Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(Cl)Cl.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>Cl>[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: CSc1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CSc1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
4-(methylthio)aniline (500 mg, 3.59 mmol) was dissolved in DCM (10 ml, 155 mmol). Pyridine (1 ml, 12.36 mmol) and methanesulfonyl chloride (0.336 ml, 4.31 mmol) were added, and the reaction was stirred at RT for 3 hours to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was triturated in Petroleum Ether to give N-(4-(methylthio)phenyl)methanesulfonamide (550 mg, 70.5% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[CH3:17][NH:18][O:19][CH3:20].CN1CCOCC1>C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CCOC(C)=O>[CH3:20][O:19][N:18]([CH3:17])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CNOC
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 73.3 %

Procedure:
2-Ethoxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.12 mmol) was reacted with N,O-dimethylhydroxy amine (609 mg), NMM (0.95 ml) and DMTMM (1.47 mg) as described above to give the title compound (1.04 g, 73%) after column chromatography (Hex/EtOAc=5/1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=O.[CH:12](=O)[CH2:13][CH:14]([CH3:16])[CH3:15]>>[CH3:15][CH:14]([CH3:16])[CH2:13][CH:12]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:9]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC(C)CC=O
Product: CC(C)CC=CCCCCCO
Yield: 50 %

Procedure:
9-methyl-6-decen-1-ol was prepared in the same manner according to Example 4 except that 111.56 g (0.5 mol) of ethyl 6-bromohexanoate was used in place of ethyl 5-bromovalerate and 43.07 g (0.5 mol) of isovaleraldehyde was used in place of 2-methyl valeraldehyde.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:14]2)=[CH:9][CH:8]=1>FC(F)(F)C(O)=O>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:14]2)=[CH:9][C:8]=1[N+:1]([O-:4])=[O:2]
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
2.24 ml of fuming nitric acid were added dropwise with stirring to 14.3 g of the product of Step C in 50 ml of trifluoroacetic acid at 0° C. The temperature was allowed to return to ambient and the mixture was stirred for 1 hour. After pouring the mixture on ice, extracting with methylene chloride, washing with water, drying, evaporating to dryness under reduced pressure, and purifying by chromatography over silica (eluent benzene - ethyl acetate 9-1), 12.3 g of 3-(4-methoxy-3-nitrophenyl)-1-(trifluoroacetyl)-piperidine were obtained which after crystallization from isopropyl ether melted at 96° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.O>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:1][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:13][CH:12]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(COC2CCOCC2)cc1
Reaction time: 24 h

Procedure:
A mixture of 2.90 mL of 4-hydroxy-tetrahydropyran in 30 mL of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 0.84 g of sodium hydride (95%, dispersion in mineral oil) in 30 mL of dry N,N-dimethylformamide at 5° C. The resulting clear solution was allowed to come to room temperature and stirring was continued for 24 hours, followed by dropwise addition of 9.40 g of 4-bromo-benzylbromide in 50 mL of dry N,N-dimethylformamide at 5° C. and stirring at room temperature for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (sodium sulfate), and concentrated. The residue was purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 5.40 g of 4-(4-bromo-benzyloxy)-tetrahydropyran as an oil. EI-MS: 270 (M+).
Reaction SMILES: [C:1]([N:20]([CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:30][CH:29]=1)[CH2:21][CH2:22][OH:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN1C(=O)N(C)[CH2:49][CH2:48][CH2:47]1.C(Br)C#C>C1COCC1.C1(C)C=CC=CC=1>[C:1]([N:20]([CH2:24][CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[O:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)=[CH:32][CH:33]=1)[CH2:21][CH2:22][O:23][CH2:49][C:48]#[CH:47])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCN(C)C1=O
Reactant: OCCN(CCOCc1ccc(-c2nc3ccccc3o2)cc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCOCCN(CCOCc1ccc(-c2nc3ccccc3o2)cc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
Dry N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-hydroxyethanamine (8.7 g; 15.7 mmol) is dissolved in THF (50 ml). NaH (1 g; 25 mmol) is added and stirred vigorously at 0° C. for 1 minute then brought to room temperature for 45 minutes. DMPU [1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone] (5 ml) is added followed by propargyl bromide (80 wt %/toluene; 2.1 ml) and stirred for 48 hours. To this is added 0.6 g NaH and 1.5 ml propargyl bromide. After stirring vigorously, an additional 48 hours the reaction mixture is quenched with MeOH, concentrated and purified by column chromatography using 10 Et3N/10 CH2Cl2 /80 petroleum ether. The product is triturated with ether to give solid N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(prop-2-ynyloxy)ethanamine which is used directly in Step F.
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:33][C:34]([F:45])([F:44])[CH2:35]OS(C(F)(F)F)(=O)=O>C1COCC1>[N:1]1([C:11]([C:13]2[CH:17]=[C:16]([CH:18]3[CH2:19][CH2:20][N:21]([CH2:35][C:34]([F:45])([F:44])[F:33])[CH2:22][CH2:23]3)[S:15][CH:14]=2)=[O:12])[C@@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1csc(C2CCN(CC(F)(F)F)CC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Reaction time: 2 h
Yield: 68.9 %

