Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([NH2:29])[CH:23]=2)=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].C([O-])(O)=O.[Na+].[C:35](O)(=O)[CH2:36][OH:37]>>[CH:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]2[C:22]2[CH:27]=[CH:26][C:25]3[N:28]=[C:35]([CH2:36][OH:37])[NH:29][C:24]=3[CH:23]=2)=[CH:9][CH:10]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(-n2c(-c3ccc(N)c(N)c3)nc3ccccc3c2=O)cc1
Reactant: O=C(O)CO
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(C)c1ccc(-n2c(-c3ccc4nc(CO)[nH]c4c3)nc3ccccc3c2=O)cc1
Yield: 41 %

Procedure:
A solution of 3-(4-sec-butylphenyl)-2-(3,4-diaminophenyl)quinazolin-4(3H)-one (0.130 g, 0.34 mmol) was refluxed in a 70% aqueous solution of glycolic acid (10 mL) for 2 hours. The reaction was poured into a saturated solution of NaHCO3 and extracted with EtOAc. The organics were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 3% to 10% MeOH in CH2Cl2, afforded the title compound as a white solid (0.060 g, 41%). 1H-NMR (300 MHz, DMSO-d6): δ12.22-12.53 (m, 1H), 8.19 (d, J=7.5 Hz, 1H), 7.87-7.92 (m, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.56-7.61 (m, 2H), 7.00-7.26 (m, 6H), 5.67-5.69 (m, 1H), 4.51-4.71 (m, 2H), 1.37-1.50 (m, 2H), 1.11 (d, J=6.8 Hz, 3H), 0.58 (t, J=7.2 Hz, 3H). MS (APCI) m/z: 425 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][C:31]1[CH:35]=[C:34]([CH3:36])[N:33]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[N:32]=1>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:41][C:40]2[CH:42]=[CH:43][C:37]([N:33]3[C:34]([CH3:36])=[CH:35][C:31]([CH3:30])=[N:32]3)=[CH:38][CH:39]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: Cc1cc(C)n(-c2ccc(N)cc2)n1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: Cc1cc(C)n(-c2ccc(Nc3nc(N[C@@H]4CCCC[C@@H]4N)ncc3C(N)=O)cc2)n1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 4-(3,5-dimethyl-1H-pyrazol-1-yl)aniline in step 1. MS: 421.5 (M+H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:13](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc([N+](=O)[O-])c(O)cc1F
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(F)c(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-fluoro-4-methyl-2-nitrophenol (2.83 g, 16.5 mmol) was dissolved in N,N-dimethylformamide (25 mL). Potassium carbonate (3.4 g, 25 mmol) and iodomethane (1.2 mL, 20 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was then poured into water and stirred until solids crashed out. The solids were filtered and air dried to give 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene without further purification (2.76 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92 (d, J=8.1 Hz, 1 H), 7.25 (d, J=11.7 Hz, 1 H), 3.89 (s, 3H), 2.19 (d, J=1.5 Hz, 3 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:16]3[C:17]([O:25][CH3:26])=[N:18][C:19]([NH:22][CH2:23][CH3:24])=[N:20][CH:21]=3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([NH:22][C:19]1[N:18]=[C:17]([O:25][CH3:26])[C:16]([C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:31]4[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[CH:21][N:20]=1)[CH3:24]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCNc1ncc(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(OC)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Temperature: 90 °C
Yield: 70.9 %

