Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH:10]=O)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH3:19])[N:5]=1.[C:20](O)(=O)[C:21](O)=[O:22].[OH-].[Na+]>O1CCCC1.C(#N)C.O.CN(C)C=O>[CH3:3][C:4]1[C:9](/[CH:10]=[CH:20]/[CH:21]=[O:22])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH3:19])[N:5]=1
Reactant: Cc1cc(-c2ccc(F)cc2)c(C=O)c(C)n1
Reactant: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(F)cc2)c(/C=C/C=O)c(C)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
778 mg (3.2 mmol) of diethyl [2-(cyclohexylamino)vinyl]-phosphate in 3 ml of tetrahydrofuran are added under a nitrogen atmosphere to 75.5 mg (3.2 mmol) of sodium hydride in 3 ml of absolute tetrahydrofuran during the course of 15 minutes at 0° C., the mixture is stirred for 15 minutes at 0° C. and a solution of 0.6 g (2.6 mmol) of the compound from Example 30 in 3 ml of acetonitrile/3 ml of dimethylformamide is added dropwise. After stirring for 1 h at 0° C. and 30 minutes at 25° C., the mixture is hydrolyzed using 50 ml of water, washed with ether (3×50 ml), and the organic phase is dried, concentrated in vacuo, taken up in 8 ml of toluene and stirred with 1.2 g (13.5 mmol) of oxalic acid/20 ml of water for 1.5 h at 60° C.-80° C. under a nitrogen atmosphere. After cooling, the mixture is adjusted to pH 10 using 2N sodium hydroxide solution and washed four times with ether, and the ether phase is dried, concentrated in vacuo and chromatographed over 100 g of silica gel using dichloromethane/methanol 30:1.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:25])(=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH3:32])[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:6]([OH:25])=[O:24]
Reactant: Cc1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1C
Temperature: 5 °C
Reaction time: 2 h

