Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>N1C=CC=CC=1>[CH3:24][C:20]1[N:19]=[C:18]([C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=3)[CH:10]=2)=[O:17])[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (10.41 g, 32.5 mmol), p-toluenesulfonyl chloride (6.83 g, 35.8 mmol) and pyridine (75 mL) was stirred at 80° C. for 2 hr. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate-hexane to give the title compound (14.8 g, 96%) as a pale-brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccncc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccncc1F)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 3-fluoropyridin-4-amine (2.20 kg, 19.6 mol) in anhydrous tetrahydrofuran (25 L) was cooled to −5° C. and flushed with nitrogen. This solution was charged with triethylamine (3.99 kg/5.5 L, 39.4 mol). Benzoylchloride (3.173 kg/2.62 l, 22.57 mol) was added drop-wise via an addition funnel over two hours while the internal temperature was maintained between −5° C. to 5° C. and the reaction mixture was left to stand for an additional two hours. The reaction mixture was then filtered and washed with dry tetrahydrofuran (5×20 L). The tetrahydrofuran solution was concentrated under vacuum to give crude product which was recrystallized from ethyl acetate and hexane, filtered and dried to afford N-(3-fluoro-pyridin-4-yl)-benzamide, 3.90 kg, (92%). 1H NMR (400 MHz, CDCl3): δ 8.51 (1H, t, J=5.46 Hz), 8.45 (1H, d, J=2.34 Hz), 8.39 (1H, d, J=5.46 Hz), 8.30 (1H, s), 7.89 (2H, d, J=8.20 Hz), 7.62 (1H, t, J=7.03 Hz), 7.53 (2H, t, J=7.81 Hz).
Reaction SMILES: [OH:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.C(N(CC)CC)C.[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19]>C(Cl)Cl>[N:2]1([O:1][C:18](=[O:19])[C:17]([Br:16])([CH3:22])[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Br)C(=O)ON1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A solution of N-hydroxysuccinimide (NHS) (3.0 g, 26 mmol) in dry methylene chloride (300 mL) was stirred under an inert (argon or nitrogen) atmosphere. Triethylamine (7.3 mL, 52 mmol) was added, the mixture was cooled to 0° C., and 2-bromo-2-methylpropionyl bromide (3.9 mL, 31 mmol) was added dropwise over a period of 15 minutes. The mixture was stirred for 1 hour at 0° C., then warmed to room temperature and stirred overnight. Most of the solvent was removed by evaporation, and the remaining mixture was diluted with cold water (400 mL), and extracted with diethyl ether (3×30 mL), then washed with aqueous potassium carbonate (3×30 mL) and 1M HCl(aq) (3×30 mL). The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated to give a brown solid. Crystallization from ethyl acetate gave the desired product as a white powder (2.62 g, 39%). 1H NMR (CDCl3) δ (ppm) 2.09 (s, 6H, CH3)2Br), 2.88 (s, 4H, HNHS); 13C NMR (CDCl3) δ (ppm) 25.7 (CNHS), 30.8 (C(CH3)2Br), 51.3 (C(CH3)2Br), 167.6 (C═O), 168.7 (CNHS═O).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[CH2:7])[CH2:5][OH:6].Cl[CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14].O>O1CCCC1>[CH3:7][C:4](=[CH2:3])[CH2:5][O:6][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14]
Reactant: C=C(C)CO
Reactant: O=C(O)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)COCc1cccc(C(=O)O)c1
Yield: 85.9 %

