Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])=[C:33]([O:44]C)[N:32]=2)=[CH:13]\[C@@H:14]2[N:18](CC3C=CC(OC)=CC=3OC)[C:17](=[O:30])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:31]2[NH:32][C:33](=[O:44])[C:34]([CH2:37][CH2:38][CH2:39][CH2:40][N:41]([CH3:42])[CH3:43])=[CH:35][CH:36]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:30])[NH:18]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(CCCCN(C)C)c(OC)n2)c(OC)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)CCCCc1ccc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)[nH]c1=O
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
48% hydrobromic acid (1.5 mL) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-{5-[4-(dimethylamino)butyl]-6-methoxypyridin-2-yl}ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one in 1,4-dioxane (2 mL), and the mixture was stirred at 65° C. for 30 minutes. The reaction solution was poured into saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. A solution of the residue in trifluoroacetic acid (4 mL) and anisole (2 mL) was stirred at 80° C. for five hours. The reaction solution was poured into saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1→3:1) and solidified with diethyl ether-hexane to give the title compound as a light yellow amorphous (13 mg, 12% (four steps)).
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[C:14]1[C:23]2[C:18](=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16][CH:15]=1>>[F:27][C:24]([F:25])([F:26])[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[C:5]12[CH:8]=[CH:9][CH:10]=[CH:11][CH:4]1[C:3]([NH:2][C:6]2=[O:7])=[O:12]
Reactant: FC(F)(F)c1cccc2c(Br)ccnc12
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1NC(=O)C2(c3ccnc4c(C(F)(F)F)cccc34)C=CC=CC12

Procedure:
N-hydroxy-phthalimide and 4-bromo-8-trifluoromethylquinoline (a known compound) were reacted to obtain 0-(8-trifluoromethyl-4-quinolyl)-phthalimide which was reacted to obtain 0-(8-trifluoromethyl-4-quinolyl)-hydroxylamine melting at 152° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[C:24]([F:31])[CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)c(F)c3)c2CC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)NC(=O)c1ccc(CSc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 3-tert-butoxycarbonyl-6-(4-carboxy-3-fluoro-benzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 2.36 mmol) in DMF (7 mL), add tert-butylamine (12.05 g, 165.2 mmol), EDC (1.81 g, 9.44 mmol) and HOBt (1.44 g, 10.62 mmol) and stir in a sealed tube at 70° C. overnight. Dilute with EtOAc, wash with water, dry over anhydrous MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-6-(4-tert-butylcarbamoyl-3-fluorobenzylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil. MS (APCI+) m/z: 421 (M+H)+. Use a method similar to the General Procedure 1-4 to give the title compound as a white powder. MS (APCI+) m/z: 421 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14](=[O:26])[CH:15]=[CH:16][C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][NH:23]2)=[CH:19][CH:18]=1>O>[CH3:12][O:13][C:14](=[O:26])[CH2:15][CH:16]([C:17]1[CH:25]=[C:24]2[C:20]([CH:21]=[CH:22][NH:23]2)=[CH:19][CH:18]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(=O)C=Cc1ccc2cc[nH]c2c1
Reactant: COc1cccc(B(O)O)c1
Solvent: O
Product: COC(=O)CC(c1cccc(OC)c1)c1ccc2cc[nH]c2c1
Temperature: 90 °C
Reaction time: 6 h
Yield: 61.4 %