Procedure:
Concentrated sulfuric acid (1470 gms; 15 moles) were charged to a glass reactor equipped with a condenser, mechanical stirrer, thermometer, and addition funnel and cooled to about 5° C. Toluene (1380 gms; 15 moles) was then added over a two hour period while maintaining the temperature below 10° C. When the addition of toluene was complete, 831 gms (3 moles) oleic acid was incrementally added over a period of two hours. The reaction mixture was maintained below 10° C. for 1/2 hour and then allowed to rise to room temperature with continued stirring for 2 hours. Tolylstearic acid (1118.6 gms; 86.1% crude yield; acid value 154) was recovered and vacuum distilled.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[C:18]([NH:21][NH2:22])(=O)[CH3:19]>C(O)CCC>[CH3:19][C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:22][N:21]=1
Reactant: CC(=O)NN
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Solvent: CCCCO
Product: Cc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A 6.0 g. portion of 3-chloro-6-(α,α,α-trifluoro-m-tolyl)pyridazine (prepared as in Example 10), 3.44 g. of acetylhydrazine and 75 ml. of n-butyl alcohol is refluxed for 48 hours. The solvent is removed under vacuum and the residue dissolved in ethyl alcohol and treated with activated carbon. The filtrate is concentrated, chilled and filtered to give an orange solid. Recrystallization from methyl alcohol affords the product of the example as crystals, m.p. 193°-194° C.
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][S:13][C:14]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17]>>[CH3:12][S:13][C:14]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:15]=1[C:16]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:17]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: CSc1cc(C(F)(F)F)ccc1C(=O)O
Product: CSc1cc(C(F)(F)F)ccc1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, light yellow oil, MS: m/e=372.2 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate C).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6].CC([O-])(C)C.[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)CC>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][OH:6])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(CO)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCO
Product: COc1ccc(CO)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A solution of 3-hydroxy-4-methoxy-benzyl alcohol (61.67 g, 400 mmole) in 1-propanol (600 ml) was treated at 60° C. with 97% t-BuOK (55.52 g, 480 mmole), at 90° C. with benzyl chloride (66.57 ml, 560 mmole) and the resulting mixture heated under reflux for 2 hours. Then at 90° C. a second batch of t-BuOK (9.25 g, 80 mmole) was added. After a further hour at reflux a third batch of t-BuOK (9.25 g, 80 mmol) and a second batch of benzyl chloride (9.51 ml, 80 mmole) was added at 90° C. After a further 2.5 hours at reflux the mixture was cooled to room temperature and the solid filtered off. The solvents were removed in vacuo, the residue treated with water (300 ml) and one-third of the solvent removed in vacuo. Water (100 ml) was added to the residue, which was then distilled off in vacuo and the procedure repeated. The resulting suspension was filtered, the solid was collected, dried and triturated with petroleum ether (2×600 ml) to give 3-benzyloxy-4-methoxy-benzyl alcohol, (86.21 g, 88.2%) mp 62-65° C.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=1)[N:14]([CH3:27])[C:13]3=[O:28])[CH2:3][CH2:2]2.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>ClCCl>[Cl:26][C:22]1[CH:21]=[C:20]([C:15]2[N:14]([CH3:27])[C:13](=[O:28])[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([N:4]4[CH:5]5[CH2:6][CH2:7][N+:1]([O-:37])([CH2:9][CH2:8]5)[CH2:2][CH2:3]4)[CH:11]=3)[N:16]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCN4CCC3CC4)cc2c1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CC[N+]4([O-])CCC3CC4)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
To a solution of 6-(1,4-Diazabicyclo[3.2.2]nonan-4-yl)-2-(3-chlorophenyl)-3-methylquinazolin-4(3H)-one (400 mg, 1.013 mmol) (Example 2AL) in dichloromethane (12 mL) was added 3-chloroperbenzoic acid (250 mg, 1.013 mmol) and the reaction stirred at ambient temperature for 3 h. Sodium carbonate solution was added to neutralise the acid and the aqueous saturated with sodium chloride. The organic layer was separated off and chromatographed on 10 g silica, eluting with dichloromethane with 10% ammonia in methanol (1 M). To remove the remaining impurities the mixture was purified by acidic prep hplc, product passed through a carbonate on silica cartridge (2 g) to remove the acid to afford 4-(2-(3-chlorophenyl)-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)-1,4-diazabicyclo[3.2.2]nonane 1-oxide (112 mg, 0.273 mmol).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C@@H:20]([CH2:30][OH:31])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:22][C@H:21]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C@@H:20]([CH:30]=[O:31])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 4.3 mL (49.8 mmol) of oxalyl chloride in 90 mL of CH2Cl2 at −78° C. was treated with 5.4 mL (75.7 mmol) of DMSO maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 5 min. A solution of 6.4 g (21.6 mmol) of 1-tert-butoxycarbonyl-3-(R)-(hydroxymethyl)-4-(S)-(3-fluoro)phenylpyrrolidine (from Step B) in 10 mL of CH2Cl2 was added maintaining the temperature at less than −60° C. The resulting mixture was stirred cold for 60 min. The mixture was treated with 30 mL (173.1 mmol) of N,N-diisopropylethylamine maintaining the temperature at less than −60° C. The reaction was warmed to 0° C., stirred for 20 min and quenched with 20 mL 0.5 N KHSO4. The mixture was partitioned between 250 mL of CH2Cl2 and 100 mL of H2O and the layers were separated. The aqueous layer was extracted with 250 mL of CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated. Purification by Biotage Flash 75 using 75 L cartridge and 6.0 L of 9:1 v/v heptane/ethyl acetate as the eluant afforded the title compound: 1H NMR (500 MHz, CDCl3) δ 1.48 (s, 9H), 2.48 (1H), 3.17–3.89 (6H), 6.96–7.35 (4H), 9.67 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[S:14])[N:12]([CH2:15]O)[C:11](=[S:17])[O:10]2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:20])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[S:14])[N:12]([CH2:15][Cl:20])[C:11](=[S:17])[O:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(-n2oc(=S)n(CO)c2=S)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(-n2oc(=S)n(CCl)c2=S)cc1

Procedure:
2-(4-Cyanophenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dithione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-cyanophenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dithione as the residue.
Reaction SMILES: NCCCN.[CH2:6]([OH:14])[CH2:7][C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]>CCCCCC>[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13]
Reactant: CCCCC#CCCO
Agent: NCCCN
Solvent: CCCCCC
Product: C#CCCCCCCO
Temperature: 25 °C

Procedure:
35% KH in mineral oil (27 g, 240 mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3-diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0° C. and 3-octyn-1-ol (10 g, 79 mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50 mL) and the product was extracted into ether. The organic layer was washed with 10% HCl and brine and dried (MgSO4). Evaporation gave a colorless oil which was used without further purification: 1H NMR (90 MHz CDCl3) δ3.65 (t, J=5 Hz, 2H, O-CH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) nmax 3350, 2930, 2125 cm-1.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH:9]=[O:10])=[CH:5][CH:4]=1)#[N:2].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:10])[C:12]([F:14])([F:13])[F:11])=[CH:7][N:8]=1)#[N:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: N#Cc1ccc(C=O)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(O)C(F)(F)F)cn1
Yield: 81.6 %