Procedure:
A solution of Example C1 (0.12 g, 0.26 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.070 g, 0.35 mmol) in dioxane (4 mL) was sparged with Ar, treated with a solution of K2CO3 (0.07 g, 0.51 mmol) in water (1 mL), Pd(PPh3)4 (0.03 g, 0.026 mmol) and heated at 90° C. for 2 h. The mixture was cooled to RT, diluted with water, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by column chromatography (MeOH/DCM) to afford N-ethyl-4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine as a white solid (77 mg, 71%). 1H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (d, J=0.7 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.36 (br s, 1H), 7.25 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.96 (s, 3H), 3.84 (s, 3H), 3.40-3.30 (m, 2H), 2.37 (s, 3H), 1.14 (br m, 3H); MS (ESI) m/z: 418.2 (M+H+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1OC)[CH:2]1[O:4][CH2:3]1.[OH-:16].[Na+].[CH3:18][C:19]([CH3:21])=[O:20]>O.C(O)C>[CH2:18]([O:16][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:18][C:19](=[O:20])[CH:21]=[CH:10][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH:2]3[O:4][CH2:3]3)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1)[CH:19]1[O:20][CH2:21]1
Reactant: [OH-]
Reactant: COc1cc(C=O)ccc1OCC1CO1
Reactant: CC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1ccc(OCC2CO2)cc1)C=Cc1ccc(OCC2CO2)cc1

Procedure:
p-Glycidyloxybenzaldehyde (80 g; prepared according to Method B) in acetone (13 g) and ethanol (80 g) was added over 1 hour to a stirred solution of sodium hydroxide (9 g) in a mixture of water (90 g) and ethanol (80 g), keeping the temperature at 25° to 30° C. On complete addition the mixture was stirred at 25° to 30° C. for a further hour, then filtered. The residue was dissolved in epichlorohydrin (400 ml), washed at 60° C. with 5% aqueous sodium hydrogen sulfate (100 ml), then with water (200 ml). The solution was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 1,5-bis(p-glycidyloxyphenyl)-1,4-pentadien-3-one. The yield was 58 g (68% of theoretical yield) and the product had an epoxide content of 4.5 equivalents/kg (theoretical value 5.29 equivalents/kg). On recrystallisation from ethanol the epoxide content of the product was 5.18 equivalents/kg. This product was shown to be identical with an authentic sample of 1,5-bis(p-glycidyloxyphenyl)-1,4-pentadien-3-one by gel permeation chromatography and by NMR, UV, and IR spectral analysis.
Reaction SMILES: [F:1][C:2]([F:25])([C:6]([F:24])([F:23])[C:7]([F:22])([F:21])[C:8]([F:20])([F:19])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[C:3]([OH:5])=[O:4].[CH3:26]O.S(=O)(=O)(O)O>O>[F:1][C:2]([F:25])([C:6]([F:23])([F:24])[C:7]([F:21])([F:22])[C:8]([F:19])([F:20])[C:9]([F:17])([F:18])[C:10]([F:15])([F:16])[C:11]([F:14])([F:13])[F:12])[C:3]([O:5][CH3:26])=[O:4]
Reactant: CO
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 89 %

Procedure:
A 2-1, four-necked, round-bottomed flask equipped with stirrer, addition funnel, thermometer and reflux condenser, is charged with 828 g (2 mol) of dried perfluorooctanoic acid, 160 g (5 mol) of methanol. The mixture is stirred and 50 ml concentrated sulfuric acid is added dropwise. Then the mixture is heated to reflux for 4 hr. At the end of the reflux period the mixture is cooled to room temperature and poured into 2 l cold water. After separation of the phases, the lower organic phase is washed with water till pH neutral and dried over CaCl2. Distillation of the crude gives 762 g (89%) of methyl perfluorooctanoate, bp 160° C.
Reaction SMILES: C([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([Cl:16])[N:7]=1)(C)(C)C>C(O)=O.O>[Cl:16][C:8]1[NH:7][C:6](=[O:5])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CC(C)(C)Oc1nc(Cl)cc2ccccc12
Solvent: O
Solvent: O=CO
Product: O=c1[nH]c(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
0.5 g (2.12 mmol) of 1-t-butoxy-3-chloroisoquinoline from example 16.3 was dissolved in 5.0 ml of formic acid and stirred at room temperature for 20 h. The solution was then diluted with 10 ml of H2O, and the precipitated solid was filtered off through a glass frit, washed with 10 ml of H2O/formic acid (2:1) and dried under high vacuum. 0.30 g (1.67 mmol, 78.8%) of 3-chloroisoquinolin-1(2H)-one was obtained. The combined aqueous phases were concentrated to dryness under reduced pressure and the resulting solid was purified by column chromatography (5:1 dichloromethane/ethyl acetate), whereupon a further 0.040 g (0.22 mmol, 10.4%) of 3-chloroisoquinolin-1(2H)-one was obtained.
Reaction SMILES: C(OC([C:6]1[N:7]([CH2:19][CH:20]([NH:22][C:23]([O:25]C(C)(C)C)=O)[CH3:21])[N:8]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1)=O)C.C([O-])([O-])=O.[Na+].[Na+]>Cl.O1CCOCC1.C(Cl)Cl>[CH3:21][CH:20]1[CH2:19][N:7]2[N:8]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[C:6]2[C:23](=[O:25])[NH:22]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CC(C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1Cn2nc(COc3ccccc3)cc2C(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.8 %