Procedure:
cis-(Octahydro-quinolin-1-yl)-(5-piperidin-4-yl-thiophen-3-yl)-methanone (CC-159) (0.072 g, 0.21 mmol) was dissolved in dry THF (5 mL) and DIPEA (0.66 mmol) was added followed by 2,2,2-trifluoroethyltrifluoromethanesulphonate (0.26 mmol) and the resulting mixture stirred for 2 hours. 2,2,2-Trifluoroethyltrifluoromethanesulphonate (0.26 mmol) was added and the mixture refluxed overnight. The solvent was evaporated and the resulting gum was purified by HPLC eluting with 10%-98% acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (0.06 g). LCMS m/z 415.13 [M+H]+ RT=12.16 min (Analytical Method 2).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:13][C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH2:22][N:21]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:20]2)[S:17][CH:18]=1>CN1CCCC1=O>[CH:1]1([NH:4][CH2:13][C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH:23]([C:25]4[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=4)[CH2:22][N:21]([C:33]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[O:34])[CH2:20]3)[S:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCc1ccc(C2CC(c3nc(CNC4CC4)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
24 mg (0.411 mmol) of cyclopropylamine and 70 mg (0.685 mmol) of triethylamine were added to a solution of 119 mg (0.274 mmol) of the compound from Example 141A in 2 ml of N-methylpyrrolidone. The reaction mixture was stirred at 80° C. overnight. Diastereomer separation of 13 mg of the cis/trans isomer mixture according to Method 15C gave 5 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[S:13])[NH:11][N:12]=2)[O:5][C:6]=1[CH3:7].[Br-].Br[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][NH+:19]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([S:13][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[N:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: BrCCc1cccc[nH+]1
Reactant: Cc1cc(-c2n[nH]c(=S)[nH]2)oc1C
Agent: [Br-]
Product: Cc1cc(-c2nc(SCCc3ccccn3)n[nH]2)oc1C
Yield: 55 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 5a) and 2-(2-bromoethyl)pyridinium bromide (example 8a). Yield 55%. 1H NMR (500 MHz, CDCl3): δ 1.96 (s, 3H), 2.24 (s, 3H), 3.28 (t,2H), 3.49 (t, 2H), 6.77 (s, 1H), 7.13-7.23 (m, 2H), 7.65 (t, 1H) 8.58 (s, 1H). MS(M+H, 301).
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)C(=O)OC(C)(C)C)[CH3:2].Cl.[OH-].[Na+]>CO.O>[CH2:1]([NH:3][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)[CH3:2]
Reactant: CCN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNCCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A solution of tert-butyl ethyl(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (0.4 g, 0.896 mmol) in methanol (10 mL) was treated with 3 N HCl (3.88 mL, 11.64 mmol) and stirred at reflux for 1.5 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and basified with 1N NaOH. The product was extracted into dichloromethane (2×25 mL). The combined organic layer was dried (Na2SO4) and concentrated. The crude material was subjected to column chromatography on silica gel (5:95 (2M NH3 in MeOH):CH2Cl2) to give a yellow solid (0.142 g, 45.8%). 1H-NMR (DMSO-d6) δ 7.69 (dd, J=0.9, 3.6 Hz, 1H), 7.56 (d, J=5.1 Hz, 1H), 7.07 (dd, J=3.6, 4.8 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 6.49 (dd, J=2.1, 8.4 Hz, 1H), 6.45 (d, J=2.1 Hz, 1H), 6.31 (brs, 2H), 3.55-3.51 (m, 2H), 3.30-3.24 (m, 2H), 3.04-3.00 (m, 2H), 2.62 (t, J=6.9 Hz, 2H), 2.56 (q, J=7.2 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); ESI-MS (m/z, %): 347 (MH+, 75%), 276 (100%); HPLC purity: 99.5% by area.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Si:19]([O:36][CH2:37][CH2:38][CH:39]([OH:41])[CH3:40])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.ClCCCl>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:41][CH:39]([CH3:40])[CH2:38][CH2:37][O:36][Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
Triethylamine (4.64 mL), p-toluenesulfonyl chloride (4.66 g) and DMAP (271 mg) were added to a solution of 4-(tert-butyldiphenylsilanyloxy)butan-2-ol (7.3 g; CAS #114079-44-6) in 1,2-dichloroethane (80 mL) at 0° C., and the reaction solution was stirred at 60° C. for three hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. Ethyl acetate and brine were added to the residue, and the organic layer was separated. The resulting organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 6.4 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.Cl.[NH2:15][C:16]1[N:27]=[CH:26][C:25]([Br:28])=[CH:24][C:17]=1[C:18](N(OC)C)=[O:19]>C1COCC1>[NH2:15][C:16]1[C:17]([C:18]([C:2]2[CH:7]=[N:6][C:5]([F:8])=[CH:4][CH:3]=2)=[O:19])=[CH:24][C:25]([Br:28])=[CH:26][N:27]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CON(C)C(=O)c1cc(Br)cnc1N
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1C(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 5-bromo-2-fluoropyridine (5.6 ml, 54.2 mmol) in THF (50 ml) at 0° C. under nitrogen was added dropwise a 2 M solution of iso-propylmagnesium chloride in THF (27 ml) over a period of 10 minutes. The ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The resulting slurry was added dropwise via cannula to a solution of 2-amino-5-bromo-N-methoxy-N-methyl-nicotinamide hydrochloride (3.0 g, 11.5 mmol) in THF (50 ml) at room temperature under nitrogenover a period of 30 minutes. After stirring for 3 hours, the reaction was quenched by addition of a saturated aqueous solution of ammonium chloride (50 ml) at 0° C. and the mixture was stirred at room temperature for another 20 minutes. Water was added and the mixture was extracted with ethyl acetate (three times). The combined organic layers were dried over sodium sulfate, then filtered and concentrated. Crystallization from methanol (ca. 60 ml) afforded the title compound as dark yellow crystals (1.48 g, 49% yield). 1H NMR (DMSO-d6): δ 8.49 (s, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.23 (dt, J=2.5, 8.0 Hz, 1H), 7.81 (d, J=2.5 Hz, 1H), 7.74 (broad s, 2H), 7.36 (dd, J=2.0, 8.0 Hz, 1H); MS: m/z 295.9, 297.9 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=[S:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[CH:17]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:28]([C:17]1[S:14][C:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:15][C:18]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccc(CCC(N)=S)cc1OC
Reactant: COc1ccc(C(=O)C(Br)Cc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc(CCc3ccc(OC)c(OC)c3)sc2Cc2ccccc2)cc1
Yield: 71.6 %