Procedure:
To the suspension of Sodium Hydride (1.516 g, 95%, 60 mmol) in tetrahydrofuran (150 ml), 2-Methyl-prop-2-en-1-ol (4.323 g, 4.1 ml, 60 mmol) was added. After the reaction mixture was refluxed for 30 min, 3-Chloromethyl-benzoic acid (4.10 g, 24 mmol) was added and the reaction was kept to reflux for additional 10 h. After cooling down, water (100 ml) was added and the tetrahydrofuran was removed under vacuum. This resulting aqueous solution was adjusted with 6N HCl to pH 2 at 5° C., and the mixture was extracted with Et2O (50 ml×3). The organic phase was combined and washed with water (10 ml×2) respectively. The ether extract was dried with anhydrous sodium sulfate and then concentrated to give 3-(2-Methyl-allyloxymethyl)-benzoic acid as colorless oil (4.25 g, 85.9%). 1H-NMR (400 MHz, d6-DMSO): 7.90 (m, 1 arom.H); 7.85 (m, 1 arom.H); 7.55 (m, 1 arom.H); 7.45 (m, 1 arom.H); 4.96, 4.88 (2 s-like; C═CH2); 4.50 (s, —OCH2—C6H4); 3.90 (s, CH2O); 1.69 (s, CH3). 13C-NMR (100 MHz, d6-DMSO): 167.22 (—C═O); 142.03; 139.00; 131.72; 130.78; 128.56; 128.31; 128.07; 111.71; 73.41; 70.58; 19.30.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH:15]([CH:17]=[CH2:18])=[O:16]>>[CH3:3][C@H:2]([C@@H:15]([OH:16])[CH:17]=[CH2:18])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: C=CC=O
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Product: C=C[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
This compound was prepared according to the procedure of paragraph C, by reaction of N-propionyl-2-benzoxazolone with acrolein. 1H-NMR (CDCl3, 400 MHz) δ 8.06 (m, 1 H), 7.27–7.20 (m, 2 H), 5.91 (ddd, J=17,10, 5 Hz). 5.37 (dt, J=1, 17 Hz, 1 H), 5.24 (dt, J=1, 10 Hz, 1 H), 4.60 (m, 1 H), 4.06 (dq, J=3, 6 Hz, 1 H), 2.62 (d, J=4 Hz, 1 H), 1.30 (d, 6 Hz, 3 H). 13C-NMR (CDCl3, 100 MHz) δ 175.4, 151.1, 142.2, 137.2, 127.7, 125.5, 124.9, 116.6, 116.2, 109.9, 72.7, 44.0, 10.7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][OH:20])[N:18]=1.CC(C)([O-])C.[Na+].Cl[C:28]1[N:29]=[N:30][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]2[CH:42]=[CH:41][N:40]=[N:39]2)=[CH:32][CH:33]=1.C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH:12]=[CH:13][C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:28]2[N:29]=[N:30][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[CH:42]=[CH:41][N:40]=[N:39]3)=[CH:32][CH:33]=2)[N:18]=1
Reactant: OCc1coc(C=Cc2ccc(C(F)(F)F)cc2F)n1
Reactant: Clc1ccc(CCCCn2ccnn2)nn1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(C(F)(F)F)ccc1C=Cc1nc(COc2ccc(CCCCn3ccnn3)nn2)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
{2-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-yl}-methanol (0.114 g, 0.40 mmol) is dissolved in anhydrous tetrahydrofuran (THF) (3 ml) followed by the addition of sodium tert-butoxide (NaOtBu) (0.043 g, 0.43 mmol). After stirring for 15 min at r.t. 3-chloro-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine (0.075 g, 0.32 mmol) is added slowly and stirred for further 4 h at 60° C. Ethyl acetate (20 ml) is added; the mixture is washed with saturated ammonium chloride (NH4Cl), dried over MgSO4 and concentrated in vacuo. After flash column chromatography (ethyl acetate/methanol 98:2) 3-{2-[2-(2-fluoro-4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-6-(4-[1,2,3]triazol-1-yl-butyl)-pyridazine is obtained as a colorless solid. Yield 0.115 g (75%).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:21][C:22](=[S:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>N1C=CC=CC=1>[C:31]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:13]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]([NH:21][C:22](=[S:30])[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:10][CH:11]=2)=[CH:15][CH:16]=1)(=[O:33])[CH3:32]
Reactant: Oc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(-c2cnc(NC(=S)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
Under an argon atmosphere, 3-benzyl-5-(4-hydroxyphenyl)-2-(phenylthioacetyl amino)pyrazine (h-coelenterathioamide) (c-14) (183 mg, 444 μmol) was dissolved in pyridine (2 mL) and cooled to 0° C. To this was added acetic anhydride (55 μL, 0.58 mmol) and stirred for 2 h after warming to room temperature. To this was further added acetic anhydride (25 μL, 0.26 mmol) and stirred at room temperature for 2.5 h. To this was added saturated aqueous solution of sodium bicarbonate and ethyl acetate to stop the reaction, and after separating the aqueous layer and organic layer, the organic layer was washed 3 times with water and once with brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. After purifying the residue by silica gel column chromatography (22 g, n-hexane/ethyl acetate=2/1), the obtained solid was further purified by silica gel column chromatography (7 g, n-hexane/ethyl acetate=2/1) to give 5-(4-acetoxyphenyl)-3-benzyl-2-(phenylthioacetylamino)pyrazine (c-31) as a pale yellow solid (96.3 mg, 47.8%). Rf=0.36 (n-hexane/ethyl acetate=2/1). Mp. 143-145° C. UV (MeOH) λmax (log ε) 320 (4.30), 258 (4.41). UV (pH 7.4 PB) λmax (log ε) 346 (4.36), 274 (4.35). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.95 (s, 2H), 4.14 (s, 2H), 7.00 (d, J=6.6 Hz, 2H), 7.12-7.24 (m, 3H), 7.26-7.32 (AA′BB′, 3H), 7.36 (t, J=7.3 Hz, 2H), 7.51 (d, J=7.5 Hz, 2H), 8.12-8.18 (AA′BB′, 2H), 9.04 (s, 1H), 12.23 (s, 1H). 13C NMR (75.5 MHz, DMSO-d6) δ 20.9, 39.4, 51.6, 122.6 (2C), 126.4, 127.0, 128.0 (2C), 128.3 (2C), 128.4 (2C), 128.9 (2C), 129.0 (2C), 132.8, 136.8, 137.9, 138.6, 145.9, 149.0, 151.9, 152.4, 169.1, 204.7. IR (KBr, cm−1) 700, 1128, 1165, 1179, 1200, 1238, 1368, 1389, 1416, 1441, 1493, 1508, 1730, 3265. HRMS (FAB+) m/z 454.1583 (M+H, C27H24N3O2S requires 454.1589).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:26])([F:25])[C:12]1[CH:13]=[C:14]([N:22]=[C:23]=[S:24])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>C1COCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:23]([NH:22][C:14]2[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=[C:12]([C:11]([F:10])([F:25])[F:26])[CH:13]=2)=[S:24])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: C=Cc1ccc(N)cc1
Reactant: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: C=Cc1ccc(NC(=S)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Yield: 60 %

