Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]4[CH2:34][P:35](=[O:52])([O:44]CC4C=CC=CC=4)[O:36]CC4C=CC=CC=4)[CH2:18]3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][N:19]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]4[CH2:34][P:35](=[O:36])([OH:52])[OH:44])[CH2:18]3)[CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=P(CC1CCCCC1N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1)(OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=P(O)(O)CC1CCCCC1N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Yield: 72.5 %

Procedure:
A solution of 39 mg (0.054 mmol) 2-(R/S)-(3-(S)-((4-(3-phenylpropyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexylmethylphosphonic acid, dibenzyl ester (from EXAMPLE 93, Step D) in 2.3 mL of MeOH was hydrogenated using 17 mg of 10% palladium on carbon under 47 psi of hydrogen gas on a Parr shaker. After TLC indicated the absence of the starting benzyl ester, the reaction was filtered through a 0.45 micron nylon membrane polypropylene filter and concentrated to give 21.1 mg (73%) of the title compound: 1H NMR (500 MHz, CD3OD) δ 0.99-3.57 (m, 35H), 6.97-7.29 (m, 10H); ESI-MS 539 (M+H); HPLC A: 2.59 min.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@H:15]([CH:32]1[CH2:34][CH2:33]1)[C@H:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[N:19]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])(=O)=O>C(Cl)Cl.ClCCCl>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:35])[C@H:15]([CH:32]1[CH2:33][CH2:34]1)[C@H:16]([C@H:18]1[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[N:19]1[C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[O:17][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@H](O)[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C2CC2)COC1(C)C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: ClCCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)C2CC2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a −40° C. solution of tert-butyl (4R)-4-{(1R,2R)-3-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-cyclopropyl-1-hydroxy-3-oxopropyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.80 g, 3.68 mmol) in anhydrous DCM (10 mL), 2,6-lutidine (0.85 mL, 7.3 mmol) was added under an atmosphere of nitrogen. After 10 min., a solution of tert-butyldimethylsilyl trifluoromethanesulfonate (1.1 mL, 4.9 mmol) in anhydrous DCM (1 mL) was added. The reaction mixture was allowed to warm gradually to ambient temperature while stirring overnight. The crude reaction mixture was diluted with 1,2-dichloroethane and cooled to 0° C. prior to quenching with saturated NaHCO3 (aq.). Upon separation of the two layers that resulted, the organic layer was washed with water and brine, dried over Na2SO4, concentrated under reduced pressure and purified by flash chromatography (120 g silica gel, eluting with 0-30% EtOAc/hexanes) to afford the sub-title compound (2.1 g, 95%). LC/MS (ESI) m/z calc. for C32H50N2O7SiNa: 625.3 [M+Na]+. found 625.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH3:10][C:11]1[CH:12]=[C:13]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][N:28]=2)[CH:14]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH3:10][C:11]1[CH:16]=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=2)[CH:14]=[C:13]([NH:26][C:27]2[N:32]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:30]=[CH:29][N:28]=2)[CH:12]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C=O)nc2)c1

