Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:26])=[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:35](Br)[CH:36]1[O:40][CH2:39][CH2:38][CH2:37]1.O>CN(C=O)C>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:26])[C:12]3[CH:18]=[C:17]([CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)[S:16][C:13]=3[N:14]([CH2:35][CH:36]3[CH2:37][CH2:38][CH2:39][O:40]3)[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: BrCC1CCCO1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(CN3CCOCC3)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccc(Cl)cc1)c1cn(CC2CCCO2)c2sc(CN3CCOCC3)cc2c1=O
Temperature: 60 °C
Reaction time: 18 h
Yield: 3 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-2-(4-morpholinylmethyl)thieno[2,3-b]pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152 mg) are suspended in DMF (10 mL) and to the mixture is added tetrahydrofurfurylbromide (125 μL). The reaction mixture is heated to 60° C. for 4 h and then allowed to stand at room temperature for 18 h. The reaction mixture is poured into water (25 mL) and extracted with EtOAc (3×25 mL). The organic layer is dried (Na2SO4) and concentrated. The resulting crude solid is purified by recrystallization from ethanol to afford 15 mg (3%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:15][C:16]=2[CH3:17])=[O:10])=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(O)(C(F)(F)F)=O.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:12]=[CH:13][C:14]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:15][C:16]=2[CH3:17])=[CH:4][C:3]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1nc(N2CCNCC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 80 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 209 mg of 1-Boc-piperizine in 1 mL of BuOH. The reaction mixture was evaporated to afford tert-butyl 4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate. 150 mg of tert-butyl 4-(5-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-1-carboxylate was treated with TFA (1 mL) containing trace amounts of H2O for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 0.1N sodium hydroxide and brine, dried (MgSO4) and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide. MS (Q1) 408.3 (M)+.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9](O)([CH3:16])[CH:10]([CH3:15])[CH2:11][CH2:12][O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O>>[C:1]1([CH2:7][CH:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([CH3:16])=[C:10]([CH3:15])[CH2:11][CH2:12][O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCC(C)C(C)(O)C(Cc1ccccc1)NCc1ccccc1
Agent: O=S(=O)(O)O
Product: COCCC(C)=C(C)C(Cc1ccccc1)NCc1ccccc1
Yield: 63.3 %

Procedure:
The procedure described in Example 11 is repeated except that 10 g of 1-phenyl-2-(N-benzyl)amino-3-hydroxy-3,4-dimethyl-6-methoxyhexane obtained according to the procedure described in Example 5 is used in place of 1-(p-methoxy)phenyl-2-(N-benzyl)amino-3-hydroxy-3,4-dimethyl-6-methoxyhexane and 95% sulfuric acid is used in place of 93% sulfuric acid. As the result, 6 g of 1-phenyl-2-(N-benzyl)amino-3,4-dimethyl-6-methoxy-3-hexene is obtained as fractions having a boiling point of 191° - 196°C/1 mm Hg.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7](O)=[O:8])([CH3:3])[CH3:2].[NH4+:18]>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([NH2:18])=[O:8])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(N)=O

