Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8].[CH2:17]([Sn:21](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>>[CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[C:7]([C:9]1[N:10]=[CH:11][N:12]2[CH:16]=[C:15]([Sn:21]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:17][CH2:18][CH2:19][CH3:20])[S:14][C:13]=12)=[O:8]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ncsc1C(=O)c1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3scnc3C)c2s1

Procedure:
The title compound (254 mg) was prepared in substantially the same manner as in step c) of Synthesis Example 1, except that 502 mg of 7-(4-methylthiazol-5-yl)carbonylimidazo[5,1-b]thiazole, 0.598 ml of tri-n-butylstannyl chloride, and 4.0 ml of a 1.0 N lithium bis(trimethylsilyl)amide/THF solution were used as the starting materials.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][C:20]([I:22])=[CH:21][C:15]=2[N:14]=1)=O)(C)(C)C.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[I:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[N:14][C:15]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc(I)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Ic1ccc2[nH]c([C@@H]3CCCN3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring mixture of (S)-2-(5-Iodo-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (20 g, 48 mmol) in CH2Cl2 (200 mL) at 0° C. is added TFA (200 mL). The reaction mixture is stirred at room temperature for 2 hours and concentrated in vacuum. The residue is dissolved in CH2Cl2 and saturated aqueous NaHCO3, the organic layer is washed with saturated aqueous NaHCO3, dried over sodium sulfate and concentrated in vacuum to afford (S)-5-iodo-2-(pyrrolidin-2-yl)-1H-benzo[d]imidazole-TFA salt (12 g).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH2:17][CH3:18])[CH:9]=1)[CH2:4][CH:5]([OH:7])[CH3:6].[C:19]([NH:22][C:23]1[CH:33]=[CH:32][CH:31]=[C:25]2[C:26]([O:28][C:29](=O)[C:24]=12)=[O:27])(=[O:21])[CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH2:17]([O:16][C:10]1[CH:9]=[C:8]([CH:3]([N:2]2[C:29](=[O:28])[C:24]3[C:25](=[CH:31][CH:32]=[CH:33][C:23]=3[NH:22][C:19](=[O:21])[CH3:20])[C:26]2=[O:27])[CH2:4][CH:5]([OH:7])[CH3:6])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15])[CH3:18]
Reactant: CC(=O)Nc1cccc2c1C(=O)OC2=O
Reactant: CCOc1cc(C(N)CC(C)O)ccc1OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CC(C)O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Temperature: 85 °C
Yield: 64.8 %

Procedure:
A mixture of 4-amino-4-(3-ethoxy-4-methoxyphenyl)butan-2-ol hydrochloride (0.5 g, 1.81 mmol), 3-acetamidophthalic anhydride (0.37 g, 1.81 mmol) and triethylamine (0.18 g, 1.81 mmol) in dimethylformamide (10 mL) was heated at 80-90° C. for 7 hours. The mixture was concentrated in vacuo to an oil. The oil was dissolved in ethyl acetate, washed with water, brine, dried, filtered and concentrated to an oil. This oil was purified by chromatography (silica gel, methylene chloride/ethyl acetate 8:2) to give N-{2-[1-(3-ethoxy-4-methoxyphenyl)-3-hydroxybutyl]-1,3-dioxoisoindolin-4-yl}acetamide as a white solid (0.5 g, 65%); mp 132-134° C.; 1H NMR (CDCl3) δ9.54 (s, 1H), 8.73 (d, J=8.4 Hz, 1H), 7.62 (t, J=7.4 Hz, 1H), 7.46 d, J=7.3 Hz, 1H), 7.12-7.08 (m, 2H), 6.83 (d, J=8.0 Hz, 1H), 5.46 (t, J=7.8 Hz, 1H), 4.12 (q, J=7.1 Hz, 2H), 3.84 (s, 3H), 3.80 (m, 1H), 2.59-2.42 (m, 2H), 2.25 (s, 3H), 1.65 (s, 1H), 1.45 (t, J=7.0 Hz, 3H), 1.27 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3) δ170.36, 169.20, 167.96, 149.04, 148.26, 137.29, 135.70, 131.50, 131.35, 124.60, 120.61, 117.85, 113.10, 111.25, 66.00, 64.39, 55.89, 52.43, 40.19, 24.92, 24.33, 14.73; Anal. Calcd. For C23H26N2O6: C, 64.78; H, 6.15; N, 6.57. Found: C, 64.86; H, 6.10; N, 6.46.
Reaction SMILES: [CH3:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH:19]([NH:22][C:23]([C@H:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[NH2:30])=[O:24])([CH3:21])[CH3:20]>CC(N(C)C)=O>[CH:19]([NH:22][C:23]([C@H:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[NH:30][C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([Cl:8])[N:4]=1)=[O:24])([CH3:21])[CH3:20]
Reactant: CC(C)NC(=O)[C@H]1CCC[C@H]1N
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Cl)nc1N[C@@H]1CCC[C@@H]1C(=O)NC(C)C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1 g (6.1 mmol, 1 eq) 5-methyl-2,4-dichloropyrimidine (prepared analogously to A-1a) are dissolved in 3 mL DMA and then 5.3 mL (30.5 mmol, 5 eq) Hünig base are added dropwise. 1.03 g (6.1 mmol, 1 eq) (1S,2R)-2-aminocyclopentanecarboxylic acid isopropylamide are added and the reaction mixture is stirred for 1 h at 70° C. HPLC monitoring shows that the reaction is total and only one regioisomer is formed. The reaction mixture is combined with RP gel, the volatile constituents are eliminated in vacuo, the product is purified by column chromatography through an RP phase and isolated (from water/MeCN (+0.2% HCOOH in each case) from 82/18 to 60/40 in 15 min). Corresponding product fractions are combined, freed from the solvent by freeze-drying and 956 mg of C-1d are obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20]>CN(C)C=O>[CH2:19]([N:21]([CH2:22][CH3:23])[C:2]1[C:3]2[N:4]([C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:20]
Reactant: CCNCC
Reactant: FC(F)(F)c1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccccc2n2c(C(F)(F)F)nnc12

