Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:14]3[C:13](=[O:24])[N:12]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30]C4CCCCO4)[C:11](=[O:37])[N:10]([CH3:38])[C:9]=3[N:8]=2)=[CH:4][C:3]=1[C:41]([F:44])([F:43])[F:42].C(Cl)(=O)C>C(O)C>[Cl:1][C:2]1[CH:40]=[CH:39][C:5]([O:6][C:7]2[N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[C:14]3[C:13](=[O:24])[N:12]([CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30])[C:11](=[O:37])[N:10]([CH3:38])[C:9]=3[N:8]=2)=[CH:4][C:3]=1[C:41]([F:42])([F:43])[F:44]
Reactant: Cn1c(=O)n(CCOCCOC2CCCCO2)c(=O)c2c1nc(Oc1ccc(Cl)c(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: Cn1c(=O)n(CCOCCO)c(=O)c2c1nc(Oc1ccc(Cl)c(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 8-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-3-methyl-1-(2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)ethyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.15 mmol) in ethanol (5 mL) was added acetyl chloride (0.2 mL) at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to give a crude product, which was purified via preparative HPLC to give 8-(4-chloro-3-(trifluoromethyl)phenoxy)-7-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (37 mg, 43.1% yield) as white solid. 1H-NMR (DMSO-d6) δ 7.95(d, 1H), 7.85(d, 1H), 7.77-7.80(m, 1H), 7.44(s, 4H), 5.44(s, 2H), 4.58-4.61(m, 1H), 4.06(t, 2H), 3.59(t, 2H), 3.43-3.46(m, 4H), 3.29(s, 3). LCMS retention time 3.070 min; LCMS MH+ 573.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].[S:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=O>[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Cl-].[Zn+2]>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=2[N:10]=[C:14]2[CH2:15][CH2:16][S:11][CH2:12][C:13]=12
Reactant: O=c1ccccs1
Reactant: N#Cc1ccc(F)cc1N
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])c1ccccc1
Product: Nc1c2c(nc3cc(F)ccc13)CCSC2
Temperature: 50 °C
Yield: 62.4 %

Procedure:
A mixture of 4-fluoroanthranilonitrile (4.47 g) and freshly fused, pulverized ZnCl2 (6.7 g) in 20 ml of nitrobenzene was heated at 50° C. for 45 minutes. To the resulting suspension was added thiopyran-2-one (5.1 g). This was heated at 130° C. for 3 hours. The resulting precipitate was filtered, rinsed with ether and partioned between 2-butanone and NH4OH solution. The aqueous layer was extracted with 2-butanone and the combined organics were washed with water and dried (MgSO4). This resulted in 4.8 g of a tan solid, m.p. 234°-237° C. d., which was recrystallized from ethyl acetate to give 3.0 g of a white powder, m.p. 235°-237° C. d.
Reaction SMILES: [C-:1]1([CH2:6][C:7](Cl)=[O:8])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15].N1C=CC=CC=1.[OH2:22]>CN(C)C1C=CN=CC=1>[C-:1]1([CH2:6][C:7]([OH:8])=[O:22])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Fe+2:15]
Reactant: O
Reactant: O=C(Cl)C[c-]1cccc1
Agent: [Fe+2]
Agent: CN(C)c1ccncc1
Agent: c1cc[cH-]c1
Solvent: c1ccncc1
Product: O=C(O)C[c-]1cccc1
Reaction time: 0.17 h

