Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]=[CH:3]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Br:33][C:34]1[CH:39]=[C:38]([CH2:40][NH:41][CH:42]([CH3:44])[CH3:43])[CH:37]=[CH:36][N:35]=1>C(#N)C>[Br:33][C:34]1[CH:39]=[C:38]([CH2:40][N:41]([CH:42]([CH3:44])[CH3:43])[C:7]([C:5]2[N:4]=[CH:3][N:2]([CH3:1])[CH:6]=2)=[O:9])[CH:37]=[CH:36][N:35]=1
Reactant: CC(C)NCc1ccnc(Br)c1
Reactant: Cn1cnc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)N(Cc1ccnc(Br)c1)C(=O)c1cn(C)cn1
Temperature: 25 °C
Reaction time: 23 h
Yield: 97.6 %

Procedure:
After a solution of methyl-1H-imidazole-4-carboxylic acid (1.45 g), 1-hydroxybenzotriazole hydrate (HOBT.H2O) (2.08 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (2.60 g) in acetonitrile (35 mL) was stirred at room temperature for 10 min, a solution of N-[(2-bromopyridin-4-yl)methyl]propan-2-amine (2.59 g) in acetonitrile (15 mL) was added thereto, and the resulting solution was then stirred at room temperature for 23 hr. The solvent was distilled off under reduced pressure, and the residue was then diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution. After extracting with chloroform, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel cartridge, chloroform:methanol=98:2-82:18) and (the same column, chloroform:methanol=98:2-85:15) to afford the title compound (3.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[S:18][C:17]([C:19](Cl)=[O:20])=[C:16]4[CH2:22][CH2:23][CH2:24][CH2:25][C:15]=34)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][CH:32]=1>N1C=CC=CC=1>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:19]([C:17]2[S:18][C:14]([C:11]3[CH2:10][C:9]([C:4]4[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=4)([C:26]([F:27])([F:29])[F:28])[O:13][N:12]=3)=[C:15]3[CH2:25][CH2:24][CH2:23][CH2:22][C:16]=23)=[O:20])=[CH:32][CH:33]=1)(=[O:36])[NH2:37]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2c1CCCC2
Solvent: c1ccncc1
Product: NC(=O)c1ccc(NC(=O)c2sc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c3c2CCCC3)cc1
Yield: 61.8 %

Procedure:
Stir a mixture of 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carbonyl chloride (48 mg, 0.1 mmol) and 4-aminobenzamide (27 mg, 0.2 mmo) in pyridine (3 mL) at ambient temperature overnight. After removal solvent under vacuum, purify the residue by preparative HPLC to afford N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-1-carboxamide as a white solid (36 mg, 62.0%). MS (m/z): 582.1 (M+1). 1H NMR (CDCl3, 400 MHz) δ 7.84 (d, J=8.4 Hz, 2H), 7.65-7.63 (m, 3H), 7.49 (s, 2H), 7.44 (s, 1H), 6.03 (s, 1H), 5.61 (s, 1H), 4.09-4.05 (d, J=16 Hz, 1H), 3.72-3.68 (d, J=16 Hz, 1H), 3.07 (s, 2H), 2.94 (s, 2H), 1.76 (s, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C:10]([CH2:12][C:13](O)=[O:14])=[CH2:11]>CCCCCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:13](=[O:14])[CH2:12][CH:10]([C:9]([OH:17])=[O:16])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)C1CC(=O)N(c2ccc(Br)cc2)C1
Temperature: 130 °C
Reaction time: 0.83 h
Yield: 95.1 %

Procedure:
A mixture of 4-bromoaniline (8.6 g) and itaconic acid (6.5 g) was stirred at 130° C. for 50 minutes. After cooling, a n-hexane-ethyl acetate mixed solution was added to the resulting solid. The compound was collected by filtration to obtain the title compound (13.5 g).
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][C:13]3[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: COC(=O)c1ccccc1CBr
Agent: N#Cc1ccc(CCl)cc1
Product: COC(=O)c1ccccc1CN1CCN(c2nc(C)c(C(=O)NCc3ccccc3)s2)C1=O
Yield: 52 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with methyl 2-(bromomethyl)benzoate (prepared according to Dvornikovs, V., and Smithrud, D. B., J. Org. Chem., (2002), 67, 2160-2167) to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 52% yield: mp 130-133° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.97-7.94 (m, 1H), 7.51-7.27 (m, 8H), 5.95 (br s, 1H), 4.90 (s, 2H), 4.56 (d, J=5.6 Hz, 2H), 4.10-4.05 (m, 2H), 3.90 (s, 3H), 3.56-3.51 (m, 2H), 2.62 (s, 3H); MS (ES+) m/z 465.2 (M+1).
Reaction SMILES: CO.C1COCC1.[OH:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30]/[C:31](=[N:38]\[O:39][CH3:40])/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:10][C:11]([O:13]C)=[O:12].[OH-].[Na+]>O>[OH:8][CH:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30]/[C:31](=[N:38]\[O:39][CH3:40])/[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][CH:24]=2)=[CH:19][CH:20]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)OC)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.6 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 2 mL of Methanol and 2 mL of THF. To the stirred solvent was added methyl 3-hydroxy-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoate (0.04 g, 0.08 mmol) and NaOH was added followed by water (0.5 mL). Then it was stirred at RT for 12 h, after completion of the reaction (reaction monitored by TLC), reaction mixture was evaporated completely and the crude was washed with ether, and diluted with water and then neutralized with 1N HCl, then extracted with ethyl acetate, organic layer was washed with water and brine, dried over Na2SO4. The organic layer was evaporated on rotavapor under reduced pressure to give the product as a white colour solid. (0.02 g, yield: 52.6%); Purity: 45.3% and 43.6%.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:27]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C.O>ClCCl>[N:27]1([C:33]([N:14]2[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11][CH:12]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=3)[CH2:13]2)=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)c1ccc(C2CNCC(NC(=O)c3ccccc3)C2)cc1
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 25 °C