Procedure:
A mixture consisting of 700 mg. (0.0025 mole) of 4-chloro-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline (prepared as described above) and 560 mg. (0.0075 mole) of diethylamine (0.8 ml.) in 10 ml. of N,N-dimethylformamide was stirred at room temperature overnight and then poured over ice. The resulting mixture was then filtered and the recovered solid product washed with water and then dissolved in ethyl acetate. The latter organic solution was next washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there was ultimately obtained a light yellow solid which after recrystallization from diethyl ether gave pure 4-diethylamino-1-trifluoromethyl-[1,2,4]triazolo[4,3-a]quinoxaline. The yield of the first crop melting at 155°-157° C. amounted to 260 mg. (34%), while the yield of the second crop melting at 153°-156° C. amounted to 170 mg. (22%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[C:32](O)(=[O:35])[CH2:33][CH3:34]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:35])[CH2:33][CH3:34])[CH2:28][CH2:27]2)[N:10]=1
Reactant: CCC(=O)O
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 20 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and propionic acid (Aldrich), to give 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-propan-1-one. H RMS, observed: 384.2034; Calcd for (M+H)+: 384.2030.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1)[CH3:20]
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Cc1ccc(-c2nnc(Br)s2)cc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 120 °C
Yield: 97.8 %

Procedure:
To a suspension of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D26) (151 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (203 mg) and tripotassium phosphate (249 mg) in N,N-dimethylformamide (DMF) (6 mL) and water (1.5 mL) under nitrogen was added Pd(Ph3P)4 (54.2 mg). The reaction vessel was sealed and heated under microwave at 120° C. for 10 min. Water was added. The reaction mixture was extracted with EA for 3 times, the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, the dried solution was concentrated, and purified by column chromatography to afford 5-(5-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D30) (185 mg) as a yellow oil. MS (ES): C24H25N3OS requires 403. found 404.2 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:10]2[CH:11]=[C:12]([C:15]3[C:16]([C:39]4[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=4)=[N:17][N:18]([C:20]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1.[N-:46]=[N+:47]=[N-:48].[Na+].[Cl-].[NH4+].O>CN(C)C=O>[NH:46]1[C:44]([C:42]2[S:43][C:39]([C:16]3[C:15]([C:12]4[CH:13]=[CH:14][C:9]5[N:10]([C:6]([C:2]6[S:1][CH:5]=[CH:4][N:3]=6)=[CH:7][N:8]=5)[CH:11]=4)=[CH:19][N:18]([C:20]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:17]=3)=[CH:40][CH:41]=2)=[N:45][N:48]=[N:47]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4nccs4)n3c2)s1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cc(-c3ccc4ncc(-c5nccs5)n4c3)c(-c3ccc(-c4nnn[nH]4)s3)n2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
100 mg 5-[4-(3-thiazol-2-yl-imidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]-thiophen-2-carbonitrile (compound in Example 440) was dissolved in 3 mL N,N-dimethylformamide, and 12 mg sodium azide and 9.5 mg ammonium chloride were added thereto and stirred at 100° C. for 18 hours in a stream of nitrogen. 24 mg sodium azide and 19 mg ammonium chloride were further added thereto and stirred for additional 24 hours. Water was added to the reaction solution which was then extracted with ethyl acetate and purified by silica gel column chromatography (ethyl acetate/hexane), to give 60 mg of the title compound (pale pink solid).
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[NH:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[O:12]>>[CH:11]([C:7]1[N:6]([CH2:2][C:3]([OH:5])=[O:4])[CH:10]=[CH:9][CH:8]=1)=[O:12]
Reactant: O=Cc1ccc[nH]1
Reactant: O=C(O)CBr
Product: O=Cc1cccn1CC(=O)O