Procedure:
A 50 ml round-bottom flask, equipped with magnetic stirrer and nitrogen inlet, is charged with 0.50 g (0.19 mmol) of ferrocene acetic acid chloride (prepared in analogy to a process slightly modified from Macromolecules 26 (1993) 1936-1940), 10 ml of pyridine, 1.28 g (0.95 mmol) of brominated and, hydroxymethylated tetra(α-2,4-dimethyl-3-pentyloxy)palladium-phthalocyanine and 12 mg (0.1 mmol) of 4-dimethylaminopyridine under argon, and the dark green solution is stirred for 20 hours at room temperature. The reaction mixture is then poured, with thorough stirring, on 100 ml of water and the precipitate is collected by filtration and washed with 4×50 ml of water. After drying the residue for 4 hours at 60° C. and 125 torr, it is dissolved in 15 ml of toluene and then 1.3 g of silica gel are added and the mixture is stirred for 10 minutes. The suspension is filtered and the residue is washed with 3×10 ml of toluene. Using a rotary evaporator, the filtrate is concentrated by evaporation to 4.8 g of a solution which is then poured, with stirring, on 49 ml of acetonitrile and stirred for 10 minutes. The precipitate is collected by filtration, washed with 3×50 ml of acetonitrile and dried overnight at 60° C. and 125 torr, yielding 1.2 g (80.5% of theory) of a green powder (brominated and hydroxymethylated tetra(α-2,4-dimethyl-3-pentyloxy)palladium-phthalocyanine which is esterified with ferrocene acetic acid) having the following analytical values:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[C:23]=3[CH:24]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:25]([N:16]1[C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:11][CH:10]=3)=[CH:24][C:23]=2[C:22]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(9-benzyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenoxy]-acetic acid methyl ester (0.355 g, 0.834 mmol) was reacted with 1N KOH (1.7 ml) in THF/MeOH (6 ml/4 ml) to give the product (0.261 g, 0.634 mmol, 74%) as a pale-yellow solid, mp 176-180° C. 1H NMR (DMSO-d6) δ 1.77-1.86 (m, 4H), 2.65 (t, J=5.3 Hz, 2H), 2.70 (t, J=6.0 Hz, 2H), 4.69 (s, 2H), 5.33 (s, 2H), 6.96 (d, J=8.7 Hz, 2H), 7.03 (d, J=7.3 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.25-7.30 (m, 3H), 7.39 (d, J=8.6 Hz, 1H), 7.56 (d, J=8.7 Hz, 2H), 7.58 (d, J=1.7 Hz, 1H), 13.00 (broad s, 1H); IR (solid) 3020, 2920, 1740, 1520, 1470, and 1240 cm−1; [ESI(−)], rn/z 410 (M−H)−; Anal. Calcd. for C27H25NO3: C, 78.81; H, 6.12; N, 3.40; Found: C, 78.69; H, 6.21; N, 3.20.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:5][O:4][P:3]([CH2:14][C:8]1[CH:13]=[C:12]2[C:11]([CH:10]=[CH:9][C:8]([CH2:14][P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[CH:13]2)=[CH:10][CH:9]=1)(=[O:2])[O:6][CH3:7]
Reactant: COP(OC)OC
Reactant: Cc1ccccc1
Product: COP(=O)(Cc1ccc2ccc(CP(=O)(OC)OC)cc2c1)OC

Procedure:
The crude product from Example 27(a), a 1:1 mixture of dibromo and tribromo products (assumed to contain 0.010 mole of each), is dissolved in toluene (25 mL) and trimethylphosphite (10 mL, 0.085 mole). The mixture is heated at reflux temperature for 24 h after which excess toluene and trimethylphosphite are removed under reduced pressure. The dark red residue is chromatographed (400 g of 40-63 μm silica gel, 10% methanol in chloroform, 50 mL fractions), with fractions 31-36 containing 4.90 g of material which is rechromatographed (400 g of 40-63 μM silica gel, ethyl acetate, 50 mL fractions). The column is eluted with ethyl acetate (1 L) and then with 10% methanol in ethyl acetate. Fractions 70-92 (2.09 g) still contained two components (tlc, silica gel, 10% CH3OH--CHCl3, 4% CH3OH--CH2Cl2) and is chromatographed (400 g of 40-63 μM silica gel, CH2Cl2, 50 mL fractions) a third time. Elution is with 4% CH3OH--CH2Cl2 through fraction 80 and then with 10% CH3OH--CH2Cl2. Fractions 41-47 contained the desired diphosphonate (1.418 g) as a viscous oil which slowly solidifies. Crystallization from acetone-hexane give crystals, mp 87°-88° C.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[O:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.[OH-].[Na+].Cl>CO.O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:23])=[O:2])=[C:7]([O:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[CH:8]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)CCc1ccc(C(C)(C)C)cc1OC1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(CCC(=O)O)c(OC2CCOCC2)c1
Reaction time: 12 h
Yield: 100.1 %