Procedure:
To a stirred solution of 4-aminostyrene (3.5 mmol) in dry THF (20 mL) under nitrogen was added 3,5-bis-(trifluoromethyl)phenyl isothiocyanate (3.5 mmol). The solution was refluxed overnight and then the solvent was evaporated under reduced pressure. The resulting solid residue was purified by column chromatography to yield the desired product in 60% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Na].Br[CH:11]([CH:15]([CH3:18])[CH2:16][CH3:17])[C:12]([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C@H:11]([C:12]([OH:14])=[O:13])[C@H:15]([CH2:16][CH3:17])[CH3:18])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CCC(C)C(Br)C(=O)O
Agent: [Na]
Product: CC[C@H](C)[C@H](Nc1ccc(Cl)cc1)C(=O)O

Procedure:
N-(4-chlorophenyl)isoleucine is prepared by the reaction of 4-chloroaniline with the sodium salt of α-bromo-3-methylpentanoic acid neat at 100°.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][O:4][CH:3]=1.[CH3:7][C:8]1[N:9]=[CH:10][O:11][C:12]=1[C:13](=[O:16])[CH2:14][CH3:15]>>[O:4]1[CH:5]=[CH:6][C:2]([C:13]([C:12]2[O:11][CH:10]=[N:9][C:8]=2[CH3:7])([OH:16])[CH2:14][CH3:15])=[CH:3]1
Reactant: Brc1ccoc1
Reactant: CCC(=O)c1ocnc1C
Product: CCC(O)(c1ccoc1)c1ocnc1C

Procedure:
Starting with 3-bromofuran and 4-methyl-5propionyloxazole and following the general method of Example 4 the title compound was prepared.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.CCOCC>[CH2:18]([O:11][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: c1ccc(COc2cccc3c2CCCC3)cc1
Yield: 99.1 %