Procedure:
In a similar manner, when the halogenated alkanoic acids listed in Table 1 are substituted for bromoacetic acid and reacted with pyrrole-2-carboxaldehyde, the products listed in Table 1 are obtained.
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[C:14]([S:19]([CH3:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:22])[CH:10]=1>C(O)(=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[C:14]([S:19]([CH3:21])(=[O:1])=[O:20])[CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:22])[CH:10]=1
Reactant: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(S(C)=O)c2n1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(S(C)(=O)=O)c2n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 61.3 %

Procedure:
H2O2 (30%, 18.0 mg, 0.53 mmole) was added dropwise to a solution of (3,4-dichlorobenzyl)-(8-methanesulfinyl-2-methylquinolin-4-yl)-amine (50 mg, 0.132 mmole) in acetic acid (3.5 mL) at 0° C. The mixture was stirred at 70° C. for 16 hrs, concentrated by half, 2N NaOH was added and the resulting mixture was extracted with ethyl acetate. The organic phases were dried and concentrated. Precipitation in ethyl acetate gave the product as white solid (32 mg, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33]O)[CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH:29]([CH2:33][O:1][C:2]2[CH:3]=[C:4]([O:9][S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])(=[O:12])=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCC2CCCN(C(=O)OC(C)(C)C)C2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in step c of Example 3, N-(tert-butoxycarbonyl)-3-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step a of Example 2, and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (15 mL) at 0° C. was treated with diethyl azodicarboxylate (349 mg, 2.0 mmol). The reaction mixture stirred at 0° C. for 2 h and at room temperature for 3 h. Water (50 mL) was added and the reaction mixture was extracted into ethyl acetate (3×50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo The residue was purified by flash column chromatography (2:1 ethyl acetate:hexane) to give the title compound as a colorless syrup (875 mg, 88%). 1H-NMR (300 MHz, CDCl3) δ 1.28 (m, 1H), 1.45 (s, 9H), 1.64-1.96 (m, 4H), 2.23 (s, 3H), 2.87 (M, 2H), 3.69 (m, 2H), 3.90 (d, 2H), 6.46 (s, 1H), 6.52 (s, 1H), 6.58 (s, 1H), 7.40 (t, 1H), 7.62 (m, 2H), 7.96 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[S:25][C:26]([CH3:29])=[CH:27][CH:28]=2)[S:22][CH:23]=1>>[N:12]1([CH2:11][CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:18][C:19]3[N:20]=[C:21]([C:24]4[S:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[S:22][CH:23]=3)=[CH:3][CH:4]=2)[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: Cc1ccc(-c2nc(CCl)cs2)s1
Reactant: Oc1ccc(CCCCn2ccnc2)cc1
Product: Cc1ccc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)cs2)s1
Yield: 74 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[4-(4-hydroxyphenyl)butyl]imidazole was reacted with 4-chloromethyl-2-(5-methyl-2-thienyl)thiazole to obtain 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(5-methyl-2-thienyl)thiazole. The yield was 74%. Recrystallization from ethyl acetate-hexane gave pale yellow needles, mp 81-82° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][OH:40])[O: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][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:41](Br)[CH:42]=[CH2:43]>CN(C)C=O.O>[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][O:40][CH2:43][CH:42]=[CH2:41])[O: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][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Sodium hydride (1.78 g. of 50 wt. % dispersion in mineral oil, 37 mmoles) was added at 60° C. to a solution of 1,2-di-O-(n-hexadecyl)-glycerol (10 g., 18.5 mmoles) in N,N-dimethylformamide (100 ml.), and the resulting solution stirred for 20 minutes at 60° C. Allyl bromide (4.47 g., 37 mmoles) was then added dropwise and the resulting mixture stirred for 3 hours at 90° C., cooled, cautiosly diluted with water (200 ml.) to quench the reaction, and extracted with ether (3×150 ml.). The combined ether extract was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene) [10 g., 93% yield, oil, n.m.r. (CDCl3) δ 5.66-6.16 (m, 1, --OCH2CH=CH2), 5.25 (d of doublets, 2, --OCH2CH=CH2) and 4.03 (d, 2, --OCH2CH=CH2)].
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[ClH:15].[CH2:16]([NH:23][CH2:24][CH2:25][Cl:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[ClH:26].[ClH:15].[N:3]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:25][CH2:24][NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Oc1ccc(-n2ccnc2)cc1
Reactant: ClCCNCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CNCCOc2ccc(-n3ccnc3)cc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 39.5 g (0.82 mol) sodium hydride in 500 mL DMF add 37.3 g (0.233 mol) 4-(1H-imidazol-yl)phenol portionwise. Chill the reaction mixture on an ice/MeOH bath during the addition. After addition, stir the reaction mixture at room temperature until gas evolution ceases. After this time, return the reaction mixture to the ice bath and add 50.2 g (0.29 g) N-benzyl-2-chloroethylamine hydrochloride portionwise. After addition is complete, heat the stirring suspension to 65° C. Followthe progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1). At the completion of the reaction, cool to room temperature and slowly add 20 mL H2O. Remove the solidsby suction filtration and evaporate the solvents. Chromatograph the resulting oil on silica gel using (CH2Cl2 :MeOH, 98:2), to isolate the title compound as the free base. Dissolve the free base in excess 3 M methanolic HCl and evaporate the solvents to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:22][CH:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][NH:31][CH3:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:22][CH:23]2[CH2:24][CH2:25][CH:26]([N:31]([CH3:32])[CH3:30])[CH2:27][CH2:28]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(=O)CC3)c2C)c(=O)[nH]1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(Cl)cc(SC3CCC(N(C)C)CC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
To a stirred solution of 5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-((4-oxocyclohexyl)thio)benzamide (0.45 g, 1.03 mmol) and dimethylamine (0.14 g, 3.11 mmol) in dichloroethane (5 mL) was added acetic acid (0.37 g, 6.16 mmol) and the mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (0.66 g, 3.11 mmol) was added at 0° C. and the mixture stirred overnight at room temperature. On completion of the reaction, the solvent was removed under reduced pressure. Water was added to the residue and extraction was performed using 5% MeOH/DCM. The combined organic layers were dried and concentrated to afford crude material which was purified by column chromatography to afford the title compound (0.016 g, 3.3%). Analytical Data: LCMS: 462.35 (M+1)+; HPLC: 89.00% (@ 210-370 nm) (Rt; 4.949; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 7.44 (s, 1H), 7.16 (s, 1H), 6.10 (s, 1H), 4.44 (s, 2H), 3.63 (m, 1H), 3.13 (m, 1H), 2.38 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H), 2.31 (s, 3H), 2.24 (s, 3H), 1.75-2.08 (m, 8H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][NH:11][C:10]=2[CH:14]=1)=O)C.O.[NH2:16][NH2:17]>C(O)C>[NH:11]1[C:10]2[CH:14]=[C:6]([C:4]([NH:16][NH2:17])=[O:3])[CH:7]=[CH:8][C:9]=2[N:13]=[CH:12]1
Reactant: NN
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc2nc[nH]c2c1
Yield: 88 %