Procedure:
3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]propionic acid methyl ester (14.1 mg, 0.044 mmol, 1 eq) and sodium hydroxide (8.8 mg, 0.220 mmole, 5 eq) were added in methanol and H2O. The reaction mixture was stirred for 12 hrs. The reaction mixture was acidified with 5% HCl solution. The reaction mixture was concentrated in vacuo to yield 3-[4-tert-Butyl-2-(tetrahydropyran-4-yloxy)phenyl]propionic acid (13.5 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[C:11]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3]1.CCN(C(C)C)C(C)C.[C:17]([O:21][C:22]([NH:24][C:25]1([CH:29]([OH:33])[C:30](O)=[O:31])[CH2:28][CH2:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:33][CH:29]([C:25]1([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:28][CH2:27][CH2:26]1)[C:30]([NH:7][C:4]1[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=1)=[O:31]
Reactant: CC(C)(C)OC(=O)NC1(C(O)C(=O)O)CCC1
Reactant: Cn1ccc(N)n1
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: Cn1ccc(NC(=O)C(O)C2(NC(=O)OC(C)(C)C)CCC2)n1
Reaction time: 2 h
Yield: 92.3 %

Procedure:
1-Methyl-1H-pyrazol-3-amine (158 mg, 1.63 mmol) and DIEA (1.08 mL, 6.52 mmol) was added to a solution of 2-(1-(tert-butoxycarbonylamino)cyclobutyl)-2-hydroxyacetic acid (400 mg, 1.63 mmol) dissolved in DMF (20 mL). The solution was cooled to 0° C. and after 10 minutes HATU (620 mg, 1.63 mmol) was added. After approximately 2 hours at RT, LC-MS showed product and no starting material and the solvent was removed by rotary evaporation. The crude product was dissolved in 40 mL EtOAc and washed with 25 mL sat. NaHCO3(aq). The organic phase was dried with Na2SO4, filtered and evaporated to dryness. The crude product was purified on a 25 g silica column on a Biotage Flashmaster, which gave the title product as a white solid (488 mg, 92%). TLC rf: 0.07 in heptane:ethyl acetate 1:1. [M+H]+=325.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1([CH2:18][CH2:19][Cl:20])[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[Cl-].[Cl-].IC1C=CC=CC=1.Cl.[OH2:31]>N1C=CC=CC=1>[Cl:20][CH2:19][CH2:18][C:4]1([CH2:3][CH2:2][Cl:1])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[S:11](=[O:31])[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: ClCCC1(CCCl)c2ccccc2Sc2ccccc21
Reactant: O
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: Ic1ccccc1
Product: O=S1c2ccccc2C(CCCl)(CCCl)c2ccccc21
Reaction time: 0.25 h

Procedure:
A solution of 9,9-bis(2'-chloroethyl)thioxanthene in pyridine (25 ml.) and water (5 ml.) is cooled in an ice/salt bath to -5° to 0° C. and a solution of iodobenzene dichloride (2.7 g.) in dry pyridine (10 ml.) is added slowly during 15 minutes with stirring. Stirring at 0° C. is continued for a further 15 minutes, the reaction mixture is poured into water, acidified with concentrated hydrochloric acid and extracted with chloroform. The product is crystallised from cyclohexane to give 9,9-bis(2'-chloroethyl)-thioxanthene 10-oxide, m.p. 126°-127° C.
Reaction SMILES: BrC1C=C2C(C=CN2)=CC=1OC.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:25]1[C:33]([O:34][CH3:35])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:25]1[CH:26]=[C:30]2[C:31]([CH:27]=[CH:28][NH:29]2)=[CH:32][C:33]=1[O:34][CH3:35])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1c(OC)ccc2[nH]ccc12
Agent: COc1cc2cc[nH]c2cc1Br
Product: CCOC(=O)C=C(c1ccccc1)c1cc2[nH]ccc2cc1OC

Procedure:
3-(5-Methoxy-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester CXXXIII was prepared from 6-bromo-5-methoxyindole XLVII uisng the procedure described above for preparation of 3-(5-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester XLVIII (Example 12).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1.O.[NH2:25][NH2:26]>C(O)C>[NH:25]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[N:3]=1)[NH2:26]
Reactant: NN
Reactant: FC(F)(F)c1nc(Cl)c(-c2ccccc2)c(-c2ccccc2)n1
Solvent: O
Solvent: CCO
Product: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Yield: 97.1 %

