Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:30][CH3:31])=[C:8]([C:19]([CH2:22][S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:21]=2)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:2]1.[N:32]#[C:33][NH2:34].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(#N)C>[C:33]([N:34]=[S:23]([CH2:22][C:19]1[C:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[C:7]([O:30][CH3:31])[C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:32]
Reactant: COc1c(-c2ccoc2)ccc(CSc2ccccc2)c1C(=O)OCc1ccccc1
Reactant: N#CN
Solvent: CC#N
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Product: COc1c(-c2ccoc2)ccc(CS(=NC#N)c2ccccc2)c1C(=O)OCc1ccccc1
Yield: 16.2 %

Procedure:
A solution of benzyl 3-(furan-3-yl)-2-methoxy-6-(phenylthiomethyl)benzoate (Intermediate 226, 0.96 g), cyanamide (0.19 g) and iodobenzene diacetate (0.79 g) in acetonitrile (20 ml) was stirred for 16 hours. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with ethyl acetate and DCM with a gradient of 0-5% to give benzyl 6-[(N-cyano-S-phenylsulphinimidoyl)methyl]-3-(furan-3-yl)-2-methoxybenzoate (0.17 g) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=1[F:25]>>[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:12]2[CH2:11][CH2:10][N:9]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=3)[CH2:14][CH2:13]2)=[O:21])=[CH:18][C:17]=1[F:25]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)c(F)c3)CC2)c(C)c1
Yield: 67.4 %

Procedure:
Using 1-(3,5-dimethylpyridin-2-yl)piperazine (2.87 g) described in Preparation Example 79 and 4-bromo-3-fluorobenzoic acid (3.29 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (3.97 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(OCC)(=O)C.C(O)(=O)C.ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 6.0 g N-t-butyloxycarbonyl-4-piperidone, 3.3 g of 2-aminophenol, 25 mL of 1,2-dichloroethane, 25 mL of glacial acetic acid, and 500 mg powdered 4 Å molecular sieves was stirred under inert atmosphere. After 30 min, 6.4 g sodium triacetoxyborohydride was added stirring was continued for 38 h. The reaction mixture was poured into 400 mL ethyl acetate and 200 mL saturated aqueous NaHCO3 and the layers separated. The organic layer was washed with brine (2×100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with a gradient of 1-3% methanol/methylene chloride containing 0.5% concentrated NH4OH gave 1-t-butyloxycarbonyl-4-(2-hydroxyphenylamino)piperidine as an orange foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:13][OH:14])[CH2:6][CH2:5]2
Reactant: NO
Reactant: O=C1CCc2cc(F)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: ON=C1CCc2cc(F)ccc21
Reaction time: 1 h
Yield: 89.1 %

Procedure:
A solution of 5-fluoroindanone (10 g), hydroxylamine hydrochloride (9 g), potassium carbonate (23 g) and water (3.5 ml) in 96% ethanol (40 ml) was heated to reflux, cooled to ca 45 and additional hydroxylamine hydrochloride (4.5 g) and potassium carbonate (11.5 g) were added and refluxed for an additional 30 min. At this time the mixture was poured into cold water (300 ml) and stirred in an ice bath for one hour; 5-fluoroindanone oxime (9.8 g) was isolated by filtration.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][OH:32])[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2].[C:33](Cl)(=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].O>C1(C)C=CC=CC=1>[C:1]([NH:4][C@@H:5]1[C@@:14]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([OH:15])[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][C:33](=[O:41])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[O:11][CH:6]1[O:7][CH2:8][CH:9]=[CH2:10])(=[O:3])[CH3:2]
Reactant: CCCCCCCC(=O)Cl
Reactant: C=CCOC1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOC1O[C@H](COC(=O)CCCCCCC)[C@@H](OCc2ccccc2)[C@@](O)(Cc2ccccc2)[C@H]1NC(C)=O
Temperature: 92.5 °C
Yield: 70.4 %