Procedure:
To a 50 ml eggplant-shaped bottle were added 0.12 g (0.533 mmol) 3-(3,4-dimethoxy-phenyl)-thiopropanamide prepared in the step 3, 0.17 g (0.533 mmol) 2-bromo-1-(4-methoxy-phenyl)-3-phenyl-propan-1-one prepared in the step 3 of Example 1, 0.04 g (0.533 mmol) anhydrous sodium acetate and 20 ml anhydrous ethanol. The resulting mixture was refluxed for 4 hours, when TLC showed the completion of the reaction, and concentrated under a reduced pressure. The reaction mixture was partitioned between water and ethyl acetate each 20 ml, the ethyl acetate layer was washed with saturated brine 2×10 ml, dried over anhydrous Na2SO4, filtered and concentrated to give a solid crude product which was recrystallized with petroleum ether and ethyl acetate to obtain a 0.17 g product as a thick liquid in a yield of 70.8%. 1H-NMR (CDCl3, 400 MHz) δ: 3.06 (2H, t, J=8.40 Hz, CH2), 3.25 (2H, t, J=8.40 Hz, CH2), 3.83 (3H, s, CH3O), 3.84 (3H, s, CH3O), 3.86 (3H, s, CH3O), 4.20 (2H, s, CH2), 6.70˜6.80 (3H, m, ArH), 6.95 (2H, d, J=8.80 Hz, ArH), 7.15˜7.35 (5H, m, ArH), 7.54 (2H, d, J=8.80 Hz, ArH); EI-MS m/e (%): 445.1 (M, 100), 151.1 (93); HREI-MS Calcd. for C27H27NO3S: 445.1712. found: 445.1716.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][C:15]3C=NC=[CH:19][CH:20]=3)[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3].[Cl:37]CCCC1OCCO1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH2:15][CH2:20][CH2:19][Cl:37])[CH2:12][C@@H:11]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]([S:28]([C:31]3[S:32][CH:33]=[CH:34][CH:35]=3)(=[O:30])=[O:29])[CH2:9][C:8]=2[CH:36]=1)#[N:3]
Reactant: ClCCCC1OCCO1
Reactant: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2Cc1cccnc1
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)CN(S(=O)(=O)c1cccs1)[C@H](Cc1ccccc1)CN2CCCCCl
Reaction time: 1 h

