, filtered and concentrated by evaporation. Distillation of the residue gives 63.1 g of benzyl 4-hydroxypentanoate of b.p. 139°-140° C./2.10-2 torr as a colourless oil.