Procedure:
To a mixture of 3-methoxyphenylboronic acid (0.23 g, 1.5 mmol) and [RhCl(cod)]2 (49 mg, 0.1 mmol) in degassed water (3 ml) was added 3-(1H-indol-6-yl)-acrylic acid methyl ester XXX (200 mg, 1.0 mmol). The mixture was stirred at 90° C. for 6 hours, cooled to room temperature, and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) to provide 3-(1H-indol-6-yl)-3-(3-methoxy-phenyl)-propionic acid methyl ester XXXI (190 mg, 61% yield) as a yellow film.
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][C:6]12[CH2:17][CH2:16][CH2:15][C:13]3[C:14]1=[C:9]([CH:10]=[CH:11][CH:12]=3)[NH:8][C:7]2=[O:18])=O.Cl.[C:20]([C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])[CH3:21].C(O)(=O)C.C(OCC)(=O)C>ClCCCl>[C:20]([C:23]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:25][N:26]([CH2:1][CH2:3][CH2:4][CH2:5][C:6]23[CH2:17][CH2:16][CH2:15][C:13]4[C:14]2=[C:9]([CH:10]=[CH:11][CH:12]=4)[NH:8][C:7]3=[O:18])[CH2:27][CH2:28]1)(=[O:22])[CH3:21]
Reactant: CC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=CCCCC12CCCc3cccc(c31)NC2=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(=O)C1(c2ccccc2)CCN(CCCCC23CCCc4cccc(c42)NC3=O)CC1
Yield: 23.6 %

Procedure:
2a-(3-Formylpropyl)-2a,3,4,5-tetrahydrobenz[cd]indole-2(1H)-one (180 mg, 0.72 mmol), 4-acetyl-4-phenylpiperidine hydrochloride (190 mg, 0.79 mmol), acetic acid (430 mg, 7.2 mmol) and sodium triacetoxyborate (310 mg, 1.4 mmol) were stirred in 1,2-dichloroethane (3 ml) at a room temperature for 20 hours. The reaction solution was mixed with ethyl acetate (80 ml), washed with sodium hydroxide aqueous solution (1 N) and saturated brine and dried with anhydrous sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated and purified by a silica gel column chromatography to obtain 74 mg of the title compound (0.17 mmol, 24% in yield).
Reaction SMILES: [C:1]([NH:4][C:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:6]([CH3:12])[C:7]([O:9]CC)=[O:8])(=[O:3])[CH3:2].[OH-].[Na+].O.Cl>C(O)(C)C>[C:1]([NH:4][C:5]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[C:6]([CH3:12])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(C)=C(NC(C)=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(=O)NC(=C(C)C(=O)O)c1ccccc1
Yield: 59.2 %

Procedure:
80 g of the product of Step A were stirred for 5 hours in 400 ml of isopropanol and 48.5 ml of sodium hydroxide and the solution was poured into a liter of water taken to pH 1 with concentrated hydrochloric acid. The precipitate was separated, washed with water and dried under reduced pressure to obtain 42 g of the expected product melting at 190° C.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:45])[CH2:33][C:34]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[O:43][CH3:44])=[O:35])=[CH:27][C:26]=3[F:46])[CH:16]=2)=[O:14])[CH2:10]1)(C(C)(C)C)(C)C.CO>>[F:46][C:26]1[CH:27]=[C:28]([NH:31][C:32](=[O:45])[CH2:33][C:34]([NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[O:43][CH3:44])=[O:35])[CH:29]=[CH:30][C:25]=1[O:24][C:21]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:16]=[C:15]([C:13]([N:11]3[CH2:10][CH:9]([OH:8])[CH2:12]3)=[O:14])[S:23][C:22]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O[Si](C)(C)C(C)(C)C)C4)sc23)c(F)c1
Solvent: CO
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CC(O)C4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
To a suspension of N1-(4-(2-(3-(tert-butyldimethylsilyloxy)azetidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-N3-(2-methoxyphenyl) malonamide 275 (179 mg, 0.268 mmol) in MeOH (18 mL) HCl (1N in dioxane, 0.54 mL, 0.54 mmol) was added dropwise and the mixture was stirred for 15 min at room temperature. The solvent was removed under reduced pressure, MeOH was added to the residue and concentrated, the residue was suspended in water and lyophilized affording 271 (104.6 mg, 0.18 mmol, 67% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.68 (s, 1H), 9.64 (s, 1H), 8.64 (d. J=5.5 Hz, 1H), 8.06 (dd, J=1.9 Hz, J=9 Hz, 1H), 7.94 (s, 1H), 7.89 (dd, J=12.9 Hz, J=2.4 Hz, 1H), 7.51 (t, J=8.8 Hz, 1H), 7.46 (dd, J=1.6 Hz, J=8.8 Hz, 1H), 7.11-7.04 (m, 2H), 6.92 (m, 1H), 6.84 (dd, J=5.5 Hz, J=1 HZ, 1H), 6.90 (m, 1H), 4.59 (m, 1H), 4.36-4.31 (m, 2H), 3.88-3.84 (m, 4H), 3.67 (s, 2H). MS (m/z): (M+1) 551.0 (100%).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([NH:18][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[N:25][C:21]=3[N:22]=[CH:23][N:24]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][C:6]=2[NH:18][C:19]2[C:20]3[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[N:25][C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3nc(C(C)C)ccc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(O)cc3)ncnc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.6 %