Procedure:
4-Chloro-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (1.8 g, 5.3 mmol) (synthesized according to the procedure described in example 1) was stirred in ethanol (10 ml) containing hydrazine hydrate (0.64 g, 12.8 mmol) for 2 hours at 35° C. The crystals thus obtained in the reaction mixture was filtered under vacuum, washed with ethanol (5 ml) and dried to yield the title compound (1.7 g, 95.7%, HPLC purity 99.2%), mp: 182-186° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl[CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=2[O:19][CH2:18][C:17]1=[O:28].C([O-])([O-])=O.[K+].[K+]>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([CH2:13][CH2:14][CH2:15][N:16]3[C:21]4[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[O:19][CH2:18][C:17]3=[O:28])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C1COc2c(F)ccc(F)c2N1CCCCl
Reactant: C1CC(OCC2CC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)ccc(F)c2N1CCCN1CCC(OCC2CC2)CC1
Yield: 37.3 %

Procedure:
4-Cyclopropylmethoxypiperidine (0.085 g, 0.55 mmol), 4-(3-chloropropyl)-5,8-difluoro-4H-benzo[1,4]oxazin-3-one (0.146 g, 0.56 mmol), K2CO3 (0.152 g, 1.1 mmol), and KI (0.164 g, 1.1 mmol) were mixed according to GP3. Purified by prep TLC (SiO2; Heptanes/EtOAc 1:1) to give the title compound (0.078 g, 37%). 1H NMR (CDCl3) δ 6.82-6.69 (m, 2H), 4.57 (s, 2H), 4.07-4.03 (m, 2H), 3.31-3.22 (m, 3H), 2.72-2.64 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 2.02 (t, J=10.4 Hz, 2H), 1.88-1.76 (m, 4H), 1.59-1.48 (m, 2H), 1.07-0.95 (m, 2H), 0.53-0.47 (m, 2H), 0.19-0.14 (m, 2H); 13C NMR (CDCl3) δ 164.6, 148.3 (dd, J=243.3 Hz, J=2.7 Hz), 147.7 (dd, J=243.9, J=2.8 Hz), 136.6 (dd, J=11.2 Hz, J=4.9 Hz), 120.0 (d, J=11.1 Hz), 111.2 (dd, J=20.4 Hz, J=9.6 Hz), 110.3 (dd, J=24.8 Hz, J=7.7 Hz), 75.0, 72.6, 68.6, 55.6, 51.5, 42.7 (d, J=10.8 Hz), 31.5, 25.7 (d, J=2.7 Hz), 11.1, 3.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH2:17]([N:21]=[C:22]=[S:23])[CH2:18][CH2:19][CH3:20].C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C=CC1C=CC=C(C=C)C=1.C=CC1C(C=C)=CC=CC=1>O1CCCC1>[CH2:17]([NH:21][C:22](=[S:23])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN=C=S
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Agent: C=Cc1ccc(C=C)cc1
Agent: C=Cc1cccc(C=C)c1
Agent: C=Cc1ccccc1C=C
Solvent: C=Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCNC(=S)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Reaction time: 0.17 h

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and poly(4-vinyl pyridine) (50 mg, 0.400 mmol, 2% cross-linked) in tetrahydrofuran (2 mL) were allowed to stand 10 min. Butyl isothiocyanate (41 μL, 0.344 mmol) was added and the reaction mixture was mixed for 96 h at ambient temperature. An addition amount of butyl isothiocyanate (100 μL, 0.829 mmol) was added to the reaction mixture and mixing was continued for another 6 days. Polystyrene methylisocyanate (230 mg, 0.230 mmol, 1% crosslinked poly(styrene-co-divinylbenzene) was added, and the reaction mixture was mixed 7 days at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. Glacial acetic acid (0.5 mL) was added to the filtrate solution and the solution was mixed. This mixture was poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was purified by radial chromatography (silica gel, 1000 micron rotor, methylene chloride:2M ammonia in methanol, 100:2 then 100:4). The solvent was concentrated in vacuo to give 20.3 (53%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([CH3:27])[CH:21]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][C:22]=1[CH3:27]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: COc1ccc(N)c(C)c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c(C)c1