Procedure:
A mixture of 5-bromopyridine-2-carbaldehyde (500 mg, 2.69 mmol), N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.23 g, 3.24 mmol), PdCl2(dppf) (216 mg, 0.295 mmol), sodium carbonate (2 M, 2.70 mL, 5.40 mmol), and dioxane (10.0 mL) was evacuated and purged with Ar(g) (3×), and then irradiated under microwave at 100° C. for 10 minutes. The mixture was filtered, diluted with ethyl acetate and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (25% ethyl acetate in hexanes) to afford 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carbaldehyde. C18H14F3N4O [M+H]+ 359. found 359.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][CH:9]([OH:12])[C:10]#[CH:11].[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[C:18]([Si:21]([O:12][CH:9]([CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=2[C:2]=1[Cl:1])[C:10]#[CH:11])([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CC(O)CCc1sc2ccccc2c1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(CCc1sc2ccccc2c1Cl)O[Si](C)(C)C(C)(C)C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
A solution of alcohol 18 (2.20 g, 8.78 mmol) in dichloromethane (15 mL) was treated with DMAP (215 mg, 1.8 mmol), TBSCl (1.59 g, 10.5 mmol), and triethylamine (1.8 mL, 13.2 mmol). The reaction was stirred for 24 h and then saturated sodium bicarbonate solution (50 mL) was added. The mixture was extracted with dichloromethane (2×50 mL) and the combined dichloromethane solution dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (4% ethyl acetate/hexane) gave 3.06 g (6.4 mmol, 73%) of the protected alcohol (19).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[F:28][C:29](I)([F:31])[F:30].OO>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].CS(C)=O>[F:28][C:29]([F:31])([F:30])[C:21]1[C:19](=[O:20])[NH:18][C:16](=[O:17])[N:15]([CH:22]=1)[C@@H:7]1[O:8][C@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]1
Reactant: FC(F)(F)I
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Agent: [Fe+2]
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CS(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(F)(F)F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Temperature: 65 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
0.32 g (1.0 mmol) of 3′,5′-di-O-acetyl-2′-deoxyuridine and 0.058 g (0.3 mmol) of ferrocene were weighed and placed in a 50 ml two-neck flask equipped with a magnetic rotor and the atmosphere in the flask was replaced with argon. The following materials were added thereinto: 1.8 ml of dimethyl sulfoxide, 2.0 ml of a 1N dimethyl sulfoxide solution of sulfuric acid, 1.0 ml of a 2.1 mol/l dimethyl sulfoxide solution of trifluoromethyl iodide and 0.2 ml of a 30% hydrogen peroxide aqueous solution. The mixture was stirred at 60 to 70° C. for 20 minutes and then the resulting solution was cooled to room temperature. Formation of 5-trifluoromethyl-3′,5′-di-O-acetyl-2′-deoxyuridine (19F-NMR yield: 75%) was confirmed by 19F-NMR with trifluoroethanol as an internal standard. 5-Trifluoromethyl-3′,5′-di-O-acetyl-2′-deoxyuridine was obtained as a white solid (0.19 g, yield: 50%) by column chromatography.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6].[C:11]1([S:17]([O-:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na+]>>[CH:5]([C:4]([CH:8]([CH3:10])[CH3:9])=[CH:3][CH2:2][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])([CH3:7])[CH3:6]
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)C(=CCBr)C(C)C
Agent: [Na+]
Product: CC(C)C(=CCS(=O)(=O)c1ccccc1)C(C)C

Procedure:
Using the procedure of Example I, 1-bromo-3-isopropyl-4-methyl-2-pentene was reacted with sodium phenyl sulfinate to form (3-isopropyl-4-methyl-2-pentenyl)-phenyl sulfone having a melting point of 50° C which was then reacted with ethyl β,β-dimethylacrylate to form ethyl dl-trans 3,3-dimethyl-2-(2'-isopropyl-3'-methyl-1'-butenyl)-cyclopropanecarboxylate. The said ethyl ester was hydrolyzed under alkaline conditions to form dl-trans 3,3-dimethyl-2-(2'-isopropyl-3'-methyl-1'-butenyl)-cyclopropane carboxylic acid having a melting point of 135° C which was then reacted with thionyl chloride to form dl-trans 3,3-dimethyl-2-(2'-isopropyl-3'-methyl-1'-butenyl)-cyclopropanecarboxylic acid chloride having a boiling point of 78° to 80° C at 0.1 mm Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27](Cl)[C:26]=1[N+:32]([O-:34])=[O:33].[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][NH:41][CH3:42]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=2)=[O:10])=[CH:4][C:3]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])[CH3:42])[C:26]=1[N+:32]([O-:34])=[O:33]
Reactant: CNCCCN(C)C
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1cccc(N(C)CCCN(C)C)c1[N+](=O)[O-]

Procedure:
In an analogous procedure to that described in the fifth paragraph of the portion of Note a) which is concerned with the preparation of starting materials, N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-chloro-2-nitrobenzamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]-3-[N-(3-dimethylaminopropyl)-N-methylamino]-2-nitrobenzamide; NMR Spectrum: (DMSOd6) 1.44-1.58 (m, 2H), 2.06 (s, 6H), 2.15 (t, 2H), 2.21 (s, 3H), 2.69 (s, 3H), 3.02 (t, 2H), 3.48-3.53 (m, 4H) 3.69-3.73 (m, 4H), 7.1 (d, 1H) 7.19-7.25 (m, 2H), 7.44-7.62 (m, 3H), 7.74-7.64 (m, 1H), 7.94 (d, 1H), 8.26 (d, 1H), 10.13 (s, 1H), 10.32 (s, 1H); Mass Spectrum: M+H+ 576.
Reaction SMILES: [OH-:1].C([N+]([CH2:15][CH2:16][CH2:17][CH3:18])(CCCC)CCCC)CCC>C(#N)C>[C:15]1([OH:1])[C:16]2[C:17]3[C:18](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: [OH-]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: Oc1cccc2c1-c1ccccc1-2