Procedure:
To a suspension of 4-(4-hydroxy-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid methyl ester (0.50 g, 1.1 mmol) in THF (5 mL) was added aqueous LiOH [prepared from LiOH monohydrate (0.15 g) and H2O (1.5 mL)] dropwise at room temperature. The mixture was stirred at room temperature for 24 hours. Additional aqueous LiOH [prepared from LiOH monohydrate (0.15 g) and H2O (1.5 mL)] was added at room temperature. The mixture was mixture was stirred at room temperature for 23 hours, and then evaporated. The aqueous mixture was diluted with 50 mL of H2O, washed with AcOEt, and treated with active charcoal. The mixture was filtered and the filtrate was carefully acidified to pH 4-5 with 10% HCl under stirring. The resulting solid was collected by filtration, washed with H2O, and dried at 40° C. for 3 days under reduced pressure to give the title compound as pale yellow crystal (0.35 g, 73%). 1H-NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (d, J=7.0 Hz, 6H), 3.22 (septet, J=7.0 Hz, 1H), 6.81-6.90 (m, 1H), 6.85 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 7.63 (br-d, J=8.4 Hz, 1H), 7.73 (br-d, J=8.1 Hz, 1H), 7.85 (br-s, 1H), 8.57 (s, 1H), 8.86 (d, J=8.4 Hz, 1H), 10.14 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH:9]([OH:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[C:9]([C:7]1[O:8][C:4]2[CH:3]=[C:2]([F:1])[CH:13]=[CH:12][C:5]=2[N:6]=1)(=[O:11])[CH3:10]
Reactant: CC(O)c1nc2ccc(F)cc2o1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1nc2ccc(F)cc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.2 %

Procedure:
6-Fluoro-2-(1-hydroxyethyl)benzoxazole (4.71 g, 26 mmol) was dissolved in 100 ml of methylene chloride, and pyridinium chlorochromate (8.38 g, 39 mmol) was added portionwise to the solution. The mixture was stirred for 4 hours at room temperature, then diluted with ether, and filtered. The filtrate was concentrated and the resulting residue was subjected to column chromatography and then recrystallization from methanol to afford 2-acetyl-6-fluorobenzoxazole (1.92 g, yield: 41%).
Reaction SMILES: C[Al](C)C.[CH3:5][CH:6]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[N:19]=[CH:18][C:17]([C:20]([O:22]C)=O)=[CH:16][N:15]=2)[CH2:9]1)[CH3:7].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1>C1(C)C=CC=CC=1>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:41][C:20]([C:17]3[CH:18]=[N:19][C:14]([N:10]4[CH2:11][CH2:12][NH:13][C@@H:8]([CH:6]([CH3:5])[CH3:7])[CH2:9]4)=[N:15][CH:16]=3)=[O:22])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: COC(=O)c1cnc(N2CCN[C@@H](C(C)C)C2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN[C@@H](C(C)C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
Trimethylaluminium (2M in toluene, 1.23 mL, 2.46 mmol) was added dropwise to a stirred suspension of (S)-methyl 2-(3-prop an-2-ylpiperazin-1-yl)pyrimidine-5-carboxylate (260 mg, 0.98 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (243 mg, 0.98 mmol) in toluene (8.38 mL) at room temperature. The reaction was then stirred at 60° C. for 18 h under a nitrogen atmosphere. The reaction mixture was quenched into methanol (100 mL) and treated with HCl (2N aqueous solution, until the pH was 7 or lower). The crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (292 mg, 62%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[N:11]#[C:12][NH2:13].[N+:14]([O-:17])([OH:16])=[O:15].NC(N)=N>>[N+:14]([O-:17])([OH:16])=[O:15].[NH:1]([C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1)[C:12]([NH2:13])=[NH:11]
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: N#CN
Agent: N=C(N)N
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccc2[nH]nnc2c1

