Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:43]=[CH:42][CH:41]=[CH:40][C:27]=1[C:28]([NH:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[CH:2]1[C:13]2[CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[CH2:8][N:7]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[CH:41][CH:42]=[CH:43][C:26]=4[CH3:25])=[CH:39][CH:38]=3)=[O:36])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)CCc1ccccc1NC2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a mixture of 0.245 g (1 mmol) of 5,6,11,12-tetrahydrodibenz[b,f]azocine hydrochloride and 30 μl (2.2 mmol) of triethylamine in 2 ml of dichloromethane is added a solution of 0.281 g (1.1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 4 ml of dichloromethane. The mixture is stirred overnight at room temperature, washed with water 2N HCl (3×2 ml) and 1N sodium bicarbonate (3×2 ml). The organic layer is dried (MgSO4) and filtered through a thin pad of hydrous magnesium silicate (pad washed with 3 volumes of CH2Cl2). The filtrate is concentrated to give 200 mg of a foam; Mass Spec.-FAB 447 (M+H). Anal. Calc'd for C30H26N2O2 : C,80.7; H,5.9; N,6.3. Found: C,79.1; H,5.7; N,6.1.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.Cl.CN.C[CH2:15][N:16]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([NH:16][CH3:15])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccnc1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1nccnc1N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-aminopyrazine-2-carboxylic acid (965 mg, 6.94 mmol), methylamine hydrochloride (697 mg, 10.3 mmol), EDCI (1.61 g, 8.4 mmol), HOBt (1.136 g, 8.4 mmol) and DIEA (2.42 mL, 13.9 mmol) in DMF (24 mL) was stirred at room temperature for 48 h. It was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was removed and the residue was purified by silica gel chromatography (combiflash-companion; DCM/MeOH gradient) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]=1[OH:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3].[K].[OH-].[K+:26].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C([N-]C(C)C)(C)C.[K+]>O.C([O-])([O-])=O.[K+].[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[CH3:1][C:2]([CH2:4][CH:5]([C:12]1[C:21](=[O:22])[O:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[O-:23])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3].[K+:26]
Reactant: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(=O)CC(c1ccccc1)c1c([O-])c2ccccc2oc1=O

Procedure:
Illustrative embodiments of the present invention provide a process for preparing APO-II comprising: i. mixing Warfarin acid in isopropanol thereby forming a Warfarin mixture; ii. adding to the Warfarin mixture a potassium base selected from either ii-i) KOH, K2CO3, KHCO3, K3PO4, KOH in water, K2CO3 in water, KHCO3 in water, K3PO4 in water, KOH in ROH, K2CO3 in ROH, KHCO3 in ROH, K3PO4 in ROH, and mixtures thereof, wherein R is selected from the group consisting of H and C1-C4 alkyl, or ii-ii) KOH, K2CO3, KHCO3, K3PO4, KH, KNH2, potassium bis(trimethylsilyl)amide, potassium diisopropylamide and mixtures thereof, thereby forming a potassium Warfarin mixture; iii. heating the potassium Warfarin mixture to a temperature in a range of from about 45° C. to about 80° C. thereby forming a first solution; iv. maintaining the first solution at a pH in a range of from about 7.0 to about 10.0 thereby forming a Warfarin potassium isopropanol solution; v. distilling the Warfarin potassium isopropanol solution thereby forming a concentrated Warfarin potassium isopropanol solution; vi. adding additional isopropanol to the concentrated Warfarin potassium isopropanol solution and distilling further to remove water thereby forming a distilled Warfarin potassium isopropanol solution; vii. distilling the distilled Warfarin potassium isopropanol solution to dryness or near-dryness thereby forming a Warfarin potassium residue; viii. dissolving the Warfarin potassium residue in ethyl acetate thereby forming a Warfarin potassium ethyl acetate solution; ix. stirring the Warfarin potassium ethyl acetate solution at a temperature in a range of from about 5° C. to about 50° C. until precipitation occurs thereby forming a precipitate; and x. isolating the precipitate thereby isolating APO-II.
Reaction SMILES: C(C(O)=O)(F)(F)F.[O:8]=[C:9]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25]>C(Cl)Cl>[O:8]=[C:9]1[C:17]2([CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CCOCC2)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CN1C(=O)C2(CCOCC2)c2ccccc21
Reaction time: 3 h