Procedure:
Diacyl biphenyl XIX is treated with a reducing agent (e.g., tetrabutylammonium hydroxide)in an organic solvent (e.g., acetonitrile) to form a biphenyl enol ##STR28##
Reaction SMILES: C([Li])CCC.CCCCCC.[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1.O>[Cl:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])=[CH:15][CH:14]=1
Reactant: Clc1ccc2cc[nH]c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1ccccc1)n1ccc2ccc(Cl)cc21
Temperature: -40 °C

Procedure:
At −78° C., n-butyl lithium (a 1.61M hexane solution, 3.34 ml) was added to a solution of 6-chloroindole (777 mg) in tetrahydrofuran (25 ml), followed by heating to −40° C. over 1 hour. The reaction mixture was cooled back to −78° C. and added with benzenesulfonyl chloride (867 μl). The resulting mixture was heated to room temperature over 3 hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (40 g of silica gel, hexane:ethyl acetate=5:7). The white solid so obtained was recrystallized from ethanol, whereby the title compound (826 mg, 55%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.O>[CH2:14]([O:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1nc(Br)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1nc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
To a solution of 6-bromo-2-nitropyridin-3-ol (1.0 g, 4.6 mmol), in anhydrous DMF (15 mL) at 0° C. was added 60% sodium hydride in mineral oil (200 mg, 5.0 mmol). The reaction mixture was stirred at 0° C. for 5 min and at room temperature for 15 min. Benzyl bromide (0.6 mL, 5.0 mmol) was added dropwise and the resulting mixture was stirred at 60° C. for 1 hour, cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was separated and washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (Si—PPC, Et2O:pentane, gradient 0:100 to 100:0) to give 3-Benzyloxy-6-bromo-2-nitropyridine as a yellow solid (956 mg, 67%). 1H NMR (400 MHz, CHCl3-d): δ 7.60 (d, J=8.6 Hz, 1 H); 7.41-7.35 (m, 6 H); 5.25 (s, 2 H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[N:17]O)[CH2:9][CH2:8]1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1.O>[O:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]([NH2:17])[CH2:9][CH2:8]1
Reactant: ON=C1CCOc2ccccc21
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: NC1CCOc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
LAH (6.35 g, 167 mmol) was suspended in THF (100 mL) at 0° C. A solution of chroman-4-one oxime (Step A) (10.92 g, 66.92 mmol) in THF (100 mL) was added drop-wise. The mixture was heated slowly to reflux for 4 h. The reaction was cooled to RT and added drop-wise to a stirred saturated solution of Rochelle's salt in H2O. The bi-phasic mixture was stirred rapidly at RT for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc until tlc analysis of the aqueous layer showed no evidence of the title compound. The combined organics were dried over MgSO4 and concentrated in vacuo to furnish the crude material, which was purified by flash column chromatography to afford the title compound. MS (APCI pos) 150 (M+H).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][C:6]1[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=1[C:8]([NH:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)=[O:9].[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[CH:24]1([NH:30][CH2:3][CH:2]([OH:1])[CH2:4][O:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[C:8]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)=[O:9])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC1CO1
Reactant: NC1CCCCC1
Solvent: CCO
Product: O=C(Nc1cccc2[nH]ccc12)c1ccccc1OCC(O)CNC1CCCCC1

Procedure:
2.5 g of 2-[(2-oxiranyl)methoxy]-N-(1H-indol-4-yl)-benzamide in 20 ml of ethanol was refluxed for 2 hours with 1.86 ml of cyclohexylamine and the solvent was eliminated under reduced pressure. The residue was chromatographed over silica (eluent:chloroform-methanol 9-1) to obtain 1.97 g of 2-[3-(cyclohexylamino)-2-hydroxypropoxy]-N-(1H-indol-4-yl)-benzamide
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[C:20]([Cl:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=1[Cl:23].Cl>[Cu]Br.O1CCOCC1>[Cl:21][C:20]1[CH:19]=[C:18]([F:22])[CH:17]=[C:16]([Cl:23])[C:15]=1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Fc1cc(Cl)c(Br)c(Cl)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(Cl)cc(F)cc1Cl
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 54.5 %