Procedure:
5-Guanidinobenzotriazole nitrate was prepared from 5-aminobenzotriazole (790 mg, 5.89 mmol), cyanamide (371 mg, in 0.75 ml H2O, 8.83 mmol) and concentrated nitric acid (0.5 ml) following the method described for the guanidine of Example 1 to give the compound as a brown solid (248 mg). δH (d6DMSO) 9.71 (1H, s), 8.0 (1H, d, J 6.5 Hz), 7.80 (1H, s), 7.41 (4H, s) and 7.26 (1H, d, J 6.7 Hz). MS (ES+) 177 (MH+, 100%).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH3:8].CN(CCC)C(Cl)=O.[H-].[Na+]>C(#N)C>[C:9]([N:7]([CH2:6][CH2:5][C:4]1[CH:3]=[CH:2][CH:18]=[CH:17][CH:16]=1)[CH3:8])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CN(CCc1cccc(O)c1)C(=O)OC(C)(C)C
Agent: CCCN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 128.1 %

Procedure:
To an ice-cooled solution of 3-hydroxy-N-Boc,N-methyl phenethylamine (5.0 g, 19.9 mmol) in dry acetonitrile (65 ml) was added under nitrogen, N-methyl,N-n-propyl carbamoyl chloride (4.66 g, 34.43 mmol), followed by the portionwise addition of NaH (60% disp. in oil, 1.03 g, 25.87 mmol). The reaction mixture was stirred at RT under nitrogen for 6 hrs and evaporated to dryness in-vacuo. Water (200 ml) was added, the pH was adjusted to ˜9 and the aqueous layer was extracted with ether (4×100 ml). The combined ether layer was washed with NaOH solution (pH 9.5), water (150 ml), dried (Na2SO4) and evaporated to dryness in-vacuo to give an oil which was purified by column chromatography (hexane:EtOAc 2:1), affording 6.0 g (86%) of the title compound as a yellow oil.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][C:23]=3[C:33]([F:36])([F:35])[F:34])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH2:64][CH:65]2[CH2:67][O:66]2)=[CH:59][CH:58]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([N:15]3[CH2:14][CH2:13][CH:12]([NH:11][C:10]4[CH:37]=[CH:38][C:7]([CH2:6][CH2:5][NH:4][CH2:67][C@H:65]([OH:66])[CH2:64][O:63][C:60]5[CH:61]=[CH:62][C:57]([OH:56])=[CH:58][CH:59]=5)=[CH:8][CH:9]=4)[CH2:17][CH2:16]3)=[O:19])=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3ccc(-n4cccn4)cc3C(F)(F)F)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O=CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(-n2cccn2)cc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 20 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[4-(1H-pyrazol-1-yl)-2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide formate (0.532 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.404 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.18 g, 0.20 mmol)
Reaction SMILES: C([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH3:18])(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CCSC)N.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:51][O:52][C:53](=[O:76])[C@H:54]([CH2:72][CH2:73][S:74][CH3:75])[N:55](C(=O)C1C=CC(N)=CC=1)[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]>C(Cl)Cl.CCN(CC)CC>[CH3:51][O:52][C:53](=[O:76])[C@H:54]([CH2:72][CH2:73][S:74][CH3:75])[N:55]([C:13](=[O:15])[C:12]1[CH:16]=[CH:17][C:9]([NH2:8])=[C:10]([CH3:18])[CH:11]=1)[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57]
Reactant: Cc1cc(C(=O)O)ccc1NC(=O)OC(C)(C)C
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)c(C)c1
Yield: 85.7 %