Procedure:
CF3CO2H (1 mL) was added to a solution of tert-butyl (2-oxo-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-1(2H)-yl)acetate from Step B (55.0 mg, 0.173 mmol) in CH2Cl2 (3 mL). After 3 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]2[CH:8]=[C:9]([CH:12]([OH:32])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:10]=[CH:11][C:4]=2[O:3]1.Cl>O.CO>[OH:7][CH2:6][C:5]1[CH:8]=[C:9]([CH:12]([OH:32])[CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=[CH:11][C:4]=1[OH:3]
Reactant: CC1(C)OCc2cc(C(O)CNCCCCCCOCCCCc3ccccc3)ccc2O1
Agent: Cl
Solvent: CO
Solvent: O
Product: OCc1cc(C(O)CNCCCCCCOCCCCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.8 %

Procedure:
To a solution of 0.6 g (1.32 mmol) [2-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-2-hydroxyethyl]-6-[4-phenylbutoxy)hexylamine in 20 ml of a 1:1 H2O/MeOH mixture is added 0.15 ml (1.75 mmol) 35% HCl. After allowing the reaction to stir for 48 hr at room temperature, the MeOH is evaporated off at reduced pressure. The resulting aqueous mixture is extracted with 20 ml CH2Cl2. The organic phase is washed sequentially with 20 ml of a saturated NaHCO3 solution and further 20 ml H2O, dried on anhydrous Na2SO4 and evaporated to dryness to yield 0.24 g (43.9%) 2-hydroxymethyl-4-{1-hydroxy-2-[6-(4-phenylbutoxy)hexylamino]ethyl}phenol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:21])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:7]=1.I[C:23]1C=C(Cl)C=C[C:24]=1C(N)=O.C(OC(OCC)C=C)C.C(N(CCCC)CCCC)CCC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:11][C:10](=[O:12])[CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:13](=[O:21])[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:24]
Reactant: O=C(O)CCc1cc(Cl)ccc1C(=O)Nc1ccccc1
Reactant: NC(=O)c1ccc(Cl)cc1I
Agent: [Pd+2]
Agent: C=CC(OCC)OCC
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)CCc1cc(Cl)ccc1C(=O)Nc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
3-(5-Chloro-2-phenylcarbamoyl-phenyl)-propionic acid: A mixture of palladium acetate (0.022 g, 0.1 mmol), 2-iodo-4-chlorobenzamide (0.954 g, 2.67 mmol), 3,3-diethoxyprop-1-ene (0.693 g, 5.32 mmol), tetrabutylammonium bromide (0.86 g, 2.67 mmol), and tributylamine (0.984 g, 5.32 mmol) in DMF (25 mL) was heated at 80° C. overnight. The reaction was quenched with 1N HCl (50 mL) and stirred at rt for 1 h. The mixture was extracted with EtOAc and the combined organic layers were washed with 1N HCl, dried (MgSO4), filtered, and evaporated to give an oil. This residue was purified by flash chromatography to give 3-(5-chloro-2-phenylcarbamoyl-phenyl)-propionic acid ethyl ester (0.287 g, 32%). LC/MS m/z 332.3 (M+H)+. This intermediate (0.278 g, 0.865 mmol) was stirred with LiOH (21 mg, 0.865 mmol) in THF (10 mL) and water (0.5 mL) for 2 d. The mixture was diluted with water and washed with EtOAc. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, evaporated, and purified by reverse phase HPLC to give 183A. LC/MS m/z 304.3 (M+H)+. 1HNMR (CDCl3) δ 7.68 (d, J=8.0 Hz, 2H), 7.48 (d, J=8.2 Hz, 1H), 7.41-7.25 (m, H), 7.15 (t, 1H), 4.00 (bs, 1H), 3.11 (t, 2H), 2.80 (tm, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[C:8]1[CH2:9][O:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([O:18]C(=O)C)[C:12]=2[CH3:22])(=O)C.N1C=CN=C1.CC1C(O)=CC=C2C=1OCC(C1C=CC(O)=CC=1)=C2>C(O)C>[CH3:22][C:12]1[C:13]([OH:18])=[CH:14][CH:15]=[C:16]2[C:11]=1[O:10][CH2:9][C:8]([C:7]1[CH:23]=[CH:24][CH:25]=[C:5]([OH:4])[CH:6]=1)=[CH:17]2
Reactant: CC(=O)Oc1cccc(C2=Cc3ccc(OC(C)=O)c(C)c3OC2)c1
Agent: Cc1c(O)ccc2c1OCC(c1ccc(O)cc1)=C2
Agent: c1c[nH]cn1
Solvent: CCO
Product: Cc1c(O)ccc2c1OCC(c1cccc(O)c1)=C2