Procedure:
To a solution of Compound B of Example 23 (410 mg, 1 mmol) dissolved in CH2Cl2 (10 mL) was added 2(chloropropyl)-1,3-dioxolane(0.53 mL, 4 mmol) followed by trifluoroacetic acid (10 mL) and triethylsilane (0.64 mL, 4 mmol). Stirring was continued for 1 hr and the solvent was removed under vacuum. The residue was neutralized with saturated aqueous Na2CO3, diluted with CH2Cl2, washed with brine and evaporated to a yellow solid (500 mg).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:17][CH:18]([F:22])[C:19](O)=[O:20].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:11][CH2:12][CH:13]([O:16][C:19](=[O:20])[CH:18]([F:22])[F:17])[CH2:14][CH2:15]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(C2CCC(O)CC2)CC1
Reactant: O=C(O)C(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC1CCC(C2CCC(OC(=O)C(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 17 h
Yield: 50.8 %

Procedure:
In 40 ml of dichloromethane were dissolved 3.0 g (13 mmol) of 4-(4-propylcyclohexyl)cyclohexanol, 2.3 g (24 mmol) of difluoroacetic acid, and 0.9 g (9 mmol) of triethylamine, and this solution was cooled down to 0° C. To this solution was added dropwise 20 ml of solution of 3.1 g (15 mmol) of DCC in dichloromethane, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 17 hours. After the crystals in the suspension thus obtained were filtered off, the solvent was distilled off under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/toluene=1/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 2.0 g (6.6 mmol) of difluoroacetic acid 4-(4-propylcyclohexyl)cyclohexyl ester. Yield of this compound based on 4-(4-propylcyclohexyl)-cyclohexanol was 51%.
Reaction SMILES: [CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([OH:28])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:43]([N:45]([CH2:48][CH2:49]O)[CH2:46][CH3:47])[CH3:44]>O1CCCC1>[CH2:1]([NH:11][C:12](=[O:30])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[CH2:25][CH:24]([C:26]([O:28][CH2:44][CH2:43][N:45]([CH2:48][CH3:49])[CH2:46][CH3:47])=[O:27])[CH2:23][C:22]2=[O:29])[CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCN(CC)CCO
Reactant: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)O)CC2=O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCCCCCNC(=O)C=Cc1cccc(N2CC(C(=O)OCCN(CC)CC)CC2=O)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 829 mg. of N-decyl-3-(3-[4-carboxy-2-oxo-pyrrolidino]phenyl)propenamide in 25 ml. of tetrahydrofuran was added 357 mg. of carbonyldiimidazole. The mixture was heated under reflux for 10 minutes, and then 258 mg. of 2-(N,N-diethylamino)ethanol was added. The mixture was again heated under reflux for 10 minutes, and then an additional 258 mg. of 2-(N,N-diethylamino)ethanol was added. The mixture was heated under reflux for 15 minutes and then it was cooled to room temperature. The solvent was removed by evaporation in vacuo, and the residue was dissolved in 75 ml. of ethyl acetate. The ethyl acetate solution was washed successively with water, 1 N sodium hydroxide, water and saturated sodium chloride solution. The ethyl acetate solution was then dried using sodium sulfate, and the ethyl acetate was removed by evaporation in vacuo. The residue (960 mg.) was recrystallized from isopropyl ether giving 570 mg. of the title compound, m.p. 78°-80° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8](Cl)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2].[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1[C:8]([C:21]2[CH:22]=[CH:23][S:19][CH:20]=2)=[N:9][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=1)[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1Cl
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)nc1-c1ccsc1
Yield: 68 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (100 mg, 0.357 mmol) was reacted with 3-thienyl boronic acid (2 eq) to give 3-(2-thien-3-yl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid ethyl ester (80 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:15]2[CH:14]=[C:13]([Cl:12])[CH:19]=[C:18]([Cl:20])[CH:17]=2)=[O:8])=[C:4]([OH:11])[CH:3]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cc1O
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1ccc(Cl)cc1O
Yield: 57.2 %

Procedure:
Using 4-chlorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17](N)=[C:12]3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1.[OH:22]S(O)(=O)=O.N([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[CH:16]=[C:17]([OH:22])[C:12]=3[C:11]([CH3:20])=[CH:10]2)=[C:4]([CH3:21])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(N)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(O)c2c(C)cn(-c3c(C)cc(Cl)cc3C)c2n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
With ice-cooling, to a suspension of 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ylamine (17.9 g) in a mixture of 1,4-dioxane (45 mL) and water (45 mL) was added dropwise a mixture of concentrated H2SO4 (17.8 mL) and water (90 mL) and then a solution of NaNO2 (6.2 g) in water (62 mL). The mixture was stirred at room temperature for 20 minutes, and heated at 100° C. for 1.5 hours. After cooling in an ice-cooling bath, the reaction mixture was poured into a cold saturated NaHCO3 aqueous solution and extracted with CHCl3. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with a mixture of ethyl acetate and diisopropylether (1:5) to give 1-(4-chloro-2,6-dimethylphenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-ol (14.4 g).