Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3(O)[CH2:19][CH2:18][C:13]4([O:17][CH2:16][CH2:15][O:14]4)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH2:19][CH2:18][C:13]4([O:14][CH2:15][CH2:16][O:17]4)[CH2:12][CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OC1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Solvent: Cc1ccccc1
Product: C1=C(c2ccc3c(c2)OCO3)CCC2(C1)OCCO2
Yield: 73 %

Procedure:
A solution of 8-(1,3-benzodioxol-5-yl)-1,4dioxaspiro[4.5]decan-8-ol in toluene was reacted as described in example 2 to give the product (73%, mp: 75°-76° C.). Calc'd for C15H16O4 : C, 69.22%; H, 6.20%. Found: C, 69.19%; H, 6.14%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[CH:14]=[CH:13][S:12][C:8]2=[N:9][C:10]=1N)=[O:4].N([O-])=[O:16].[Na+].C(=O)(O)[O-].[Na+]>[PH2](=O)O>[CH3:1][O:2][C:3]([C:5]1[C:10](=[O:16])[NH:9][C:8]2[S:12][CH:13]=[CH:14][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2ccsc2nc1N
Reactant: O=N[O-]
Agent: O=C([O-])O
Agent: O=[PH2]O
Agent: [Na+]
Product: COC(=O)c1cc2ccsc2[nH]c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-Amino-thieno[2,3-b]pyridine-5-carboxylic acid methyl ester described in Preparation Example T-7 (10 mg, 48 μmol) and sodium nitrite (10 mg, 144 μmol) were dissolved in phosphinic acid (0.5 mL), and the solution was stirred at 0° C. for 1 hour. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (10 mg, 48 μmol, quantitatively) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]4([OH:33])[CH2:32][O:31][CH2:30]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3([OH:33])[CH2:32][O:31][CH2:30]3)[CH2:27][CH2:28]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: Cn1c(CN2CCC(C3(O)COC3)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4(O)COC4)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 3-(1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)oxetan-3-ol were reacted to give 257. LCMS m/z: 519.3 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[C:3]=1[C:4]#[N:5].[Br:12]Br>C(Cl)(Cl)(Cl)Cl.ClCCl.[Fe].II>[Br:12][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([S:10][CH3:11])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: CSc1cccc(Cl)c1C#N
Reactant: BrBr
Agent: [Fe]
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc(Br)c(Cl)c1C#N
Temperature: 30 °C
Yield: 45.5 %

Procedure:
Iron powder (0.5 g) and iodine (0.05 g) were added to a solution of 2-chloro-6-(methylsulphenyl)benzonitrile (10.0 g) in a mixture of carbon tetrachloride and dichloromethane. The mixture was warmed to 30° C. and bromine (9.5 g) was added. The mixture was heated at 55° C. for 5 hours. It was cooled, washed with aqueous sodium bisulphite, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was redissolved in a mixture of carbon tetrachloride and dichloromethane and treated with iron powder (0.5 g) and iodine (0.05 g). Bromine (6.5 g) was added and the mixture was heated at 55° C. for 5 hours. It was cooled and washed with sodium bisulphite, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography eluted with a mixture of ethyl acetate and n-hexane to give 3-bromo-2-chloro-6-(methylsulphenyl)benzonitrile (6.51 g) as an orange solid NMR (CDCl3) 2.5(s,3H) 7.0(d,1H) 7.65(d,1H).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[C:26]([OH:27])=[CH:25][C:20]4[N:21]=[C:22]([CH3:24])[O:23][C:19]=4[CH:18]=3)[C:9]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:35]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:17]4=[CH:18][C:19]5[O:23][C:22]([CH3:24])=[N:21][C:20]=5[CH:25]=[C:26]4[O:27][CH2:35]3)[C:9]2=[O:28])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: Cc1nc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc2o1
Product: Cc1nc2cc3c(cc2o1)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-3-(5-hydroxy-2-methyl-1,3-benzoxazol-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one was obtained (68%) as a colorless solid: mp 240-242° C. (dichloromethane); 1H NMR (300 MHz, CDCl3) δ7.66 (d, J=7.2 Hz, 2H), 7.45-7.29 (m, 9H), 7.11-6.97 (m, 4H), 6.89 (t, J=7.2 Hz, 1H), 6.46 (d, J=7.8 Hz, 1H), 6.01 (d, J=5.7 Hz, 1H), 5.41 (d, J=5.7 Hz, 1H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ175.1, 164.5, 151.3, 146.2, 143.7, 138.6, 138.0, 137.3, 129.9, 129.8, 129.0, 128.9, 128.8, 128.3, 128.0, 127.7, 124.6, 122.8, 114.0, 112.7, 111.8, 110.7, 88.7, 75.8, 58.6, 14.8; MS (ES+) m/z 497.1 (M+39).