Procedure:
At 0° C., 500 mg (1.42 mmol) of ethyl 4-{5-[(phenylcarbonyl)amino]piperidin-3-yl}benzoate were initially charged in 8 ml of dichloromethane, and 424 mg (2.84 mmol) of morpholine-4-carbonyl chloride and 300 μl (2.13 mmol) of triethylamine were added. The mixture was slowly warmed to RT overnight. Water was added, and the reaction mixture was extracted. The organic phase was dried over magnesium sulphate and concentrated under reduced pressure. The residue was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 551 mg (83% of theory)
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1>ClCCl.O>[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][C:14]=1[Br:1]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1ccc(N)c(Br)c1
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of bromine (7.0 mL, 137.3 mmol) in dichloromethane is added dropwise to a cold (−10° C.) solution of ethyl 4-aminobenzoate (22.0 g, 133.3 mmol) in dichloromethane. The reaction mixture is allowed to come to room temperature, stirred for 18 h and diluted with water. The organic phase is separated, washed twice with brine, dried over MgSO4 and concentrated in vacuo. The resultant residue is purified by flash chromatography (SiO2, 8/1 hexanes/EtOAc as eluent) to afford the title compound as a white solid, 28.6 g (88% yield), identified by HNMR and mass spectral analyses. MS m/e 242 (M−H)+; 1H NMR (400 MHz, DMSO-d6) δ 1.28 (t, J=7.01 Hz, 3H), 4.22 (q, J=7.16 Hz, 2H), 6.18 (brs, 2H), 6.81 (d, J=7.91 Hz, 1H), 7.65 (dd, J=8.54, 1.98 Hz 1H), 7.89 (d, J=1.83 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH3:20]>CN(C)C=O>[CH2:19]([O:12][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:20]
Reactant: CCBr
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 84.5 g. (0.5 m.) of 2-nitro-4-methoxyphenol (part A), 338 g. of K2CO3 and 1200 ml. of dimethylformamide was heated on a steam bath for 60 minutes, then there was added dropwise, 76.7 ml. (108.98 g. 1.0 m.) of ethyl bromide. The mixture was heated and stirred overnight, then poured into 5 liters of ice water. The product was collected by filtration, washed with H2O and air-dried to give 92 g. m.p. 37°-39°C.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH2:22][C:23](=[O:42])[NH:24][C:25]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([N:36]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH3:37])=[CH:28][C:26]=4[N:27]=3)[CH:16]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>>[CH2:38]([N:36]([CH3:37])[C:29]1[C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:25]2[NH:24][C:23](=[O:42])[CH2:22][C:21]([C:17]3[CH:16]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=4)[CH:20]=[CH:19][CH:18]=3)=[N:27][C:26]=2[CH:28]=1)[CH:39]([CH3:41])[CH3:40]
Reactant: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c1)=N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(S(N)(=O)=O)cc3)c1)=N2

Procedure:
) The title compound was prepared from the above described 3′-[8-(isobutyl-methyl-amino)-4-oxo-7-trifluoromethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-biphenyl-4-sulfonic acid tert-butylamide (250 mg) and TFA (5 mL) according to the general procedure I step 2. Obtained as a white solid (107 mg, 39%). MS (ISN) 543.5 [(M−H)−]; mp 236° C. (dec).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:12]([NH:14][C:15]2[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=2)[O:18][C:19]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:20]=2[C:21]([O:23][CH3:24])=[O:22])=[O:13])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[CH3:4])#[N:2].CO.O1CCCC1>CN1CCCC1=O.[C].[Pd]>[NH2:29][C:26]1[CH:27]=[CH:28][C:19]([O:18][C:17]2[CH:32]=[CH:33][CH:34]=[C:15]([NH:14][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:3]([C:1]#[N:2])([CH3:4])[CH3:5])[CH:7]=3)=[O:13])[CH:16]=2)=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Agent: [Pd]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)ccc1Oc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.5 %