Procedure:
Prepared in analogy to Example A17(a) from 2-Isopropoxy-5-methanesulfonyl-benzoic acid (example B1) and ammonium hydroxyde. MS (m/e): 258.1 ([M+H+, 100%)
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][CH2:4][OH:5].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O.CCOCC>C(#N)C.O.CCCCCC>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]([CH:2]([N:1]2[C:32](=[O:33])[C:31]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]3[C:29]2=[O:38])[CH2:3][CH2:4][OH:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: CCOc1cc(C(N)CCO)ccc1OC
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CC#N
Product: CCOc1cc(C(CCO)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-amino-3-(3'-ethoxy-4'-methoxyphenyl)-1-propanol (8.4 grams, 37.3 mmol) and sodium carbonate (3.95 grams, 37.3 mmol) in acetonitrile and water (40 mL each) was stirred at room temperature for 15 minutes. To the solution was added N-carbethoxyphthalimide (8.18 grams, 37.3 mmol) as solid. After 20 minutes, the acetonitrile was removed under vacuum. The aqueous solution was extracted with methylene chloride (3×50 mL). The combined organic layers were washed with HCl (40 mL, 1N), and dried over magnesium sulfate. Removal of solvent gave a green oil. Ether (25 mL) was added to the oil, then hexane (2 mL) was added. A suspension formed and the solid was filtered to give 3-(3'-ethoxy-4'-methoxyphenyl)-3-phthalimido-1-propanol as a white solid, 1 g. The mother liquor was purified by chromatography (silica gel 500 grams, 10, 15, 20% EtOAc/CH2Cl2) to give 3-(3'-ethoxy-4'-methoxyphenyl)-3-phthalimido-1-propanol as a solid, 2.54 g. Total yield was 3.54 g (27% yield): mp, 112.0°-114.0° C.; 1H NMR (CDCl3)δ1.45 (t, J=7 Hz, 3H, CH3), 1.59-1.65 (br s, 1H, OH), 2.49-2.59 (m, 1H, CHH), 2.71-2.83 (m, 1H, CHH), 3.66-3.69 (m, 2H, OCH2), 3.84 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, MeCH2), 5.53 (dd, J=6.5, 9.5 Hz, 1H, NCH), 6.81 (d, J=8.2 Hz, 1H, Ar), 7.09-7.27 (m, 2H, Ar), 7.66-7.72 (m, 2H, Ar), 7.76-7.82 (m, 2H, Ar); 13C NMR (CDCl3)δ14.72, 33.86, 51.46, 55.88, 59.84, 64.34, 111.16, 113.05, 120.68, 123.20, 131.64, 131.86, 133.94, 148.17, 148.97, 168.49; Anal Calcd for C20H21NO5 : C, 67.59; H, 5.96; N, 3.94. Found: C, 65.40; H, 5.81; N, 3.84.
Reaction SMILES: [Na].[CH3:2][OH:3].Cl[C:5]1[N:6]=[C:7]([CH3:15])[C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1.[OH-].[Na+].Cl>>[CH3:2][O:3][C:5]1[N:6]=[C:7]([CH3:15])[C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1
Reactant: COC(=O)c1ncc(Cl)nc1C
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [Na]
Product: COc1cnc(C(=O)O)c(C)n1
Temperature: 45 °C
Reaction time: 0.67 h
Yield: 100.9 %

Procedure:
A flask was charged with sodium (0.813 g, 35.4 mmol), purged with Argon. and placed in a room temperature water bath. Methanol (47.7 mL, 1179 mmol) was added slowly. After 40 min, methyl 5-chloro-3-methylpyrazine-2-carboxylate (step 3, 2.2 g, 11.79 mmol) was added. The vessel was sealed and heated to 45° C. for 1.5 hs. Sodium hydroxide (1M, 12.97 mL, 12.97 mmol) was added and heating was continued for 1.5 hs. The reaction mixture was concentrated uncle reduced pressure and the residue was dissolved in a minimum amount of water (50 mL). The aqueous phase was extracted with diethyl ether (15 mL), which was discarded. The aqueous phase was acidified with HCl (5M, 11 mL, 55 mmol). The mixture was extracted with DCM (3×60 mL). The combined organic extracts were dried over MgSO4 and the filtrate was concentrated to afford the title compound (2.0 g, 100%). MS m/z=169 [M+H]+. Calculated for C7H8N2O3: 168. 1H NMR in CDCl3 δ: 10.70 (br, 1H), 7.98 (s, 1H), 4.00 (s, 3H), 2.91 (s, 3H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[CH3:20][O:21][C:22]1[N:27]=[C:26](/[CH:28]=[CH:29]/[C:30]([OH:32])=O)[CH:25]=[CH:24][C:23]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1.[NH2:39][N:40]1[CH2:45][CH2:44][CH2:43][CH:42]([C:46]2[CH:51]=[C:50]([F:52])[C:49]([F:53])=[C:48]([F:54])[CH:47]=2)[C:41]1=[O:55]>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[CH3:20][O:21][C:22]1[N:27]=[C:26](/[CH:28]=[CH:29]/[C:30]([NH:39][N:40]2[CH2:45][CH2:44][CH2:43][CH:42]([C:46]3[CH:47]=[C:48]([F:54])[C:49]([F:53])=[C:50]([F:52])[CH:51]=3)[C:41]2=[O:55])=[O:32])[CH:25]=[CH:24][C:23]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: COc1nc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN1CCCC(c2cc(F)c(F)c(F)c2)C1=O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1nc(/C=C/C(=O)NN2CCCC(c3cc(F)c(F)c(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.4 %

Procedure:
EDC (667 mg), HOBT (470 mg) and IPEA (1.01 mL) were added to a suspension of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic acid (300 mg) and 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one (368 mg) in DMF (10 mL). The reaction solution was stirred at room temperature for 15 hours. Then, water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 508 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CCOCC>[CH:25]([CH:26]1[N:10]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][O:1]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN[C@H](CO)c1ccccc1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CN1C(C(c2ccccc2)c2ccccc2)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 114.1 %