Procedure:
N-BOC-4-amino-3-methylbenzoic acid (2.00 g, 7.96 mmol) was reacted with methionine methyl ester hydrochloride (1.75 g, 8.76 mmol), EDCI (1.68 g, 8.76 mmol), HOBT (1.18 g, 8.76 mmol) and Et3N (1.4 ml) in dry CH2Cl2 (31.8 ml) according to the procedure described for N-BOC-4-aminobenzoyl methionine methyl ester in Example 1. The crude material was recrystallized from ethyl acetate and hexanes to yield 2.61 g (85.7%) of pure product. mp 163-165° C.; 1H NMR (CDCl3) 1.54 (9H, s), 2.06-2.18 (4H, m), 2.23-2.34 (4H, m), 2.59 (2H, t, J=6.8 Hz), 3.80 (3H, s), 4.92 (1H, m), 6.45 (1H, s), 6.88 (1H, d, J=7.5 Hz), 7.63 (1H, d, J=8.6 Hz), 7.66 (1H, s), 8.05 (1H, d, J=8.6); 13C NMR (CDCl3) 15.47, 17.61, 28.22, 30.03, 31.55, 51.93, 52.57, 81.04, 118.73, 125.62, 127.66, 129.54, 139.89, 152.34, 166.58, 172.66.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([N:3]2[CH:7]=[CH:6][CH:5]=[CH:4]2)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 736.9 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 2.4 g, 60 mmol) in DMF (100 ml) was added dropwise at an ice bath temperature a solution of pyrrole (3.35 g, 50 mmol) in DMF (5 ml). The mixture was stirred for 30 minutes at room temperature and cooled again. To the mixture was added dropwise a soluton of benzenesulfonylchloride (9.7 g, 5.5 mmol) in DMF (3 ml). The mixture was stirred for 30 minutes at room temperature and poured into ice-water, and extracted with ethylacetate. The extract was washed with water and dried. The solvent was evaporated. The obtained crystal was washed with hexane to give 1-benzenesulfonylpyrrole (8.4 g). Yield: 81%.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[N:24]1[C:28]([N:29]([CH2:31][CH2:32][CH2:33][S:34][CH2:35][CH3:36])[CH3:30])=[C:27]([S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[C:26]([C:44]#[N:45])=[N:25]1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>ClCCCl>[Cl:23][C:15]1[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]([Cl:12])[C:14]=1[N:24]1[C:28]([N:29]([CH2:31][CH2:32][CH2:33][S:34]([CH2:35][CH3:36])=[O:9])[CH3:30])=[C:27]([S:37]([C:40]([F:43])([F:42])[F:41])(=[O:38])=[O:39])[C:26]([C:44]#[N:45])=[N:25]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSCCCN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCS(=O)CCCN(C)c1c(S(=O)(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
m-Chloroperbenzoic acid (0.091 g, 77%, 0.4 mmol) was added to a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(3-ethylthiopropyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole (0.23 g, 0.4 mmol) in 1,2-dichloroethane at 0-5° C. The mixture was stirred at 0-5° C. for 0.5 hour, then poured into saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), evaporated and chromatographed on silica gel eluting with heptane-ethyl acetate (1/1 to 3/7) to give 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-[N-(ethylsulfinylpropyl)-N-methylamino]-4-trifluoromethylsulfonylpyrazole as a light brown oil (Compound number 2-15, 0.186 g, 71%),19F: −63.8, −78.7.