Procedure:
8-Methylisoflav-3-ene-3′,7-diol was prepared from 3′,7-diacetoxy-8-methylisoflav-3-ene (0.12 g, 0.4 mmol) and imidazole (0.3 g) in ethanol (2.5 ml) as described for 8-methylisoflav-3-ene-4′,7-diol. Yield: (0.07 g, 77%) m.p. 130° C. 1H NMR (CDCl3+d6-DMSO): δ 1.95 (s, 3H, CH3), 4.98 (s, 2H, H2), 6.34 (d, 1H, J 8.0 Hz, H6), 6.61-6.94 (m, 5H, ArH), 7.08 (bt, 1H, ArH). Mass spectrum: m/z 254 (M, 100%); 253 (96); 161 (45).
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].CCN(C(C)C)C(C)C.[N+:29]([C:32]1[CH:33]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[CH:36][CH:37]=1)([O-:31])=[O:30]>C(Cl)Cl.[Cl-].[Na+].O>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([S:38]([C:34]3[CH:35]=[CH:36][CH:37]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=3)(=[O:39])=[O:40])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]cnc2n(CCCC)c1=O
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCn1c(=O)c2c(ncn2S(=O)(=O)c2cccc([N+](=O)[O-])c2)n(CCCC)c1=O
Temperature: 23 °C
Reaction time: 19 h
Yield: 79 %

Procedure:
To 404 mg (1.53 mmol) of 1,3-dibutyl-3,7-dihydro-purine-2,6-dione in 15 mL of CH2Cl2 at 23° C. was added 0.40 mL (296 mg, 2.29 mmol) i-Pr2NEt followed by 373 mg (1.68 mmol) of 3-nitrobenzenesulfonyl chloride. After stirring at 23° C. for 19 h, the reaction mixture was poured into 50 mL brine and extracted with 3×50 mL of EtOAc. The combined organics were successively washed with 1×50 mL sat. NaHCO3 solution, 1×50 mL H2O, 1×50 mL brine, dried over MgSO4, filtered and evaporated to an oily yellow solid. Flash chromatography on silica gel, eluting with CH2Cl2/EtOAc (40/1), gave a white solid. Recrystallization from hot hexanes/EtOAc gave 540 mg (1.20 mmol, a 79% yield) of the title compound as a white, crystalline solid. mp: 178-179° C.; 1H NMR (300 MHz, CDCl3); δ 0.88-0.98 (m, 6H), 1.22-1.42 (m, 4H), 1.50-1.61 (m, 2H), 1.63-1.75 (m, 2H), 3.92 (t, J=7.5 Hz, 2H), 4.07 (t, J=7.5 Hz, 2H) 7.86 (t, J=8.1 Hz, 1H), 8.34 (s, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.77 (d, J=8.2 Hz, 1H), 9.01 (brt, 1H); IR (KBr, cm−1): 3142w, 2963m, 2935m, 2876w, 1716s, 1661s, 1538s, 1441m, 1396s, 1181s, 1130m, 761m, 670m; MS (ES) m/z (relative intensity): 450 (M++H, 100).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12](#[N:15])[CH:13]=[CH2:14].N12CCN(CC1)CC2>[OH-].[Na+]>[CH3:11][O:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:13]([C:12]#[N:15])[CH2:14][O:1]2)=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: COc1ccc(C=O)c(O)c1
Agent: C1CN2CCN1CC2
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(c1)OCC(C#N)=C2