Procedure:
9.5 g of (e) and 5 g of octanoyl chloride in 150 ml of toluene was heated under reflux at 90-95° C. for 4 h. After cooling, the reaction mixture was poured into 600 ml of water and extracted with toluene. The organic phases were combined, washed with NaHCO3 then with water. Finally, after drying and evaporating off the solvents, the crude product was purified over silica to recover 8.6 g of (f) (Yield: 70%).
Reaction SMILES: C([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=O)C.[C:37]1([CH3:47])[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1.[CH2:48]([OH:50])[CH3:49]>>[C:48]([C:36]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH3:12])[N:8]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)(=[O:26])=[O:27])=[O:23])=[CH:17][CH:18]=3)[C:7]=2[CH:35]=1)(=[O:50])[CH3:49].[CH3:47][C:37]1[CH:42]=[CH:41][C:40]([S:43]([OH:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCc1nc2ccc(C(C)=O)cc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91 %

Procedure:
A mixture of 5-acetyl-2-ethyl-3-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)benzimidazole (Example 78, 43 mg, 0.085 mmol), p-toluenesulfonic acid (16.2 mg, 0.085 mmol) in ethanol (0.1 ml) was stirred at room temperature for 16 h. The precipitated crystalline solids were filtered, washed with ethanol (0.05 ml×5), and dried in vacuo at 40° C. for 2 h to afford 54 mg (91%) of the title compound as white solids.
Reaction SMILES: [CH:1]1([CH:6]=[CH:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.[NH:21]1[CH:25]=[C:24]([C:26]2[C:27]3[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=3[N:29]=[CH:30][N:31]=2)[CH:23]=[N:22]1>C(#N)C.ClCCl>[CH:1]1([CH:6]([N:21]2[CH:25]=[C:24]([C:26]3[C:27]4[CH:34]=[CH:33][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C:28]=4[N:29]=[CH:30][N:31]=3)[CH:23]=[N:22]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=CC1CCCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCCC4)c3)ncnc21
Temperature: 55 °C
Yield: 97.7 %

Procedure:
3-Cyclopentylacrylonitrile (8, 273.5 g, 2.257 mol, 1.20 equiv) and DBU (28 mL, 0.187 mol, 0.10 equiv) was added to a suspension of 4-(1H-pyrazol-4-yl)-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 591.8 g, 1.876 mol) in acetonitrile (4.7 L) at room temperature. The resulting reaction mixture was heated to 50-60° C. for 17 hours (a clear solution developed midway through heating) then to 70-80° C. for 8 hours. When LCMS analysis showed the reaction was deemed complete, the reaction mixture was cooled to room temperature. The cooled solution was then concentrated under reduced pressure to give the crude product (9) as a thick amber oil. The crude product was dissolved in dichloromethane (DCM) and absorbed onto silica gel then dry-loaded onto a silica column (3 Kg) packed in 33% EtOAc/heptanes. The column was eluted with 33% EtOAc/heptanes (21 L), 50% EtOAc/heptanes (28 L), 60% EtOAc/heptanes (12 L) and 75% EtOAc/heptanes (8 L). The fractions containing the desired product (9) were combined and concentrated under reduced pressure to generate a yellow oil, which was transferred to a 3 L flask with EtOAc. The solvent was removed under reduced pressure and the residual EtOAc by co-evaporating with heptanes. The residue was further dried under high vacuum for overnight to afford racemic 3-cyclopentyl-3-{4-[7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]pyrazol-1-yl}propionitrile (9, racemic SEM-protected compound, 800 g, 819.1 g theoretical, 97.7% yield) as an extremely viscous yellow oil. For 9: 1H NMR (DMSO-d6, 400 MHz) δ ppm 8.83 (s, 1H), 8.75 (s, 1H), 8.39 (s, 1H), 7.77 (d, 1H, J=3.7 Hz), 7.09 (d, 1H, J=3.7 Hz), 5.63 (s, 2H), 4.53 (td, 1H, J=19.4, 4.0 Hz), 3.51 (t, 2H, J=8.1 Hz), 3.23 (dq, 2H, J=9.3, 4.3 Hz), 2.41 (m, 1H), 1.79 (m, 1H), 1.66-1.13 (m, 7H), 0.81 (t, 2H, J=8.2 Hz), 0.124 (s, 9H); C23H32N6OSi (MW, 436.63), LCMS (EI) m/e 437 (M++H) and 459 (M++Na).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11]3=[C:12]([C:14]4[CH2:20][CH2:19][CH2:18][CH2:17][C:16](=[O:21])[C:15]=4[N:10]3[CH2:9][CH2:8][CH2:7]2)[CH:13]=1)([O-])=O>[Pd].C(O)C>[O:21]=[C:16]1[C:15]2[N:10]3[C:11]4[C:6](=[CH:5][C:4]([NH2:1])=[CH:13][C:12]=4[C:14]=2[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:7][CH2:8][CH2:9]3
Reactant: O=C1CCCCc2c1n1c3c(cc([N+](=O)[O-])cc23)CCC1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c3c(c1)c1c(n3CCC2)C(=O)CCCC1