Procedure:
To a solution of tert-butyl (S)-(2-hydroxy-1-phenyl-ethylamino)-acetate (2.5 g, 10 mmole, obtained from Reference Example 9) in anhydrous methylene chloride (35 ml) were added diphenylacetaldehyde (2.16 g, 11 mmole) and magnesium sulfate (1.2 g, 10 mmole) under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 15 h, and diluted with ether. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The oily residue was solidified upon standing, and recrystallized from ether/hexanes to give tert-butyl ((4R)-2-benzhydryl-4-phenyl-oxazolidin-3-yl)-acetate as a white solid (4.9 g, 98%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([N:11]2[CH2:14][CH2:13][CH2:12]2)[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1)=O.[H-].C([Al+]CC(C)C)C(C)C.O>C(Cl)Cl>[C:18]([O:17][C:15]([N:7]1[CH2:8][CH2:9][CH:10]([N:11]2[CH2:12][CH2:13][CH2:14]2)[CH:5]([CH2:3][OH:2])[CH2:6]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1N1CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CCC2)C(CO)C1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-azetidin-1-yl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (373 mg, 1.25 mmol) in anhydrous DCM (10 mL) was slowly added a solution of diisobutylaluminum hydride in hexanes (1M, 3.8 mL, 3.8 mmol) at −70° C. The reaction mixture was allowed to warm to −10° C. over 90 min, then stirred at RT for 15 min. Water was added to the reaction mixture before being loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH to give 4-azetidin-1-yl-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester. To a solution of 4-azetidin-1-yl-3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester in DCM (10 mL) was added TFA (1 mL) and the resulting mixture was stirred at RT for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to give a 1:1 cis:trans mixture of the title compound as a colourless oil (188 mg, 88%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14](S(C)(=O)=O)[N:13]=2)[CH2:6]1)(=[O:4])=[O:3].CS(C)(=O)=O.O1[CH2:49][CH2:48]OCC1>>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH2:8][C@H:7]([NH:11][C:12]2[C:17]([C:18]3[N:19]=[C:20]4[CH:26]=[CH:25][NH:24][C:21]4=[N:22][CH:23]=3)=[CH:16][N:15]=[C:14]([N:19]3[CH2:20][CH2:21][N:22]([C:49]4[CH:48]=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:23][CH2:18]3)[N:13]=2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: C1COCCO1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cnc(S(C)(=O)=O)nc3N[C@H]3CCCN(S(C)(=O)=O)C3)cnc21
Agent: CS(C)(=O)=O
Product: CS(=O)(=O)N1CCC[C@H](Nc2nc(N3CCN(c4ccccn4)CC3)ncc2-c2cnc3[nH]ccc3n2)C1

Procedure:
In a dioxane solution of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methanesulfonyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine derived from Example 84, step 1,1-pyridin-2-yl-piperazine was used to displace the methylsulfone similar to examples above and the de-protection step was similar to step 5, Example 76, to give ((S)-1-methanesulfonyl-piperidin-3-yl)-[2-(4-pyridin-2-yl-piperazin-1-yl)-5-(5H-pyrrolo[2,3-b]pyrazin-2-yl)-pyrimidin-4-yl]-amine. MS: (ES+): 535
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][N:6]=[C:7]=[S:8].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:28]2[C:29]3[CH2:35][CH2:34][NH:33][CH2:32][C:30]=3[S:31][C:27]=2[N:26]2[C:36]([CH3:39])=[N:37][N:38]=[C:25]2[CH2:24][N:23]=1>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[C:28]2[C:29]3[CH2:35][CH2:34][N:33]([C:7](=[S:8])[NH:6][CH2:5][C:4]4[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=4[C:2]([F:13])([F:1])[F:14])[CH2:32][C:30]=3[S:31][C:27]=2[N:26]2[C:36]([CH3:39])=[N:37][N:38]=[C:25]2[CH2:24][N:23]=1
Reactant: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCNC3
Reactant: FC(F)(F)c1ccccc1CN=C=S
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc3c(c1C(c1ccccc1Cl)=NC2)CCN(C(=S)NCc1ccccc1C(F)(F)F)C3