Reaction SMILES: [N:1]1[NH:2][C:3](=O)[CH:4]=[C:5]2[CH2:11][CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=12.O(Cl)[Cl:18].[P+3]>>[Cl:18][C:3]1[N:2]=[N:1][C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=c1cc2c(n[nH]1)-c1ccccc1CCC2
Reactant: ClOCl
Agent: [P+3]
Product: Clc1cc2c(nn1)-c1ccccc1CCC2

Procedure:
Alternatively, 6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one was heated with 20 mL of phosphorus (III) oxychloride at 100° C. for 4.75 h. The solvent was removed under vacuum. The residue was treated with ice and saturated sodium bicarbonate solution. The solid which formed was filtered off, washed well with water and air-dried to yield the corresponding 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g); 1H NMR (CDCl3, 300 MHz) 7.82 (m, 1H), 7.44 (m, 2H), 7.39 (s, 1H), 7.27 (m, 1H), 2.55 (m, 4H), 2.32 (m, 2H) ppm; MS (ES) 231/233 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH2:6][CH2:7][C:8]3[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)[C:12]=3[C:4]=2[CH:3]=1.[CH3:25][C:26]1[C:31]([C:32](O)=[O:33])=[CH:30][N:29]=[C:28]([Cl:35])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[Cl:35][C:28]1[N:29]=[CH:30][C:31]([C:32]([NH:1][C:2]2[CH:24]=[CH:23][C:5]3[CH2:6][CH2:7][C:8]4[C:9]([C:20]([NH2:22])=[O:21])=[N:10][N:11]([C:13]5[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=5)[C:12]=4[C:4]=3[CH:3]=2)=[O:33])=[C:26]([CH3:25])[CH:27]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Reactant: Cc1cc(Cl)ncc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(Cl)ncc1C(=O)Nc1ccc2c(c1)-c1c(c(C(N)=O)nn1-c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound of example 244 (3.872 mmoles), 4-methyl-6-chloronicotinic acid from step 2 (5.828 mmoles), and HATU (5.844 mmoles) were dissolved in 20 mL DMF followed by the addition of 1.9 mL triethylamine. The mixture was stirred at room temperature overnight. The solvent was then stripped and the residue suspended in water, filtered, and washed with water. The solid was recrystallized from acetonitrile, then redissolved in acetonitrile, decolorized with decolorizing carbon, and dried over anhydrous MgSO4. The solvent was then stripped down to a solid. Mp: 280–284° C. 1H NMR (d6-DMSO, 400 MHz): δ 2.28 (s, 3H); 2.84–2.98 (m, 4H); 7.25–7.44 (m, 6H); 7.49 (s, 1H); 7.51–7.62 (m, 3H); 8.35 (s, 1H); 10.31 (s, 1H). 13C NMR (DMSO, 100 MHz): δ 19.13, 20.35, 29.67, 115.01, 117.07, 117.30, 120.08, 121.34, 126.19, 126.60, 128.72, 128.81, 129.58, 132.80, 133.42, 136.81, 136.84, 137.64, 139.71, 143.19, 148.42, 149.96, 151.59, 161.44, 163.88, 164.47, 164.78. M+1=476.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18]([O:6][CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=2)[C:15]=1[C:16]#[N:17]
Reactant: OCc1cc(F)cc(F)c1
Reactant: N#Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cccc1OCc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3,5-Difluorobenzyl alcohol (595.2 mg; 4 mmol) was added to a cooled (0° C.) slurry of sodium hydride (172.5 mg; 4.3 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. The reaction mixture was then added to a cooled (0° C.) solution of 2,6-difluorobenzonitrile in dimethylformamide, stirred for 4 hours at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered, washed with water and dried to afford 547.3 milligrams of 2-fluoro-6-(3,5-difluorophenylmethoxy)benzonitrile.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:25]=[CH:24][C:10]([O:11][C:12]2[C:13](=[O:23])[CH:14]=[C:15]([C:18]([O:20]CC)=[O:19])[O:16][CH:17]=2)=[CH:9][CH:8]=1>C(Cl)Cl.O>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][C:12]2[C:13](=[O:23])[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[O:16][CH:17]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cc(=O)c(Oc2ccc(OC)cc2)co1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc(=O)c(Oc2ccc(O)cc2)co1

Procedure:
Boron tribromide (8.8 ml) was added dropwise to a stirred solution of ethyl 5-(4-methoxyphenoxy)-4-oxo-4H-pyran-2-carboxylate (4.35 g) in methylene chloride (50 ml) causing gentle reflux. The solution was heated under reflux for a further 2 hours, then cooled and carefully diluted with water (25 ml). The solid title product was recrystallised from water (mp 257°-258° C. with decomposition).