Procedure:
30 g of 1H-benzo[d]imidazole-6-carboxylic acid ethyl ester (0.16 mol) and 150 mL anhydrous ethyl alcohol were added to a three-necked bottle, to which 50 mL of 80% hydrazine hydrate was added. After refluxing for 4 h, the ethyl alcohol was evaporated under reduced pressure and water was added to the residual solution to isolate a solid. After sucking filtration and drying, 24.9 g solid was obtained. Yield: 88%. MS: 177 (M+1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:23]
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: ClC(Cl)Cl
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 14.5 g of 3-(2-quinolinylmethyloxy)benzyl alcohol in 150 ml of CHCl3 is added dropwise 7.5 ml of thionyl chloride during 10 min. The reaction mixture is stirred for 4 hours at room temperature, and then washed with NaHCO3 solution. The organic solution is separated, dried, and evaporated to give 3-(2-quinolinylmethyloxy)benzyl chloride which is used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C[O:20][C:21]1[CH:26]=[C:25]([O:27]C)C=C[C:22]=1CCC(C1CCCC1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]2([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[O:13][C:25](=[O:27])[CH2:26][C:21](=[O:20])[CH2:22]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CCC(=O)C2CCCC2)cc1Cl
Reactant: COc1ccc(CCC(=O)C2CCCC2)c(OC)c1
Product: COc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(86), Step 2 substituting 3-(3-chloro-4-methoxy-phenyl)-1-cyclopentyl-propan-1-one from Step 1 above in place of 3-(2,4-dimethoxyphenyl)-1-cyclopentylpropan-1-one. 1H NMR (CDCl3): δ 1.41-1.86 (brm, 8H), 1.96 (m, 2H), 2.29 (t, J=7.6 Hz, 1H), 2.61 (t, J=8.6 Hz, 2H), 2.81 (s, 2H), 3.40 (s, 2H), 3.89, (s, 3H), 6.45 (d, J=8.5 Hz, 1H), 7.0 (d, J=8.5 Hz, 1H), 7.15 (brs, 1H). ESIMS (MH+): 351.8