Procedure:
To a solution of methyl 2-[3-({[3-(1-cyano-1-methylethyl)phenyl]carbonyl}amino)phenoxy]-5-nitrobenzoate (4.00 g, 8.70 mmol) in 1-methylpyrrolidin-2-one (20 mL)/methanol (40 mL)/tetrahydrofuran (10 mL) was added 10% palladium-carbon (400 mg), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere (1 atm). Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (200 mL), washed successively with water (100 mL×2) and saturated brine (100 mL×2), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (3.42 g, 92%) as a pale-yellow oil.
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([N:16](C(C)(C)C)[C:17]1[CH:18]=C2C(=O)OC(=O)[C:20]2=[CH:26][CH:27]=1)(C)(C)[CH3:13].C(C1C=C(C)C=C2C(OC(=O)C=12)=O)CC>>[CH2:12]([N:16]1[C:4]2[C:26](=[CH:20][CH:1]=[C:2]3[CH:10]=[CH:9][CH:8]=[CH:7][C:3]3=2)[CH:27]=[C:17]1[CH3:18])[CH3:13]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)N(c1ccc2c(c1)C(=O)OC2=O)C(C)(C)C
Agent: CCCc1cc(C)cc2c1C(=O)OC2=O
Product: CCn1c(C)cc2ccc3ccccc3c21

Procedure:
Also used as (I) are p-di-t-butylamino phthalic anhydride, p-dihexylaminophthalic anhyride, 3-propyl-5-methylphthalic anhydride, and the like.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]2[CH:44]=[C:43]([C:45]([CH3:51])([CH3:50])[C:46]([F:49])([F:48])[F:47])[O:42][N:41]=2)=[O:38])=[C:32]([F:52])[CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]3[CH:44]=[C:43]([C:45]([CH3:50])([CH3:51])[C:46]([F:49])([F:48])[F:47])[O:42][N:41]=3)=[O:38])=[C:32]([F:52])[CH:31]=2)[CH:7]=[N:6][C:5]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:2]
Reactant: CCOc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OCc1ccc(OC)cc1
Reactant: CC(C)(c1cc(NC(=O)Cc2ccc(Br)cc2F)no1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)on3)c(F)c2)cnc1OCc1ccc(OC)cc1
Yield: 19.9 %

Procedure:
To a mixture of 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (60 mg, 0.156 mmol), 2-(4-bromo-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (63.7 mg, 0.156 mmol) in H2O (1 mL) and 1,4-dioxane (3 mL) was added cesium carbonate (101 mg, 0.311 mmol) and PdCl2(dppf) (11.40 mg, 0.016 mmol) under a N2 atmosphere. Then the mixture was stirred and irradiated in a microwave oven at 120° C. for 30 min. The mixture was concentrated and extracted with EA. The combined organic was concentrated and the crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.5) to give a yellow solid of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (20 mg, 0.031 mmol, 19.9% yield): 1H NMR (400 MHz, CD3OD) δ: 7.97 (d, J=2.0 Hz, 1H), 7.47 (d, J=2.0 Hz, 1H), 7.46-7.37 (m, 5H), 6.97-7.89 (m, 3H), 5.39 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.85 (s, 2H), 3.83-3.79 (m, 3H), 1.60 (s, 6H), 1.45 (t, J=7.0 Hz, 3H); ES-LCMS m/z 588 (M+1).
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:5])=[O:4].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[C:29]([NH:36][C@H:37]([C:47](O)=[O:48])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[N:46])[CH:40]=1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C1COCC1>[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:47](=[O:48])[C@H:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]#[N:46])[CH:40]=2)[NH:36][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#N)c1)C(=O)O
Reactant: CS(=O)(=O)N1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(C#N)c1)C(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4.92 g (24.5 mmol) of 1-methylsulfonylpiperazine hydrochloride and 2.7 ml (24.5 mmol) of NMM was dissolved in 50 ml of DMF. After addition of 4 g (29.6 mmol) of HOBt and a solution of 5.93 g (20.4 mmol) of Boc-3-cyano-(L)-phenylalanine in 200 ml of THF, the mixture was cooled to O° C. 5.1 g (24.7 mmol) of DCC were added and the mixture was stirred for 48 hours at room temperature. Afterwards, the precipitated dicyclohexyl urea was filtered off, the THF moiety of the solution evaporated under reduced pressure, filtered and the filtrate poured into a mixture of 100 ml of 5% sodium bicarbonate solution and 200 ml of ice water. The formed precipitate was filtered off, washed with water, dissolved in methanol and the solvent was evaporated under reduced pressure. To remove the still present water, a co-distillation with toluene/isopropanol was performed several times. The only slightly impure product was processed in this form. Yield: 7.9 g (89%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][NH2:22]>O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][NH:22][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH2:13][CH2:14][CH3:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCCOc1cccc2c(Cl)cc(C)nc12
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: CCCOc1cccc2c(NCc3ccc(Cl)c(Cl)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 5, method 5.1. Starting materials were 4-chloro-2-methyl-8-propoxyquinoline and 3,4-dichlorobenzylamine. A catalytic effective amount of copper(II)sulphate hydrate was added to the reaction mixture. The product was purified using silica gel chromatography, eluting with dichloromethane:methanol 90:10.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:14]([O:13][C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C:5]([CH2:3][OH:2])([CH3:18])[CH2:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a 0° C. stirred solution of Intermediate 54 (1.17 g, 4.56 mmol) in dry THF (20 ml) was added LiAlH4 (1.0 M in THF, 9.11 ml, 9.11 mmol) dropwise and the reaction was allowed to warm to room temperature. Upon completion as indicated by TLC, the reaction was carefully quenched with saturated NH4Cl and EtOAc was added. The layers were separated, the aqueous layer was extracted with EtOAc (3×15 ml) and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to yield 0.844 g (42.1%) of 3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 55). 1H NMR (400 MHz, CDCl3) δ ppm 0.9 (s, 3H), 1.3 (m, 2H), 1.5 (s, 9H), 1.5 (m, 3H), 2.9 (s, 1H), 3.1 (s, 1H), 3.5 (d, J=11.5 Hz, 1H), 3.8 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Cl)=[CH:3][CH:2]=1.[SH:10][CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][S:10][CH2:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: ClCCc1ccncc1
Reactant: OCCS
Product: OCCSCCc1ccncc1