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (Aldrich, 5.0 g, 32.9 mmol), acrylonitrile (11 mL, 164 mmol), and 1,4-diazabicyclo[2.2.2]octane (0.92 g, 8.2 mmol) were heated in a microwave Personal Chemistry at 95° C. for 5 hours. Sodium hydroxide (200 mL) was added and the mixture was extracted with ethyl acetate (200 mL) and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Chromatography on silica gel eluting with 0-to-50% ethyl acetate in hexane afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.77 (s, 3H), 4.84 (d, J=1.36 Hz, 2H), 6.50 (d, J=2.71 Hz, 1H), 6.61 (dd, J=8.48, 2.71 Hz, 1H), 7.21 (d, J=8.48 Hz, 1H), 7.52 (s, 1H). MS (DCI) m/z 205.07 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:21]([CH:13]3[CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:12]3)=[O:22])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)C1Cc2ccccc2N1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2cnccc2c1)C1Cc2ccccc2N1
Temperature: 40 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
To a solution of 6-aminoisoquinoline (25 mg, 0.17 mmol) in DMF (1.0 mL) was added indoline-2-carboxylic acid (30 mg, 0.17 mmol), HATU (70 mg, 0.19 mmol), diisopropylethylamine (35 μL, 0.19 mmol) and stirred overnight at 40° C. The reaction mixture was concentrated and purified by prep-HPLC to afford the titled compound (3.0 mg): 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.18 (dd, J=16.11, 8.30 Hz, 1H) 3.56 (dd, J=16.20,10.54 Hz, 1H) 4.52 (dd, J=10.54, 8.40 Hz, 1H) 6.70-6.81 (m, 2H) 6.99-7.10 (m, 3H) 7.73 (d, J=6.05 Hz, 1H) 7.81 (dd, J=8.88, 2.05 Hz, 1H) 8.05 (d, J=8.98 Hz, 1H) 8.35 (d, J=5.86 Hz, 1H) 8.40 (d, J=1.95 Hz, 1H) 9.11 (s, 1H); LCMS: 290 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].C(C1OC2C=CC([N+]([O-])=O)=CC=2C=1C(=O)C1C=CC(O)=CC=1)CCC.[CH2:56]([N:60]([CH2:65][CH2:66]CCl)[CH2:61][CH2:62][CH2:63][CH3:64])[CH2:57][CH2:58][CH3:59]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:8]=2[C:9]=1[C:10](=[O:19])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:66][CH2:65][N:60]([CH2:61][CH2:62][CH2:63][CH3:64])[CH2:56][CH2:57][CH2:58][CH3:59])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OC)cc1
Reactant: CCCCN(CCCC)CCCCl
Agent: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(OCCCN(CCCC)CCCC)cc1

Procedure:
Industrial application of this last reaction step involves difficulties, because 2-n-butyl-3-(4-methoxybenzoyl)-5-nitro-benzofuran (X) is mutagenic, and aluminum chloride is harmful for the health. The resulting 2-n-butyl-3-(4-hydroxybenzoyl)-5-nitro-benzofuran (XI) on reaction with dibutylamino-propylchloride furnishes 2-n-butyl-3-[4-(3-dibutylamino-propoxy)benzoyl]-5-nitro-benzofuran (XII)
Reaction SMILES: [N:1]1([C:7](=[O:28])[CH2:8][CH2:9][CH2:10][N:11]2[C:23]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]=[C:15]([NH2:24])[C:14]=3[N:13]=[C:12]2[CH2:25][CH2:26][CH3:27])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>[Pt](=O)=O>[N:1]1([C:7](=[O:28])[CH2:8][CH2:9][CH2:10][N:11]2[C:23]3[C:22]4[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=4[N:16]=[C:15]([NH2:24])[C:14]=3[N:13]=[C:12]2[CH2:25][CH2:26][CH3:27])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCC(=O)N1CCOCC1
Agent: O=[Pt]=O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(N)nc3c(c2n1CCCC(=O)N1CCOCC1)CCCC3
Reaction time: 2 h
Yield: 92.5 %