Procedure:
Following the procedure of Example 1, Step 3, 2-nitro-8-oxo-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinoline (0.10 g, 0.37 mmol) and 5% palladium on carbon (30 mg) in ethanol (25 mL) was hydrogenated to provide 8-oxo-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:33][C:30]3[CH:31]=[CH:32][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3ccc([N+](=O)[O-])cc3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.495 mmol) and 4-nitrophenol were reacted as starting materials at 150° C. for 15 hours and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow crystalline powder (146.1 mg, 74.1%). Melting point: 197.7-201.1° C. (ethyl acetate-hexane).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)CC1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:2][NH:3][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1
Reactant: CN(CCCCOc1cccc(C(F)(F)F)c1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNCCCCOc1cccc(C(F)(F)F)c1
Yield: 25.8 %

Procedure:
A mixture of intermediate 8 (0.019 mol) in methanol (150 ml) was hydrogenated with palladium on carbon (10%, 2 g) as a catalyst. After uptake of hydrogen gas (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the free base with a NaOH solution. The aqueous solution was extracted with toluene. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was converted into the hydrochloric acid salt (1:1) in DIPE. The precipitate was filtered off and dried, yielding 1.21 g (22.5%) of N-methyl-4-[3-(trifluoromethyl)phenoxy]-1-butanamine (intermediate 9).
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH:9]([CH2:12][OH:13])[CH2:10][O:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[OH:13][CH2:12][CH:9]1[O:8][C:7]2[C:2]([O:1][CH3:14])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:10]1
Reactant: OCC1COc2cccc(O)c2O1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c1OC(CO)CO2
Temperature: 45 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A mixture of 5.52 g of 8-hydroxy-2-hydroxymethyl-1,4-benzodioxan (prepared as described in EP 210581), 4.2 g of anhydrous potassium carbonate and 2.06 ml of methyl iodide in 75 ml of anhydrous dimethylformamide was stirred at 45° C. for 8 hours. Methyl iodide (1 ml) was added to the mixture and stirring continued at the same temperature. After 8 hours, 1 ml of methyl iodide and 2.1 g of potassium carbonate were further added, and the reaction mixture was stirred at 45° C. for 6 hours. Thereafter, the mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with 6N aqueous sodium hydroxide solution, water, then dried on sodium sulfate. Evaporation of the organic layer to dryness in vacuo afforded 5.35 g of 2-hydroxymethyl-8-methoxy- 1,4-benzodioxan, which was used in the next step without further purification.
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10]C(O)=O)=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].C([O-])(=O)C.[NH4+]>>[CH:9]([C:8]1[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][CH:7]=1)=[CH2:10]
Reactant: CC(=O)Oc1ccc(C=CC(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Product: C=Cc1ccc(O)cc1
Yield: 49 %