Procedure:
A mixture containing 2-trifluoromethylbenzylisothiocyanate (1 g, 0.0046 mol) and 6-(2-chlorophenyl)-7,8,9,10-tetrahydro-1-methyl-4H-pyrido[4′,3′;4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine (1.22 g, 0.0033 mol) in 20 ml of dichloromethane is agitated at a temperature close to 20° C. for 1 hour. The reaction mixture is evaporated to dryness. 40 ml of ethyl acetate is added to the residual oil. After separation of the insoluble part, the solvent is evaporated off. 40 ml of isopropyl ether is added until precipitation of the product then filtration on frit and washing with isopropyl ether. The solid obtained (1.2 g, 63%) is dried and a beige powder is obtained. Melting point: 178–184° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[N:7][CH:8]=1)=[CH2:2].BrN1C(=[O:20])CCC1=O.[OH-].[Na+]>O.CC(O)(C)C>[O:20]1[CH2:2][CH:1]1[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[N:7][CH:8]=1
Reactant: C=Cc1ccc(-n2cnnn2)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: c1cc(-n2cnnn2)ncc1C1CO1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A solution of 5-ethenyl-2-(1H-tetrazol-1-yl)pyridine (0.664 g, 3.83 mmol) in a 2:1 ratio of H2O:t-BuOH (30 mL) was treated with N-bromosuccinimide in portions over 5 minutes (0.751 g, 4.22 mmol, 1.1 equiv) and stirred at 40° C. for 1 hour. After cooling to 5° C., the reaction was basified with drop wise addition of solution of sodium hydroxide (0.46 g in 5 mL of H2O, 11.50 mmol, 3 equiv) and stirred for another 1 hour. The reaction mixture was poured into H2O (10 mL) and the product was precipitated out as white solid, filtered, washed with water, dried, yielding the title compound.
Reaction SMILES: C[C:2]([CH3:5])([O-:4])[CH3:3].[K+].[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(C1OC1)Br>CC(N(C)C)=O>[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:3][CH:2]2[CH2:5][O:4]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Oc1ccccc1CCCCc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: BrCC1CO1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Reaction time: 0.33 h
Yield: 99.8 %

Procedure:
7.84 g of potassium t-butoxide were added at room temperature to a solution of 15.81 g of 2-(4-phenylbutyl)phenol (prepared as described in Preparation 3) in 350 ml of dimethylacetamide, and the resulting mixture was stirred at the same temperature for 20 minutes, after which 11.46 ml of epibromohydrin were added to it. The mixture was then stirred at room temperature overnight, after which the reaction mixture was partitioned between water and ethyl acetate. The organic layer was then washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 7:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 19.68 g (yield 99.8%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([OH:11])[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:4]([O:22][CH2:23][CH2:24][Cl:25])[C:3]=1[C:26](=[O:28])[CH3:27].O.O.Cl[Sn]Cl.[CH3:34][CH2:35]O>>[C:26]([C:3]1[C:4]([O:22][CH2:23][CH2:24][Cl:25])=[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6]2[O:11][C:34]([CH3:35])=[N:8][C:7]=2[C:2]=1[Cl:1])(=[O:28])[CH3:27]
Reactant: CCO
Reactant: CC(=O)c1c(Cl)c([N+](=O)[O-])c(O)c(OCCCc2ccccc2)c1OCCCl
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(=O)c1c(OCCCl)c(OCCCc2ccccc2)c2oc(C)nc2c1Cl
Temperature: 50 °C
Yield: 64 %

Procedure:
To a stirred solution 37h) (46 mg, 0.11 mmol) in dry EtOH (5 mL) under nitrogen was added SnCl2.2H2O (241 mg, 1.07 mmol). The solution was heated to reflux for 4 h. The solution was concentrated in vacuo and the residue was dissolved in EtOAc (5 mL) and treated with sodium potassium tartrate (1M, 5 mL). The mixture was warmed to 50° C. heated at this temperature until the layers visibly separated. The organic layer was separated and the aqueous further extracted with EtOAc (2×5 mL). The organics were pooled, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was taken up in dry DMF (3 mL) and to this solution triethyl orthoacetate (3 mL, excess) was added. The solution was stirred at reflux for 1 h. The solution was concentrated in vacuo and the residue was taken in CH2Cl2 (5 mL) and washed with water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, ethyl acetate/petroleum spirit 3:18) to give the title compound (30 mg, 64%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.21 (m, 5H), 4.45-4.40 (t, J=6.6 Hz, 2H), 4.29-4.25 (m, 2H), 3.75-3.72 (t, J=5.7 Hz, 2H), 2.89-2.84 (t, J=7.2 Hz, 2H), 2.65 (s, 3H), 2.59 (s, 3H), 2.19-2.09 (m, 2H), ESIMS m/z [M+H]+ 422.2.
Reaction SMILES: [CH3:1][N:2]([CH2:14][CH2:15][CH2:16][CH3:17])[C:3](=[O:13])[CH2:4][C:5]([N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:6].C(=O)=O.C([Li])CCC.[CH2:26]([O:28][CH:29](Br)[CH3:30])[CH3:27].[Br-]>O1CCCC1.C(Cl)Cl.O.C(O)C>[CH2:26]([O:28][CH2:29][CH2:30][CH:4]([C:3]([N:2]([CH3:1])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:13])[C:5]([N:7]([CH3:12])[CH2:8][CH2:9][CH2:10][CH3:11])=[O:6])[CH3:27]
Reactant: CCCCN(C)C(=O)CC(=O)N(C)CCCC
Reactant: CCOC(C)Br
Agent: O=C=O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CCCCN(C)C(=O)C(CCOCC)C(=O)N(C)CCCC