Procedure:
A reaction mixture of 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 164.6 mg (1.2 mmol) of 4-methoxy-2-methyl-aniline and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed under N2 for 3 hr. After removal of the solvent, the residue was diluted with water and neutralized to pH 7-8 with diluted sodium carbonate solution. The precipitate was filtered and washed with water and ether. After drying in vacuo, this yielded 250.2 mg (71.7%) of the product as a off red solid, m.p.>131° C(dec.), mass (electrospray, m/e): M+H 349.9.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].[C-:14]#[N:15].[K+].CCO>O>[CH3:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:2][C:14]#[N:15]
Reactant: Cc1ccc2ccccc2c1CCl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2ccccc2c1CC#N
Temperature: 80 °C
Reaction time: 18 h

Procedure:
1-Chloromethyl-2-methylnaphthalene (5.00 g, 26.3 mmol) and KCN (5.12 g, 78.8 mmol) were combined in H2O (20 mL) and EtOH (40 mL) in a round bottom flask fitted with a reflux condenser. The mix was stirred at 80° C. for 18 hours. TLC analysis (silica, 10% acetone-hexanes) indicated consumption of the starting chloromethylnaphthalene. The reaction was allowed to cool to room temperature and then was diluted with H2O. The dilution was extracted three times with EtOAc. The organic extracts were combined, washed with brine solution, dried over Na2SO4, decanted, and concentrated to give (2-methyl-naphthalen-1-yl)-acetonitrile in quantitative yield. MS (APCI) m/z 180.1 (M−H). 1H NMR (400 MHz) CDCl3 δ 7.96 (d, J=8.4 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.61 (m ,1H), 7.50 (m, 1H), 7.34 (d, J=8.4, 1H), 4.07 (s, 2H), 2.58 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:18])([CH3:17])[CH2:5][CH2:6][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(=O)([O-])O.[Na+]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH2:3][C:4]([CH3:18])([CH3:17])[CH2:5][CH2:6][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1)(=[O:29])=[O:28]
Reactant: CC(C)(CCO)CCSc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CCOS(C)(=O)=O)CCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 304 mg (1.15 mmol) of 5-(5-hydroxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine and 0.16 ml (1.15 mmol) of triethylamine in 5 ml of dichloromethane, 89 μl (1.15 mmol) of methanesulfonyl chloride was added at 0° C., followed by stirring at room temperature for 1 hour, after which saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with dichloromethane and dried, after which the solvent was distilled off to yield 5-(5-methanesulfonyloxy-3,3-dimethylpentylthio)imidazo[1,2-a]pyridine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>CCOCC>[Br:12][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(CO)c(C)c1
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: Cc1ccc(CBr)c(C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5 g of (2,4-dimethylphenyl)methanol are dissolved in 100 ml of ether. The reaction mixture is cooled to 0° C. It is admixed dropwise with 5.2 ml of phosphorus tribromide. It is stirred at ambient temperature overnight. The reaction mixture is poured onto ice and extracted with AcOEt. The organic phase is washed with saturated NaCl solution. The organic phase is dried over MgSO4, filtered and evaporated to dryness. This gives 7.3 g of the expected compound.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[C:27](O)(=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[C:27]([O:1][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:12][N:11]=2)=[CH:8][CH:9]=1)[CH3:3])(=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(C(C)O)cc2)nc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC(C)c1ccc(-c2ncc(OCCCCCCCCCC)cn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.9 %

Procedure:
Into 20 ml of dichloromethane were dissolved 1.78 g (5 millimoles) of the (+)-2-{4-(1-hydroxyethyl)phenyl}-5-decyloxypyrimidine obtained in Preparation Example [starting material compound (VI)]70 and 1.2 g (6 millimoles) of dodecanic acid, and then 1.4 g of N,N'-dicyclohexylcarbodiimide and 0.1 g of 4-pyrrolidinopyridine were added thereto, followed by stirring at room temperature for 24 hours. After completion of the reaction, the precipitates were filtered off and 200 ml of toluene were added thereto, followed by washing with water, 5% acetic acid, water, 5% aqueous sodium hydrogen carbonate solution and water in this order. After the organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; toluene:ethyl acetate) to obtain 2.53 g (yield: 94%) of (+)-2-{4-(1-dodecanoyloxyethyl)phenyl}-5-decyloxypyrimidine. The physical values are shown in Table-1.