Procedure:
5,6,7,8-tetrahydro-1-naphthol (5.9 g, 39mM) was added to a suspension of potassium carbonate (8.3 g, 60mM) in acetone (100 ml) and heated under reflux for 0.5 hour. Benzyl bromide (7.5 g, 43.8mM) was then added and the mixture was heated under reflux for a further 3 days with stirring. The resulting suspension was filtered and the filtrate was evaporated under reduced pressure to give an oil. This oil was dissolved in ether, washed with water, dried (sodium sulphate) and evaporated to giving an oil which was distilled under high vacuum to give the benzyl ether (3) (9.4 g, b.p. 170°-176° C. at 0.8 mm Hg).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[S:12][C:11]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:10][CH:9]=1)=[O:7])C.Cl>CCO.O>[C:14]1([S:13][C:11]2[S:12][C:8]([C:6]([OH:7])=[O:5])=[CH:9][N:10]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnc(Sc2ccccc2)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc(Sc2ccccc2)s1
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
Potassium hydroxide (1.58 g, 28.2 mmol, 10 eq) is added to a solution of 2-phenylsulfanyl-thiazole-5-carboxylic acid ethyl ester (0.748 g, 2.82 mmol, 1 eq) in EtOH (15 mL) and water (10.5 mL). The reaction is stirred for 1.5 hours, diluted with water (30 mL) and EtOH (30 mL), and acidified by addition of 3 N HCl until a white precipitate forms. The precipitate is filtered and purified by recrystallization from water and EtOH to give the product as a white crystalline solid (0.307 g). MS (ESI) for C10H7NO2S2 m/z 235.9 (M−H)−.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([NH:35][C:36]2[CH:46]=[CH:45][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:38][CH:37]=2)=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24]([C:33]([NH:35][C:36]3[CH:37]=[CH:38][C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:45][CH:46]=3)=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(NC(=O)N2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(NC(=O)N2C[C@H](CN[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 124 mg portion of the ethyl 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)benzoate obtained in Example 41 (1) was dissolved in 3.0 ml of ethyl acetate, and 1.0 ml of 4 M hydrogen chloride/ethyl acetate was added thereto and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol) to obtain 83 mg of ethyl 4-({[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}amino)benzoate as a pale brown amorphous substance.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl[CH2:21][CH2:22][CH2:23][O:24][C:25]1[C:26]2[CH:27]=[CH:28][NH:29][C:30]=2[CH:31]=[CH:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]3[CH2:13][CH2:14][N:15]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[CH:33]=[CH:32][CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)[CH2:16][CH2:17]3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: FC(F)(F)c1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6-trifluoromethyl-3-(piperidin-4-yl)-1H-indole (0.60 g, 2.2 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.65 g, 2.2 mmol) and potassium carbonate (0.46 g, 3.4 mmol). The product was isolated as a white foam. Yield 165 mg(17%). mp 92-97° C. FDMS m/e=442 (M+ of free base).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](OC(N2C=CN=C2)=S)[C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH3:8].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[CH2:9][C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: Cc1ccc(C(OC(=S)n2ccnc2)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Temperature: 25 °C
Yield: 57 %

Procedure:
Tert-butyl (2S)-2-{(3-fluoro-4-methylphenyl)[(1H-imidazol-1-yl carbonothioyl)oxy]methyl}pyrrolidine-1-carboxylate (0.83 g, 1.98 mmol), which had been obtained in Example 1 (1c), and a solution of tributyl tin hydride (1.73 g, 5.94 mmol) and 2,2′-azobis(isobutyronitrile) (0.07 g, 0.40 mmol) in toluene (4 mL) were stirred with heating under reflux for 6 hours. The reaction solution was cooled to room temperature. Water (20 mL) was added to the reaction solution, which was then extracted with ethyl acetate (20 mL×3). After that, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a colorless oily substance (0.33 g, yield 57%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[C:28]#[C:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[NH2:20]
Reactant: C#Cc1cccc(N)c1
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Nc1cccc(C#Cc2cc(C(F)(F)F)ccc2F)c1
Temperature: 70 °C
Yield: 70 %