Procedure:
Diethyl malonate (0.49 mol) is added to a mixture of sodium hydride (0.51 mol) and 1,4-dioxane (140 ml) at 55 to 60° C. within 2 hours. The mixture is stirred for 10 minutes at 55° C. and copper(I) bromide (0.05 mol) is added. After 15 minutes a mixture of 1-bromo-2,6-dichloro-4-fluoro-benzene (0.25 mol) and 1,4-dioxane (10 ml) is added. The reaction mixture is heated at 100° C. for 15 hours and cooled to 15° C. Hydrochloric acid (12N, 35 ml) is added slowly at 15 to 20° C. The precipitate is filtered off. The filtrate is extracted with diethylether. The organic phase is separated, dried with anhydrous sodium sulphate and filtered. The filtrate is evaporated under reduced pressure to yield 44 g of the product as yellow crystals having a melting point of 170° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C(OCC)(=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:2]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([CH:6]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: Oc1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=Cc1cc([N+](=O)[O-])ccc1Oc1ccccc1
Temperature: 70 °C
Yield: 99.5 %

Procedure:
A mixture of 2-fluoro-5-nitrobenzaldehyde (1.0 g, 5.91 mmol), phenol (0.557 g, 5.91 mmol), and K2CO3 (1.635 g, 11.83 mmol) in dioxane (6 mL) was heated at 70° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (60 mL). The solution was washed with water (2×30 mL) and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give the title compound (1.43 g, 99% yield).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH2:9][CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1.[C:12](O)(=O)[CH2:13][CH3:14].P(=O)(O)(O)O.[OH-].[Na+]>>[CH2:13]([C:14]1[NH:8][C:7]2[C:2]([N:1]=1)=[N:3][CH:4]=[CH:5][C:6]=2[CH2:9][CH2:10][CH3:11])[CH3:12]
Reactant: CCC(=O)O
Reactant: CCCc1ccnc(N)c1N
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1ccnc2nc(CC)[nH]c12
Temperature: 25 °C

Procedure:
2.6 g (0.017M) of 2,3-diamino-4-n-propylpyridine and 1.4 ml (0.019M) of propionic acid were added to 15 ml of phosphoric acid, and the mixture was heated at 140° to 150° C. for 20 hr. It was cooled to room temperature, poured into a cold aqueous NaOH solution and then extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was distilled off in vacuo to prepare a substantially pure brown oleaginous intended product. The yield was 2.9 g (this compound was used as a starting material in the preparation of the following raw material (29)).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([CH:20]([C:4]2[S:3][C:2]([Cl:1])=[CH:6][CH:5]=2)[OH:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Clc1cccs1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2ccc(Cl)s2)CC1

Procedure:
From 2-chlorothiophene (183 mg) and 4-formyl-piperidine-1-carboxylic acid tert-butyl ester (300 mg) by procedure D. Yield: 180 mg (38%). Brown oil. MS (m/z): 332.1 ([M+H]+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](O)(=[O:11])[CH3:10].N1C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])(=[O:11])[CH3:10]
Reactant: CC(=O)O
Reactant: OCCCCCCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCCCCCCl
Temperature: 10 °C

Procedure:
6-chlorohexanol (800 g) was added to anhydrous acetic acid (1,200 mL) cooled to 10° C. in an ice bath, and then pyridine (934 g) was dropped for 10 minutes. After the completion of dropping, they were refluxed for 2 hours. The reaction mixture was poured into water and toluene was further added and stirred. After neutralization the toluene layer with an aqueous saturated solution of sodium carbonate, it was washed with a small amount of water and further dried over anhydrous magnesium sulfate. Toluene and unreacted ingredients were distilled off from the toluene layer to obtain concentrates. The concentrates were purified by distillation under a reduced pressure to obtain 6-acetoxy chlorohexane (983 g). The boiling point was 82° C./5.3 hPa.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[Cl:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36](O)=[O:37].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(OCC)(=O)C>[CH2:20]([O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][CH:2]([NH:1][C:36]([C:31]1[C:32]2[C:27](=[C:26]([Cl:25])[CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:29][CH:30]=1)=[O:37])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4])[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1cccc2c(Cl)cccc12
Reactant: CC(C)(C)COc1cccc(CC(N)C(O)c2cccc(Cl)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COc1cccc(CC(NC(=O)c2cccc3c(Cl)cccc23)C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-[3-(neopentyloxy)phenyl]-1-(3-chlorophenyl)-1-propanol (0.30 g, 0.86 mmol) in N,N-dimethylformamide (5 ml) were added 5-chloronaphthalene-1-carboxylic acid (0.186 g, 0.90 mmol) and 1-hydroxybenzotriazole monohydrate (0.138 g, 0.90 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.173 g, 0.90 mmol) was finally added. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[3-(neopentyloxy)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-5-chloro-1-naphthamide (0.350 g, 76%) as colorless crystals.