Procedure:
A mixture of 4-acetyloxycinnamic acid (0.0083 mol), KOH (10%, 3 ml), ammonium acetate (1 g) and basic alumina (5 g) were taken in a 250 ml Erlenmeyer flask fitted with loose funnel at the top. The flask was placed inside the microwave oven and irradiated for 10 minutes. After completion of reaction the solid mixture washed with ethyl acetate and ethyl acetate layer was washed with dil HCl, water, brine and dried over anhydrous sodium sulphate and purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4) provided viscous liquid. 49% yield; 1H NMR (CDCl3) δ 7.31 (2H, d, J=8.48 Hz), 6.81 (2H, d, J=8.48 Hz), 6.67 (1H, dd, J=17.81 and 11.30 Hz), 5.51 (1H, s), 5.2 (1H, d, J=17.81), 5.14 (1H, d, J=11.30 Hz); 13C NMR (CDCl3) δ 155.5, 136.5, 130.9, 128.0, 115.8 and 112.0.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][C:5]=1[OH:22])([O-])=O.[H][H]>[Pt]=O.C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=[CH:6][C:5]=1[OH:22]
Reactant: CCCCCCCCCCCCc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCCCCCCCCCCCc1ccc(O)c(N)c1

Procedure:
To a solution of 310 g of acetic acid and 262 g (1 mole) of 4-dodecyl phenol maintained at 20° C. is slowly added with stirring 76 ml (1.2 moles) of HNO3 in 40 ml of water. After 30 minutes, ice water (800 ml) is added to the reaction vessel and the resulting mixture is extracted with methylene chloride. The methylene chloride phase is withdrawn and washed successively with water, an aqueous solution of NaHCO3 (5 percent) and water. The methylene chloride is then removed under vacuum to obtain the desired 2-nitro-4-dodecylphenol. A solution of 46 g (0.15 mole) of the nitrated phenol, 550 ml of absolute ethanol and 1.2 g of platinum oxide is maintained at 20° C. under 50 psi of hydrogen for 23 hours. The reaction mixture is filtered and then subjected to vacuum to remove solvent. Essentially quantitative yield of the desired 2-amino-4-dodecylphenol is recovered. A solution of 200 ml of acetone, 200 ml of water and 38.8 g (0.14 mole) of the amino phenol is stirred with 200 ml of a carbonate form (CO3=) quaternary ammonium styrene/divinyl benzene, ion exchange resin sold by The Dow Chemical Company under the trade name, Dowex® SBR, forty-nine ml (0.787 mole) of methyl iodide is added to the aforementioned solution through a dry ice condenser. After refluxing the reaction mixture with stirring for 20 hours, the mixture is filtered and excess methyl iodide is removed under vacuum. The resulting solution is contacted with the hydroxide form of the aforementioned ion exchange resin to provide the desired quaternary ammonium zwitterion.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[C:11]1[C:10]([OH:17])=[CH:9][C:8]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:7][C:6]=1[O:5]2.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][OH:31])=[CH:26][CH:25]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>CS(C)=O>[OH:17][C:10]1[C:11]2[C:12](=[O:16])[C:13]3[C:4](=[CH:3][C:2]([O:31][CH2:30][C:27]4[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=4)=[CH:15][CH:14]=3)[O:5][C:6]=2[CH:7]=[C:8]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:9]=1
Reactant: O=c1c2ccc(F)cc2oc2cc(N3CCOCC3)cc(O)c12
Reactant: OCc1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c2ccc(OCc3ccncc3)cc2oc2cc(N3CCOCC3)cc(O)c12
Temperature: 80 °C