Procedure:
Rac-2-(2-tert-butoxycarbonylamino-propyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester (5.58 g, 5.53 mmol, 40% pure) was dissolved in a 4N solution of HCl in 1,4-dioxane (40 mL) under N2 at 0° C. The mixture was stirred at room temperature for 3 hours. The mixture was basified with a saturated solution of Na2CO3 and the mixture stirred at room temperature for 3 days. Then the mixture was diluted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 70/30). The desired fractions were collected and the solvents evaporated in vacuo to yield rac-6-methyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (1.52 g, 91% yield) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(N(CC)CC)C.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>CC1C=CC=CC=1>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a stirred mixture of 28.2 parts of 3-pyridinamine, 59 parts of N,N-diethylethanamine and 450 parts of methylbenzene were added dropwise 39 parts of 4-fluorobenzoyl chloride (exothermic reaction, the temperature rose to 40° C.). Upon complete addition, stirring was continued for 2 hours at reflux temperature. After cooling, the precipitated product was filtered off and dissolved in trichloromethane. The organic layer was washed twice with water, dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 52.3 parts (80.6%) of 4-fluoro-N-(3-pyridinyl)benzamide; mp. 150.2° C. (int. 66).
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][NH:13][C:14]([NH:16][CH3:17])=[O:15].[P:18](OC1C=CC=CC=1)([O:26]C1C=CC=CC=1)[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[CH3:12][N:13]1[C:14](=[O:15])[N:16]([CH3:17])[CH:2]([C:3]2[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=2)[P:18]1(=[O:26])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CNC(=O)NC
Reactant: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Reactant: COc1cc(C=O)ccc1O
Solvent: c1ccccc1
Product: COc1cc(C2N(C)C(=O)N(C)P2(=O)Oc2ccccc2)ccc1O

Procedure:
A mixture of 76.1g (0.5 mole) of vanillin, 44.0g (0.5 mole) of 1,3-dimethylurea, and 155.0g (0.5 mole) of triphenyl phosphite in 200g of benzene is stirred under N2 and warmed at reflux (95°) for 1 hr. About half of the benzene is distilled to give a yellow solution: 31P nmr -25.3 ppm. The reaction mixture solidifies while standing for several days. Additional benzene is added to aid in breaking up the solid. Filtration gives 64.0g of slightly yellow solid. Recrystallization of an 11.0g portion from acetonitrile gives 5.2g of white solid: mp 168°-170°; 31P nmr -24.5 ppm; molecular weight 362 (mass spectrum) (theory 362).
Reaction SMILES: [Cl:1]Cl.CS[CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[C:7]=1[NH2:8].[ClH:17].O>C(Cl)CCl>[ClH:1].[Cl:17][CH2:5][C:6]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[C:7]=1[NH3+:8]
Reactant: CSCc1cccc(C(F)(F)F)c1N
Reactant: ClCl
Agent: Cl
Solvent: ClCCCl
Solvent: O
Product: [NH3+]c1c(CCl)cccc1C(F)(F)F
Temperature: 60 °C
Yield: 92.7 %