Procedure:
##STR28## 0.1 mol of N,N'-dimethyl-N,N'-dibutyl-propane diamide obtained in example 3(a) dissolved in 400 ml of anhydrous tetrahydrofuran were introduced into a one liter reactor, scavenged by an argon flow. Cooling took place to -50° C. using an acetone bath and solid carbon dioxide and pouring took place of a solution of n-butyl lithium prepared from 0.1 mol of n-butyl lithium in 100 ml of anhydrous tetrahydrofuran. Under the same conditions was prepared a solution of ethoxy-2-ethyl bromide of formula BrCH2 --CH2 --O--C2H5 prepared from 0.1 mol of bromide and 100 ml of anhydrous tetrahydrofuran. With pouring at an end, the temperature was allowed to rise to ambient temperature, followed by refluxing the tetrahydrofuran for three hours. This was followed by cooling and hydrolysis with a water-ethanol mixture. The tetrahydrofuran was expelled and a precipitate formed, followed by taking up with methylene chloride. This was followed by washing with water, drying the organic layer, expelling the solvent before performing chromatography on a silica gel column using as the eluent a mixture of ethyl acetate and cyclohexane (80:20 by volume). A yellow liquid was recovered constituted by 2-ethoxyethyl-N,N'-dimethyl-N,N'-dibutyl-propane diamide. The product was characterized by mass spectrometry, magnetic resonance of the proton and potentiometry, the eld was 40%.
Reaction SMILES: F[C:2]1C=C(SC2N(CC3C=CC=CN=3)C(CCC(OC)=O)=NC=2C(C)C)C=C(F)C=1.[Cl:31][C:32]1[CH:33]=[C:34]([S:38][C:39]2[NH:43][C:42]([CH2:44][O:45]CC3C=CC(OC)=CC=3)=[N:41][C:40]=2[CH:55]([CH3:57])[CH3:56])[CH:35]=[CH:36][CH:37]=1>>[Cl:31][C:32]1[CH:33]=[C:34]([S:38][C:39]2[N:43]([CH3:2])[C:42]([CH2:44][OH:45])=[N:41][C:40]=2[CH:55]([CH3:56])[CH3:57])[CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)CCc1nc(C(C)C)c(Sc2cc(F)cc(F)c2)n1Cc1ccccn1
Reactant: COc1ccc(COCc2nc(C(C)C)c(Sc3cccc(Cl)c3)[nH]2)cc1
Product: CC(C)c1nc(CO)n(C)c1Sc1cccc(Cl)c1

Procedure:
By the same procedures as in Reference Example 2 (1) through (4), 5-(3-chlorophenylthio)-4-isopropyl-2-(p-methoxybenzyloxymethyl)-1H-imidazole (16c) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]1(B(O)O)[CH2:29][CH2:28][CH2:27][CH:26]=1>>[C:25]1([C:2]2[CH:7]=[C:6]([C:8]3[N:12]4[CH:13]=[C:14]([NH:17][CH:18]5[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]5)[CH:15]=[CH:16][C:11]4=[N:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: OC1CCCC(Nc2ccc3ncc(-c4ccnc(Cl)c4)n3c2)C1
Reactant: OB(O)C1=CCCC1
Product: OC1CCCC(Nc2ccc3ncc(-c4ccnc(C5=CCCC5)c4)n3c2)C1

Procedure:
The title compound is prepared from (1SR,3SR)-3-[3-(2-Chloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate Q) and Cyclopent-1-enyl boronic acid using a procedure analogous to that described in Example 2.3.