Procedure:
6-Fluoro-1-hydroxy-3-morpholin-4-yl-xanthen-9-one (16 mg, 0.05 mmol) and 4-pyridylmethanol (8 mg, 0.07 mmol) were dissolved in DMSO (0.25 mL) and KHMDS (0.5 M in toluene, 0.24 mL) was added. The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture wad quenched with sat. NH4Cl/water (1:1, 2 mL) and the solids were filtered. The solid was purified via flash chromatography eluting with CH2Cl2/MeOH (98:2) to produce 3.9 mg (20%). 1H NMR (CDCl3, 400 MHz) δ: 12.80 (s, 1H), 8.66 (s, 2H), 8.16 (d, 1H), 7.38 (d, 2H), 7.00 (d, 1H), 6.80 (s, 1H), 6.27 (dd, 1H), 6.25 (s, 1H), 5.21 (s, 2H), 3.86-3.83 (m, 4H), 3.37-3.35 (m, 4H). LRMS (APCI, positive): Da/e 405.1 (m+1).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[C:20](Cl)(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O>N1C=CC=CC=1>[C:20]([O:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])(=[O:36])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
α-Hydroxypalmitic acid (3.2 g) was dissolved in pyridine (15 ml), and palmitoyl chloride (3.3 g) was added thereto at 0° C. The resulting mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into water and the aqueous solution was stirred at room temperature for 1 hour, followed by acidification with 1N hydrochloric acid, and extraction with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give a residue which was recrystallized from petroleum ether to afford crystals of 2-hexadecanoyloxyhexadecanoic acid (5.4 g). M.p. 55°-56° C.
Reaction SMILES: [CH:1]1([C:14]([OH:16])=[O:15])[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>[OH-].[Na+].O.O1CCOCC1>[CH2:21]([O:20][C:18]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:1]1[C:14]([OH:16])=[O:15])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1NCCc2c1[nH]c1ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)C1c2[nH]c3ccccc3c2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution, cooled in ice, of 3.0 g of 1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxylic acid in 7 ml of 2M sodium hydroxide solution, 17 ml of water and 17 ml of dioxan were added in alternating portions 12.5 ml of 2M sodium hydroxide solution and a solution of 3.6 ml of benzyl chloroformate in 9 ml of dioxan. After completion of the additions the mixture was stirred at room temperature overnight and the dioxan was then removed by evaporation under reduced pressure. The solution obtained was diluted with water, washed twice with diethyl ether, acidified with 25 ml of 1M sulphuric acid and extracted three times with ethyl acetate. The organic extracts were combined, washed twice with water, dried over anhydrous magnesium sulphate and evaporated to give 4.54 g of 2-benzyloxycarbonyl-1,2,3,4-tetrahydropyrido[3,4-b]indole-1-carboxylic acid, MS: m/e 351 [M+H]+, which was used without purification.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:29][N:30](C=O)C>[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[C-]#N.[Zn+2]>[C:1]([O:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][C:11]([C:29]#[N:30])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)cnc1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(C#N)cnc1C(=O)OC(C)(C)C
Temperature: 69 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-3-methyl-pyridine-2-carboxylic acid tert-butyl ester (48 g, 176 mmol) in DMF (253 mL) under N2 atmosphere was sequentially added Zn powder (1.15 g, 17.6 mmol), Pd2(dba)3 (4.04 g, 4.4 mmol), tri-tert-butylphosphine (214 g, 10.6 mmol, 10 wt % in n-hexane). The mixture was then heated to 50˜60° C. with stirring, at this point, Zn(CN)2 (14.5 g, 123.5 mmol) was added to the mixture in one portion. The reaction mixture was then heated at 69° C. with stirring. After 1 h, the reaction mixture was allowed to cool to below 30° C. and filtered. The filter cake was washed with DMF. To the filtrate was added 2-methyltetrahydrofuran with stirring and the mixture was cooled to <20° C., to the mixture was added slowly 3N aqueous ammonia solution with stirring and the mixture was then stirred vigorously for 30 min at 20˜30° C. before layer separation. The organic layer was washed with brine and concentrated in vacuo to give the title compound as a yellowish crystalline solid: ESIMS: 219; [(M+H)+]; 1H NMR (400 MHz, acetone-d6): δ 8.79 (d, 1H), 8.20 (d, 1H), 2.49 (s, 3H), 1.60 (s, 9H).