Procedure:
Chlorine (7.60 grams, 1.07 mol) was bubbled into a mechanically stirred solution of 221.0 grams (1.00 mol) of 2-methylthiomethyl-6-trifluoromethyl aniline in 2 liters of ethylene dichloride over 60 minutes while maintaining the reaction temperature below 20° C. A white suspension formed initially, became very thick halfway through the addition, and dissolved to give way to a cloudy solution at the end of the addition. The mixture was then heated to 60° C. while maintaining a steady stream of HCl bubbling through. Water (25 ml, 1.4 mol) was added and the HCl treatment was maintained at 60° C. for 15 minutes at which point a clear solution was obtained. Excess water was removed by azeotropic distillation (780 ml of solvent were removed) and the resulting solution was cooled to 0° C. with a steady stream of HCl bubbling through. Filtration, washing of the solids with 150 ml of cold ethylene dichloride and air-drying gave 228.0 grams (92.7%) of off-white 2-chloromethyl-6-trifluromethyl anilinium hydrochloride. This compound properties and analysis are described above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)O)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:43])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:19]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[Cl:43])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1(C(O)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(C(Cl)(c2ccc(C(F)(F)F)cc2)c2ccc(C(F)(F)F)cc2)CCN(C(=O)OC(C)(C)C)CC1
Yield: 80.2 %

Procedure:
A solution of 290 milligrams (0.504 mmole) of ethyl 1-[(tert-butyl)oxycarbonyl]-4-{bis[4-(trifluoromethyl)phenyl]hydroxymethyl}piperidine-4-carboxylate, 110 μL (1.513 mmole) of thionyl chloride, and 408 μL (5.04 mmole) of pyridine in 5 mL of methylene chloride was stirred at ambient temperature for 1 hour. The reaction mixture was then poured into 25 mL of an aqueous solution saturated with sodium bicarbonate, and the mixture was extracted with three 50 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:10 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 240 milligrams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH2:21][N+:22]([O-])=O)[CH2:10][P:11]([CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])(=[O:13])[O-:12])=[CH:5][CH:4]=1.N.[H][H].[CH2:28](O)[CH3:29]>[Ni]>[NH2:22][CH2:21][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:10][P:11]([CH:14]([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17])(=[O:13])[O:12][CH2:28][CH3:29]
Reactant: CCO
Reactant: [H][H]
Reactant: CCOC(OCC)P(=O)([O-])CC(C[N+](=O)[O-])c1ccc(OC)cc1
Agent: [Ni]
Agent: N
Product: CCOC(OCC)P(=O)(CC(CN)c1ccc(OC)cc1)OCC