Procedure:
A multinecked flash as described in Example 1 was charged with 4.93 g (0.020 mol) of 3-bromo-4-fluorobenzotrifluoride, 75 ml of dried, degassed triethylamine, 2.34 g (0.020 mol) of 3-aminophenylacetylene, 0.06 g (0.08 mmol) of bis(triphenylphosphine) palladium II chloride, 0.118 g (0.45 mmol) of triphenylphosphine, and 0.06 g (0.31 mmol) of cuprous iodide. The reaction mixture was heated at 70° C. for 40 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble hydrobromide salt followed by concentration of the filtrate gave the crude product (5.5 g, 89%) as an orange liquid. Short path distillation of the crude product under reduced pressure gave 4.05 g (0.014 mol, 70% yield) of the product as a yellow solid.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C@H:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[S:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:40]([N:44]=[C:45]=[O:46])([CH3:43])([CH3:42])[CH3:41]>C(Cl)Cl>[C:1]([O:5][NH:6][C:7]([C@H:9]1[CH2:14][N:13]([C:45]([NH:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:46])[CH2:12][CH2:11][N:10]1[S:15]([N:18]1[CH2:19][CH2:20][CH:21]([C:24](=[O:32])[C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)(=[O:17])=[O:16])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=C=O
Reactant: CC(C)(C)ONC(=O)[C@H]1CNCCN1S(=O)(=O)N1CCC(C(=O)c2ccc(Cl)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CCN(S(=O)(=O)N2CCC(C(=O)c3ccc(Cl)cc3)CC2)[C@@H](C(=O)NOC(C)(C)C)C1
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of N-tert-butoxy-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide [prepared as described in Example 15, above] (600 mg, 1.23 mmol) in methylene chloride (8 ml) was added triethylamine (0.15 ml, 1.1 mmol) and tert-butyl-isocyanate (0.15 ml, 1.33 mmol). The reaction was stirred for 4 h, concentrated in vacuo, and the residue was chromatographed (SiO2, PTLC, 50% ethyl acetate/hexanes) to give N-tertbutoxy-4-tert-butylaminocarbonyl-1-[4-(4-chlorobenzoyl)piperidine-1-sulfonyl]piperazine-2-(R)-carboxamide (75%) as a clear oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(#N)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: CC#N
Product: CCOC(=O)C(Nc1ccc(F)cc1)c1ccccc1
Temperature: 100 °C
Yield: 72.3 %

Procedure:
4-Fluoroaniline (2.38 ml, 24.8 mmol) was added to a solution of ethyl 2-bromo-2-phenylacetate (4.34 ml, 24.8 mmol) in acetonitrile (50 ml). The reaction was heated under microwave irradiation at 100° C. for 30 minutes. Acetonitrile was evaporated, the residue was taken up with EtOAc and washed with 1N NaHCO3, 1N HCl and brine (100 ml). The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (Petroleum ether/EtOAc=99/1 to 8/2) to afford ethyl 2-(4-fluorophenylamino)-2-phenylacetate (4.90 g, 72.3% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:5]([O:7][CH3:8])=[O:6])[CH3:4].C(Cl)(Cl)Cl.Cl[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1>>[CH3:8][O:7][C:5](=[O:6])[C@H:3]([CH3:4])[NH:2][C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: Clc1nc2ccccc2o1
Reactant: COC(=O)[C@H](C)N
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](C)Nc1nc2ccccc2o1
Temperature: 40 °C
Reaction time: 12 h
Yield: 16.6 %

Procedure:
To the suspension of 0.62 g (6 mmol) methyl alaninate hydrogen chloride salt and 4 ml chloroform 0.79 g (7.8 mmol) triethylamine and 0.46 g (3 mmol) 2-chloro-1,3-benzoxazole are added and the mixture is stirred at 40° C. for 4 hours and at room temperature for 12 hours. The chloroform solution is washed with water, citric acid solution and water, dried over sodium sulfate and evaporated in vacuum. The residue is treated with hexane, the crystals are filtered off and washed. 0.11 g title compound is obtained as white crystals. Mp: 112-113° C.