Procedure:
According to Reference Example 8-12, by use of 6-cyano-3-pyridinecarboxaldehyde (364 mg, 2.76 mmol), (trifluoromethyl)trimethylsilane (490 μL, 3.31 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 276 μL, 0.276 mmol) and tetrahydrofuran (7.0 mL), the mixture was stirred and reacted at room temperature for 5 hours. Then, purification by column chromatography (hexane/ethyl acetate=7/3) was performed to give 2-cyano-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine (Compound ES) (455 mg, yield: 82%).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH:24]3[C:29]([O:31][CH3:32])=[O:30])[C:14]=2[CH:33]=1)#[N:9].[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1/[CH:42]=[CH:43]/[CH:44]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO.C(OCC)(=O)C.O>[F:34][C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=1/[CH:42]=[CH:43]/[CH2:44][N:26]1[CH2:27][CH2:28][CH:23]([CH2:22][CH2:21][CH2:20][N:15]2[C:14]3[CH:33]=[C:10]([C:8]#[N:9])[CH:11]=[CH:12][C:13]=3[O:18][CH2:17][C:16]2=[O:19])[CH:24]([C:29]([O:31][CH3:32])=[O:30])[CH2:25]1
Reactant: O=C/C=C/c1cc(F)ccc1F
Reactant: COC(=O)C1CNCCC1CCCN1C(=O)COc2ccc(C#N)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CN(C/C=C/c2cc(F)ccc2F)CCC1CCCN1C(=O)COc2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 32.3 %

Procedure:
A solution of methyl 4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate trifluoroacetate (Intermediate 130, crude, 171, 0.48 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde [FR 2872164] (81 mg, 0.48 mmol), and triethylamine (0.13 mL. 0.96 mmol) in chloroform/methanol (6 mL, 10:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxy borohydride (200 mg, 0.94 mmol) was added. The resulting reaction mixture was allowed to warm to room temperature and stir for 18 hours. The reaction was diluted with ethyl acetate (25 mL) and water (10 mL). The aqueous phase was separated and washed twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and evaporated at reduced pressure. Chromatography on silica gel with diethyl ether gave the title compound as a off-white foam, (79 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]([O:16][CH2:17][CH3:18])=[CH2:15])CCC.[F-].[K+].C(OCC)C>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[CH2:15])[N:5]=[CH:4][N:3]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(OCC)c1cc(Cl)ncn1
Temperature: 80 °C
Yield: 45.5 %

Procedure:
4,6-Dichloropyrimidine (1.0 g, 6.71 mmol), bis(triphenylphosphine)palladium(II) chloride (0.094 g, 0.134 mmol) and tributyl[1-(ethyloxy)ethenyl]stannane (2.449 mL, 7.25 mmol) were added together in DMF (25 mL) and the resulting mixture was heated at 80° C. under argon for 18 hours. The reaction mixture was allowed to cool to room temperature and poured into an aqueous solution of potassium fluoride (5.7 g in 57 mL water). Diethyl ether (80 mL) was added and the solid was filtered, washed with diethyl ether (×2) and discarded. The filtrate was separated and the organic layer was washed with water, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (564 mg);
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>[Pd].C(O)C>[F:1][C:2]([F:20])([F:21])[CH:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(Oc1ccc(N)cc1)C(F)(F)F
Temperature: 25 °C

Procedure:
To 100 ml of dry ethanol containing 77.7 g of oa p-(1-trifluoromethyl-heptyloxy)-nitrobenzene, was added 0.5 g of 5% Pd/C (5% palladium carbon) followed by carrying out reduction within an atmosphere of hydrogen at normal pressure under stirring at room temperature. After it was confirmed that no absorption of hydrogen was observed, the catalyst was removed by filtration and then the ethanol was distilled off to obtain 6.7 g of oily oa p-(1-trifluoromethylheptyloxy)-aniline.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH3:27]O>S(Cl)(Cl)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 70 °C
Yield: 2.4 %

Procedure:
A suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (528 mg, 1.45 mmol) in thionyl chloride (10 mL) was heated at 70° C. for one hour. The solvent was evaporated under reduced pressure and the residue was dissolved in anhydrous CH2Cl2. Anhydrous methanol (65 μL, 1.6 mmol) was added at 0° C. and the reaction mixture was allowed to slowly reach room temperature overnight. After removal of solvents under reduced pressure, the crude mixture was directly loaded onto a silica gel column and the product was eluted using mixtures of ethyl acetate/isohexane (gradient 0 to 40%). Half of the material obtained was further purified by preparative HPLC, yielding 13.4 mg of Compound 86.
Reaction SMILES: [P:1]([O-:6])([O-:5])[O:2]CC.[Na].S(C1C=CC(C)=CC=1)(O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=O)=O>O1CCCC1>[CH2:27]([P:1](=[O:2])([OH:5])[OH:6])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12]
Reactant: CCOP([O-])[O-]
Reactant: CCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCP(=O)(O)O
Yield: 60.4 %