Procedure:
Using the procedures of Examples 1 to 4, 2-(4-pyridyl)ethyl chloride is reacted with 2-mercaptoethanol to yield 4-[2-(2-hydroxyethylthio)ethyl]pyridine, with 3-mercapto-2-butanol to yield 4-[2-(3-hydroxy-2-butylthio)ethyl]pyridine, with 3-mercapto-1,2-propanediol to yield 4-[2-(2,3-dihydroxy-1-propylthio)ethyl]pyridine, with 2-mercaptophenol to yield 4-[2-(2-hydroxyphenylthio)ethyl]pyridine, with methyl mercaptoacetate (preferably in methanol rather than ethanol solution) to yield methyl 2-[2-(4-pyridyl)ethylthio]acetate and with mercaptoacetone to yield 2-(4-pyridyl)ethylthioacetone.
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([CH:13]2OCC[O:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:8]1[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2ccc(C3OCCO3)o2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(Cc2ccccc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
The resulting 2-(5-benzyl-furan-2-yl)-[1,3]dioxolane (3.8 g, 16.5 mmol) was suspended in a mixture solution of methanol (15 mL), tetrahydrofuran (10 mL) and 2N hydrochloric acid (15 mL), and the solution was stirred at room temperature for 2 hours. Ethyl acetate and an aqueous solution of sodium bicarbonate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice and dried over anhydrous sodium sulfate. The solvent was evaporated, and the title compound (2.5 g, 13 mmol) was obtained as a brown oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:11]([S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[C:12]=1[Br:13].[I-].[Na+].[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>O1CCCC1.CCCCCC.O>[Br:7][C:8]1[N:9]([CH2:33][O:32][CH2:30][CH3:31])[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:11]([S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])[C:12]=1[Br:13]
Reactant: O=S(=O)(c1c(-c2ccc(Cl)cc2)[nH]c(Br)c1Br)C(F)(F)F
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCOCn1c(Br)c(Br)c(S(=O)(=O)C(F)(F)F)c1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 74.2 %

Procedure:
A solution of potassium tert-butoxide (0.62 g, 0.0055 mol) in tetrahydrofuran is treated with 2,3-dibromo-5-(p-chlorophenyl)-4-[(trifluoromethyl)sulfonyl]pyrrole (2.34 g, 0.005 mol), stirred for 15 minutes, treated with sodium iodide (0.82 g, 0.0055 mol), stirred for five minutes, treated with a solution of chloromethyl ethyl ether (0.52 g, 0.0055 mol) in tetrahydrofuran, stirred at room temperature for several hours, poured into water and extracted with ether. The combined organic extracts are washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give an orange oil. The oil is slurried in hexane and filtered to obtain the title product as a pale yellow solid (1.95 g, mp 1330°-1350° C.) which is identified by 1HNMR and 19FNMR spectral analyses.