Reaction SMILES: [C:1]1(N2CCCC2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:12](Br)[CH2:13][CH3:14].O.[OH:17]S(O)(=O)=O>C1C=CC=CC=1>[CH2:12]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1=[O:17])[CH2:13][CH3:14]
Reactant: CCCBr
Reactant: C1=C(N2CCCC2)CCCC1
Reactant: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
A solution of commercially available 1-cyclohex-1-enylpyrrolidine 1(5 g, 99.2 mmol) and propyl bromide (36 mL, 4 eq) in benzene was refluxed at 90° C. for overnight. Another 4 eq of propyl bromide (36 mL) was added and refluxing was continued for overnight. The reaction mixture was cooled to room temperature. 30 mL of water was added, and the resulting solution refluxed for 1 hour. After cooling to room temperature, 30 mL of 1M H2SO4 was added and the solution stirred for 10 minutes. The mixture was extracted with ether, and the combined organic extracts were washed with NaHCO3, H2O, brine, and dried over MgSO4. Purification by column chromatography using EtOAc/hex (1:3) as eluant afforded 2.12 g (15.3%) of 2-propylcyclohexanone. Spectroscopic data: 1H NMR (CDCl3, 300 MHz) δ=0.90 (t, 3H, J=7.035 Hz), 1.14-1.45 (m, 5H), 1.63-1.88 (m, 4H), 1.99-2.14 (m, 2H), 2.23-2.42 (m, 2H).
Reaction SMILES: NC1C=CC=CC=1.C1C(=O)N([Cl:15])C(=O)C1.[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:18]=1[NH2:19].O>CC#N>[Cl:16][C:17]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:15])[C:18]=1[NH2:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: CC#N
Solvent: O
Solvent: Nc1ccccc1
Product: Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 5-L, two-necked, round-bottomed flask equipped with magnetic stirbar was charged with 50 g freshly distilled aniline (0.54 mol) in 1 L MeCN. One neck was equipped with a reflux condenser and N2 purge, and the second neck was glass stoppered. The solution was brought to reflux. N-Chlorosuccimide (86 g, 1 equiv) was added through the glass-stoppered neck in one portion. The color of the reaction became purple-brown. After 1 h, a second addition of 86 g NCS (1 equiv) was made in one portion. After 1 h, NMR of the reaction mixture showed only traces of NCS remained in addition to formation of primarily 2,4-dichloroaniline. The final addition of 86 g NCS (1 equiv) was made in eight ˜10-g portions, reaction occurs with a vigorous exotherm. After the addition, TLC showed the reaction was complete. The mixture was cooled to room temperature and poured into 3 L vigorously stirred H2O. After stirring 1 h, the light purple solid was collected on a coarse-porosity glass frit, washed with 1 L H2O, and air-dried on the frit for 2 h. The crude was dissolved in 1 L Et2O and washed with 500 mL H2O and 500 mL brine. The organic layer was dried with anhydrous MgSO4 and filtered. The filtrate was treated with 11 g Darco G-60 for 1 h. The mixture was filtered through diatomaceous earth, and the solvent was rotary evaporated. The red-brown solid was dissolved in 1 L hexanes. The solution was filtered through 300 g SiO2 on a medium-porosity glass frit that removed most of the color. The filtrates were rotary evaporated, leaving 111.6 g of the title compound as a pale yellow solid that was >97% by 1 H NMR (88%). Recrystallization from EtOH gave the title compound in analytically pure form as soft, colorless needles. Mp 68-70° C., 77.5° C. δH (CDCl3): 7.13 (s, 2 H), 4.36 (bs, NH2); δC (CDCl3): 139.24, 127.81, 122.06, 119.92. Elemental analysis calculated for C6H4Cl3N: C, 36.68; H, 2.05; N, 7.13. Found: C, 36.87; H, 1.93; N, 7.07.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:14]([F:17])([F:16])[F:15])([OH:13])[C:4]([F:12])([F:11])[CH:5]([OH:10])[C:6]([F:9])([F:8])[F:7].C(N(CC)CC)C.C1(C)C=CC=CC=1.[C:34](Cl)(=[O:38])[C:35]([CH3:37])=[CH2:36]>O>[C:34]([O:10][CH:5]([C:6]([F:9])([F:8])[F:7])[C:4]([F:11])([F:12])[C:3]([OH:13])([C:14]([F:15])([F:16])[F:17])[C:2]([F:18])([F:19])[F:1])(=[O:38])[C:35]([CH3:37])=[CH2:36]
Reactant: OC(C(F)(F)F)C(F)(F)C(O)(C(F)(F)F)C(F)(F)F
Reactant: C=C(C)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC(C(F)(F)F)C(F)(F)C(O)(C(F)(F)F)C(F)(F)F