Procedure:
A solution of 6.6 g of ethyl (2-(4-methoxyphenyl)-3-nitropropyl(diethoxymethyl)phosphinate in 50 ml of ethanol is added to 52 g of an 8% solution of ammonia in ethanol. To this are added 8 ml of Raney Nickel and the resulting mixture is hydrogenated at 1 bar until the theoretical amount of hydrogen has been taken up. The mixture is then filtered and the filtrate is concentrated under reduced pressure to give ethyl 3-amino-2-(4-methoxyphenyl)propyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+44.5 ppm (CDCl3).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH:7]1[CH2:8][CH2:9][CH:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.4 mL, 31 mmol) was slowly added to a dichloromethane solution (75 mL) of ethyl 4-hydroxycyclohexanecarboxylate (4.63 mL, 28.7 mmol) and triethylamine (8.2 mL, 59 mmol) at 0° C. The reaction mixture was stirred for 30 minutes, concentrated in vacuo and diluted in diethyl ether (100 mL). The solution was washed with 10% hydrochloric acid (25 mL), water (25 mL), and saturated sodium bicarbonate (15 mL). The organics were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 1.23 (t, J=7.1 Hz, 3H), 1.54-1.82 (m, 4H), 1.87-1.97 (m, 2H), 2.00-2.08 (m, 2H), 2.34-2.41 (m, 1H), 3.00 (s, 3H), 4.13 (q, J=7.1 Hz, 2H), 4.88-4.92 (m, 1H).
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH2:3][S:4][C:5](=[O:7])[CH3:6].[OH-].[Li+].[C:31](Cl)(=O)[CH2:32][CH2:33]CC.O>CN(C=O)C.CCOC(C)=O>[O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:10][CH:9]=1)[CH2:3][S:4][C:5](=[O:7])[CH2:6][CH2:31][CH2:32][CH3:33]
Reactant: CC(=O)SCC(=O)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCCCC(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(=O)SCC(=O)c1ccc(NS(=O)(=O)c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
Thioacetic acid S-{2-oxo-2-[4-(4-trifluoromethoxy-benzenesulfonylamino)-phenyl]-ethyl}ester (SI-4) (0.5 g, 1.15 mmol) was dissolved in anhydrous DMF (5 ml). Lithium hydroxide (28 mg, 1.15 mmol) was added and the solution was sonicated until homogeneous and heated to 90° C. for 4 hours. The solution was allowed to cool to room temperature and valeryl chloride (150 mg, 1.27 mmol) was added and the mixture stirred for 16 hours. The solution was partioned between 20 ml each water and EtOAc. The organic layer was washed with water, then brine and dried over Na2SO4. The solution was then filtered, stripped of solevent and the product purified by flash chromatography (100% DCM). The solvent was evaporated to afford 107 mg (0.22 mmol, 19%) product as a clear oil. 1H-NMR: (400 MHz, DMSO): 8.07 (d, 2H), 7.60 (d, 2H), 7.40 (d, 2H), 7.25 (d, 2H), 2.40 (s, 2H), 2.10 (t, 2H), 1.42 (t, 2H) 1.11 (t,2H), 0.09 (t, 3H); LC-MS (ES+): 476 [M]+ m/e.
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[C:13]1([C:19]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][CH2:23][C:22](=[O:25])[CH:21]=[CH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+:32]([CH3:35])([O-:34])=[O:33]>CO.CC(O)(C)C.O1CCCC1>[N+:32]([CH2:35][CH:20]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O-:34])=[O:33]
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Reactant: C[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C(C[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 144 h
Yield: 92.4 %

Procedure:
A solution (11.45 g) of benzyltrimethylammonium hydroxide in methanol is added to a solution of 4,4-diphenyl-2-cyclohexenone (60 g) and nitromethane (14.75 g) in 2-methyl-2-propanol (400 cc) and anhydrous tetrahydrofuran (200 cc), and the reaction mixture is stirred at +25° C. for 144 hours: a crystalline solid precipitates slowly. This suspension is filtered and the crystals are washed with petroleum ether (50 cc) cooled to 0° C., drained and dried. (RS)-3-Nitromethyl-4,4-diphenylcyclohexanone (69.1 g) is obtained in the form of white crystals, m.p. 164° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15]OS(C)(=O)=O)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:21]#[N:22].[K+]>CS(C)=O.CCOC(C)=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:21]#[N:22])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Yield: 77.2 %

Procedure:
To 4-methanesulfonyloxymethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.440 g, 1.43 mmol) dissolved in DMSO (3 mL) is added potassium cyanide (0.373 g, 5.73 mmol). The mixture is heated to 130° C. for 18 hours. The reaction mixture is cooled and diluted with EtOAc and water. The organic layer is concentrated, taken up in MeOH and concentrated again to give the title compound as a brown oil (263 mg, 77% yield).