Procedure:
A mixture of 1-(4-morpholin-4-yl-4-oxobutyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.62 g, 1.6 mmol, prepared as described in Example 1), platinum (IV) oxide (0.25 g, 1.1 mmol), and trifluoroacetic acid (25 mL) was placed in a Parr vessel and shaken under hydrogen pressure (50 psi, 3.5×105 Pa) for two hours. An analysis by LC/MS indicated the reaction was incomplete. Additional platinum (IV) oxide (0.5 g) was added, and the reaction was continued overnight. The trifluoroacetic acid was removed under reduced pressure, and the residue was dissolved in methanol (35 mL). Aqueous sodium hydroxide (10 mL of 25%) was added to the solution, and the mixture was stirred for 15 minutes and then diluted with dichloromethane (100 mL). The mixture was filtered through a layer of CELITE filter aid, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with 5% aqueous sodium hydroxide (2×25 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure. The resulting solid was recrystallized from water:acetonitrile; the crystals were triturated with 25% aqueous sodium hydroxide for one hour, diluted with water, isolated by filtration, and recrystallized from water:ethanol. The resulting crystals were dried overnight in a vacuum oven at 70° C. to provide 0.5706 g of l-(4-morpholin-4-yl-4-oxobutyl)-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine as white crystals, mp 181-183° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:20]([Cl:24])(Cl)(=[O:22])=[O:21].[NH2:25][C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][C:27]=1S(O)(=O)=O.C(N(CCCC)CCCC)CCC>ClCCl>[NH2:25][C:26]1[C:31]([CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][C:27]=1[S:20]([Cl:24])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: Nc1c(C2CCCC2)cccc1S(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: Nc1c(C2CCCC2)cccc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2.42 g (9.2 mmol) of triphenylphosphine in 5 ml of dichloromethane is added dropwise, at 0° C. under a nitrogen atmosphere, 0.70 ml (8.8 mmol) of sulphuryl chloride. The reaction medium is left stirring for 10 minutes at 0° C., followed by addition over 5 minutes of a solution containing 1.06 g (4.4 mmol) of 2-amino-3-cyclopentylbenzenesulphonic acid and 1.04 ml of tributylamine in 3 ml of dichloromethane. The mixture is brought to room temperature and is left at this temperature for 2 hours, then it is purified by chromatography on a column of silica gel, eluting with a dichloromethane/pentane mixture (1:1).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([C:27](OC)=[O:28])[CH:24]=[N:25][CH:26]=2)=[CH:17][CH:16]=1.[BH4-].[Na+].O1CCCC1.CO>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:32]=[CH:31][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][OH:28])[CH:24]=[N:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1cncc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cncc(CO)c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
To a mixture of methyl 5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridinecarboxylate (2.09 g), sodium tetrahydroborate (0.93 g) and tetrahydrofuran (100 mL) was dropwise added methanol (10 mL) at 50° C., and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (1.85 g, 94%) of [5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 128-130° C.
Reaction SMILES: C[O:2][C:3](=[O:21])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)\[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+]>CO>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13](/[C:7](/[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:21])=[O:2])=[CH:18][CH:17]=1
Reactant: CCCCC/C(=C\C=C\C(=O)OC)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC/C(=C\C=C\C(=O)O)c1ccc(OC)cc1
Reaction time: 0.75 h
Yield: 81 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid methyl ester (6.1 g) was saponified in a refluxing mixture of methanol (25 mL) and 2N NaOH (25 mL). After 45 minutes the reaction was worked up in the usual way and the crude acid crystallized from 2-propanol to give 4.7 g of (E,E)-5-(4-methoxyphenyl)-2,4-decadienoic acid, mp 126°-127.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[CH3:26]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([CH3:26])[CH:19]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Cc1cc(B(O)O)ccc1F
Product: Cc1cc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)ccc1F

Procedure:
The title compound, MS: m/e=326.4 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-fluoro-3-methyl-benzene boronic acid.
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].I[CH3:21].CO>CC#N.CCCCCC.CC(=O)OCC>[C:1]([N:8]1[CH2:9][CH:10]([N:12]([CH3:21])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:11]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nccs2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(c1nccs1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A suspension of 270 mg (1.05 mmol) of 1-Boc-3-(thiazol-2-ylamino)azetidine in MeCN (5 ml) was combined with 68 mg (1.2 mmol, 60% strength in mineral oil) of sodium hydride and stirred for 30 min at RT. 151 μl (1.73 mmol) of iodomethane were then added and stirring continued for a further 16 h at RT. After addition of MeOH (200 μl), evaporation under a vacuum was carried out. 166 mg (0.62 mmol, 59%) of 1-Boc-3-(methyl(thiazol-2-yl)amino)azetidine were obtained by CC (hexane/EA 3:2) with the residue.