Yield: 71.3 %

Procedure:
To a mixture of 138 g of 1,1,1,3,3,5,5,5-octafluoro-2-(trifluoromethyl)pentane-2,4-diol (Synthesis Example [1-1]), 53.0 g of triethylamine, and 700 g of toluene, under ice cooling and with stirring, 45.4 g of methacrylic acid chloride was added dropwise. The mixture was stirred for 2 hours. Water was added to the reaction mixture to quench the reaction, followed by conventional work-up steps of washing, drying and concentration to give a crude product. It was purified by silica gel column chromatography, yielding 119 g (yield 71%) of the end compound, fluorinated ester.
Reaction SMILES: [O-][CH2:2][CH3:3].[Na+].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[S:7])[CH3:6].C(O)C.ICC>ClCCl>[CH2:2]([S:7][C:5](=[N:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:3]
Reactant: CC[O-]
Reactant: CC(=S)Nc1ccccc1
Agent: [Na+]
Solvent: CCI
Solvent: CCO
Solvent: ClCCl
Product: CCSC(C)=Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
Next, 4.5 g of sodium ethoxide, 9.8 g of thioacetanilide, and 50 mL of ethanol were put in a 100 mL three-neck flask, and stirred at room temperature for 1 hour. Then, 5.3 mL of iodoethane was added to this mixture, and heated and stirred at 60° C. for 5 hours to be reacted. After the reaction, ethanol was distilled off under a reduced pressure to give a brown oily substance. This oily substance was dissolved in dichloromethane, and washed with water and then a saturated aqueous solution of sodium hydrogen carbonate. Anhydrous magnesium sulfate was added to the resulting organic layer for drying. After the drying, the solution was subjected to gravity filtration. The resulting filtrate was concentrated, so that N-[1-(ethylsulfanyl)ethylidene]aniline was prepared (a brown solid, yield: 73%). The synthetic scheme of Step 2 is shown by (b-2).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:16])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[O:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][N:13]([C:30]([CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[O:31])[CH2:12][CH:11]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:16])[CH2:10]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: O=C(Cl)C1CCOCC1
Reactant: CCc1ccc(C2CNCC(C(=O)Nc3ccccc3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)C3CCOCC3)C2)cc1

Procedure:
62 mg (0.18 mmol) of 5-(4-ethylphenyl)-N-phenylpiperidine-3-carboxamide (Example 17A) and 41 mg (0.27 mmol, 1.5 eq.) of tetrahydro-2H-pyran-4-carbonyl chloride were reacted according to General Method 2. Yield: 67 mg (88% of theory)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8](Cl)(Cl)=[O:9])[CH3:2].[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>C(OCC)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([C:12]([S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:7][P:8]([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])([NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:9])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)CN(CP(=O)(Cl)Cl)C(=O)SCc1ccccc1
Solvent: CCOCC
Product: CCCCNP(=O)(CN(CC(=O)OCC)C(=O)SCc1ccccc1)NCCCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
Freshly prepared ethyl-N-[(benzylthio)carbonyl]-N-[dichlorophosphinylmethyl]-glycinate (11.3 g.; 0.029 mol.) dissolved in 100 ml. of diethyl ether was added to a solution containing n-butylamine (8.6 g.; 0.118 mol.) in 100 ml. of diethyl ether. The reaction mixture was stirred for 16 hours at 25° C., then filtered. The filtrate was washed with water, dried over magnesium sulfate and concentrated in vacuo to yield ethyl-N-[(benzylthio)carbonyl]-N-[bis(n-butylamino)phosphinylmethyl]-glycinate (12.5 g.) as a solid having a melting point of 45°-48° C. and the following analysis:
Reaction SMILES: C(C1C=NC(C2C=CC(OCCCCCC(OCC)C)=CC=2)=NC=1)CCCCCCC.[CH2:32]([C:42]1[CH:43]=[N:44][C:45]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]([O:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]CCC)[CH3:61])=[CH:50][CH:49]=2)=[N:46][CH:47]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]CC.N1C=CC=NC=1.C(C1C=NC(C2C=CC(OCCCCCC(OCC)C)=CC=2)=NC=1)CCCCCCCCC.C(C1C=NC(C2C=CC(OCCCCCC(OCCCC)C)=CC=2)=NC=1)CCCCCCCCC>>[CH2:32]([C:42]1[CH:47]=[N:46][C:45]([C:48]2[CH:49]=[CH:50][C:51]([O:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]([O:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH3:61])=[CH:52][CH:53]=2)=[N:44][CH:43]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCC(C)OCCCCCCCC)cc2)nc1
Agent: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCC(C)OCC)cc2)nc1
Agent: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCC(C)OCCCC)cc2)nc1
Agent: CCCCCCCCc1cnc(-c2ccc(OCCCCCC(C)OCC)cc2)nc1
Solvent: c1cncnc1
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCC(C)OCCCCC)cc2)nc1

Procedure:
5-n-octyl-2-[4-(6-ethoxyheptyloxy)phenyl]pyrimidine; 5-n-decyl-2-[4-(6-octyloxyheptyloxy)phenyl]pyrimidine; 5-n-dodecyl-2-4-(6-pentyloxyheptyloxy)phenyl]pyrimidine; 5-n-decyl-2-[4-(6-ethoxyheptyloxy)phenyl]pyrimidine; 5-n-decyl-2-[4-(6-butoxyheptyloxy)phenyl]pyrimidine; 5-n-octyl-2-4-(6-butoxyheptyloxy)phenyl]pyrimidine; and 5-n-decyl-2-4-(6-dodecyloxyheptyloxy)phenyl]pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]([O-])=O.[Na+].[Sn](Cl)(Cl)(Cl)[Cl:21]>Cl.O>[ClH:21].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:13][NH2:16])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(OCc2ccccc2)cc1
Reactant: Cl[Sn](Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(OCc2ccccc2)cc1
Temperature: 3 °C
Reaction time: 1 h

Procedure:
To the suspension of 4-benzyloxyaniline (10 g) in concentrated hydrogen chloride (100 ml) was added dropwise a solution of sodium nitrite (3.2 g) in water (10 ml) over 10min at between −15 and −10° C., and then the mixture was stirred at 3° C. for 1 hr. To the mixture was added dropwise a solution of tin chloride (33.5 g) in concentrated hydrogen chloride (80 ml) at between −20 and −10° C. over 30 min, and then the mixture stirred at 0° C. for 1 hr.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([OH:14])=O)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[CH2:36]([O:35][CH2:34][C@H:16]([NH:15][C:12](=[O:14])[CH2:11][N:8]1[CH2:7][CH2:6][N:5]([CH:2]([CH3:3])[CH3:4])[CH2:10][CH2:9]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)N1CCN(CC(=O)O)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: CC(C)N1CCN(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 45.1 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-isopropylpiperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound III, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-isopropylpiperazin-1-yl)acetamido)propanamide (19.8 mg, 45.1%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (s, 1H), 7.92 (d, 1H), 7.59 (d, 2H), 7.30 (m, 5H), 7.21 (t, 2H), 7.04-6.98 (m, 4H), 4.70 (m, 1H), 4.52 (s, 2H), 3.77 (m, 1H), 3.71 (m, 1H), 2.96 (d, 2H), 2.61 (m, 1H), 2.50 (t, 8H), 0.95 (d, 6H). MS (EI) for C31H37FN4O4. found 549.7 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22]5[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=5[N:20]=4)=[CH:14][CH:13]=3)[C:9](=[O:11])[NH:10][C:3]=12.I[CH2:37][CH3:38].[H-].[Na+].O>CN(C=O)C>[CH2:37]([N:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])[N:8]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:19]3[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:30])[CH3:31])[C:22]4[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=4[N:20]=3)=[CH:16][CH:17]=2)[C:9]1=[O:11])[CH3:38]
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(Oc2nc3ccccc3n2COCC[Si](C)(C)C)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2nccc(C)c21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.15 g), iodoethane (0.027 mL) and sodium hydride (0.015 g) (60% in oil) in DMF (4.0 mL) was stirred at room temperature for 4 h. To the mixture was added H2O, and the mixture was extracted with AcOEt. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-ethyl-7-methyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (90 mg) as pale yellow crystals.