Procedure:
To ethyl phosphite (1.6 g) dissolved in 5 ml of tetrahydrofuran was added sodium (180 mg), and the mixture was dissolved. To this solution was added cetyl tosylate (514 mg), and the mixture was refluxed for ten hours. The reaction solution was concentrated to dryness under reduced pressure. To the residue was added water, which was acidified with concentrated hydrochloric acid, followed by extraction with ether and dried on Na2SO4. From the extract was removed the solvent by evaporation, and the residue was subjected to a silica-gel (7 g) chromatography. Fractions eluted with chloroform were collected and concentrated to dryness. To the residue was added concentrated hydrochloric acid (3 ml), which was refluxed for 18 hours. The resulting precipitates were collected by filtration, followed by recrystallization from n-hexane to give 240 mg (60%) of colorless needles.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([C:17]([N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]3[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=3)[C:25]([O:27]C)=[O:26])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:38]=[CH:37][C:16]([C:17]([N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:20]3[CH:21]=[CH:22][C:23]([F:30])=[C:24]([CH:29]=3)[C:25]([OH:27])=[O:26])=[O:18])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(C(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)O)c1
Temperature: 100 °C
Reaction time: 0.69 h
Yield: 89.2 %

Procedure:
To a solution of methyl 5-[{4-[(4-butylphenyl)ethynyl]benzoyl}(hexyl)amino]-2-fluorobenzoate (170 mg; 0.33 mmol) in THF (7 mL) were added lithium hydroxide monohydrate (139 mg; 3.31 mmol) and water (3 mL). The reaction mixture was stirred under MW at 100° C. for 2500 s. Then an aqueous solution of HCl (1N) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure to give 147 mg (88.9%) of the title compound as a colorless solid. HPLC, Rt: 5.54 min (purity=98.4%), LC/MS: M−(ESI): 498.3. 1H NMR (MeOD) δ: 7.61 (m, 1H), 7.29 (d, J=7.9 Hz, 5H), 7.22 (d, J=7.9 Hz, 2H), 7.08 (d, J=7.9 Hz, 2H), 7.03 (s, 1H), 3.8 (m, 2H), 2.52 (t, J=7.5 Hz, 2H), 1.49 (q, J=7.4 Hz, 4H), 1.25 (m, 8H), 0.82 (m, 6H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1CCCCC1>C(OCC)C>[CH:10]([NH:23][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCBr
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1

Procedure:
19.5 g of ethyl 4-bromobutyrate, 55 g of benzhydrylamine and 30 ml of cyclohexane are stirred at room temperature for 12 days. The resultant crystal paste is diluted with diethyl ether, filtered at the pump and the filtrate concentrated by evaporation. The residue (after evaporation) is distilled in vacuo. The first run which distils over at 100° to 110° (0.02 mm Hg) is excess benzhydrylamine. The main distillate obtained is 21.1 g (71% of theory) of ethyl 4-benzylhydrylaminobutyrate [B.P. 150° to 155° (0.02 mm Hg)].
Reaction SMILES: [CH2:1]([CH:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:4][CH:5]([OH:9])[C:6]([NH2:8])=[O:7])[CH3:2]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[CH2:1]([CH:3]([CH:10]([N+:12]([O-:14])=[O:13])[CH3:11])[CH2:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7])[CH3:2]
Reactant: CCC(CC(O)C(N)=O)C(C)[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CCC(CC(=O)C(N)=O)C(C)[N+](=O)[O-]
Temperature: 100 °C
Yield: 14 %

Procedure:
To a solution of 4-ethyl-2-hydroxy-5-nitrohexanamide (0.36 g) in acetic acid (5 ml) was added chromium trioxide (0.23 g). The resulting mixture was heated at 100° C. for 40 minutes with stirring. After cooling, the mixture was evaporated to dryness. The resulting residue was diluted with water and then extracted with ethyl acetate. The extract was washed successively with water, an aqueous sodium bicarbonate and brine, and then dried over magnesium sulfate. The solvent was removed by distillation to give an oil. The oil was purified by a preparative thin layer chromatography [solvent:methanol-chloroform (5:95)] to give 4-ethyl-5-nitro-2-oxo-hexanamide (50 mg).