Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:19][CH:18]=[CH:17][N:13]3[C:14](=[O:16])[CH:15]=2)=[CH:4][CH:3]=1.[I:20]I.O>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[N:11]=[C:12]3[S:19][CH:18]=[CH:17][N:13]3[C:14](=[O:16])[C:15]=2[I:20])=[CH:4][CH:3]=1
Reactant: O=c1cc(/C=C/c2ccc(Cl)cc2)nc2sccn12
Reactant: II
Solvent: CC#N
Solvent: O
Product: O=c1c(I)c(/C=C/c2ccc(Cl)cc2)nc2sccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Step 2 intermediate (3.0 g, 0.018 mmol), iodine (2.75 g, 0.018 mmol) and ceric ammonium nitrate (CAN) (4.93 g, 0.009 mmol) in CH3CN (30 ml) was stirred at 80° C. for 2 h. The reaction mixture was allowed to cool to room temperature. Distilled water (50 ml) was added to the residue obtained after concentration of the reaction mixture and stirred at room temperature for 1 h. The reaction mixture was filtered, dried under vacuum to give 5.30 g of the product as a light yellow solid; 1H NMR (300 MHz, CDCl3) δ 6.87 (d, J=15.6 Hz, 1H), 6.94 (d, J=4.8 Hz, 1H), 7.33 (d, J=9.0 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.73 (d, J=15.6 Hz, 1H), 7.90 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 289.37 (M+H)+.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1.C(O)(=O)C.C(=O)(O)[O-].[Na+].Cl[C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=1>CS(C)=O.O>[CH3:32][N:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([C:22]2[C:21](=[O:33])[NH:20][C:19](=[O:34])[C:18]=2[C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:8][CH2:7][CH2:6][NH:5][C:45]3[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][CH:48]=[CH:47][N:46]=3)[CH:10]=2)=[CH:24]1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cn1cc(C2=C(c3cn(CCCN)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: O
Product: Cn1cc(C2=C(c3cn(CCCNc4ncccc4[N+](=O)[O-])c4ccccc34)C(=O)NC2=O)c2ccccc21
Temperature: 100 °C
Yield: 52.9 %

Procedure:
A solution of 100 mg of 3-[1-(3-aminopropyl)-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione acetate, containing an extra equivalent of acetic acid, in 10 ml of dimethyl sulphoxide (DMSO) was treated with 35 mg of sodium bicarbonate and 36 mg of 2-chloro-3-nitropyridine. The mixture was heated at 60° C. for 1 hour and at 100° C. for 2 hours. The solution was allowed to cool, water was added and the precipitate was filtered off and chromatographed on silica gel with 1% to 5% methanol in dichloromethane. The product was purified further by crystallization from hexane/ethyl acetate to give 60 mg of 3-(1-methyl-3-indolyl)-4-[1-[3-(3-nitro-2-pyridylamino)propyl]-3-indolyl]-1H-pyrrole-2,5-dione, m.p. 218°-220° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22]Cl)=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2].[N-:32]=[N+:33]=[N-:34].[Na+].O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[C:28]([F:29])=[C:27]([NH2:30])[C:9]2[C:10](=[O:26])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:24])[CH2:22][N:32]=[N+:33]=[N-:34])=[C:16]([F:25])[CH:15]=3)[O:13][C:8]=2[C:7]=1[F:31])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CCl)c(F)c3)oc2c1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(F)c(N)c2c(=O)cc(-c3ccc(NC(=O)CN=[N+]=[N-])c(F)c3)oc2c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
To a solution of 7-(acetoxymethyl)-5-amino-2-[4-(chloroacetamido)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (1.00 g, 2.20 mmol) in dimethylformamide (50 mL) was added sodium azide (715 mg, 11 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added thereto, and the crystals precipitated were collected by filtration to afford 7-(acetoxymethyl)-5-amino-2-[4-(azidoacetamido)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one (1.01 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH3:10])=[C:5]([OH:12])[CH:4]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH3:10])=[C:5]([OH:12])[CH:4]=1
Reactant: COc1ccc(C(C)=O)c(O)c1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(OC)cc1O
Reaction time: 24 h
Yield: 99.3 %

Procedure:
1-(4-Methoxy-2-hydroxy-phenyl)-ethanone (11.0 g) was dissolved in MeOH (100 mL), treated with 10 wt % Pd/C (4.0 g, Degussa type) and stirred under a balloon of H2 for 24 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to give the product as an oil (10.0 g). 1H NMR (300 MHz, CDCl3): δ 1.20 (t, J=7.85 Hz, 3 H) 2.60-(q, J=6.22 Hz 2 H), 3.75 (s, 3 H), 6.40 (dd, J=9.04 Hz, 2.64 Hz, 1 H), 6.45 (d, J=2.64 Hz, 1 H) 7.00 (d, J=8.29 Hz, 1 H), 12.90 (s, 1 H).
Reaction SMILES: Cl.[C:2](SCC1C=CC=CC=1)(=[NH:4])[CH3:3].[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]2[CH2:24][S:23][C:22]([NH2:25])=[N:21]2)[CH:17]=[CH:18][CH:19]=1.C(SCC1C=CC=CC=1)(=N)C>C(O)C.O>[NH2:25][C:22]1[S:23][CH2:24][CH:20]([C:16]2[CH:15]=[C:14]([NH:13][C:2](=[NH:4])[CH3:3])[CH:19]=[CH:18][CH:17]=2)[N:21]=1
Reactant: CC(=N)SCc1ccccc1
Reactant: NC1=NC(c2cccc(N)c2)CS1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(=N)Nc1cccc(C2CSC(N)=N2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
0.15 g of benzyl ethanimidothioate hydrochloride and then 5 cm3 of ethanol are added, under an inert atmosphere and at a temperature in the region of 0° C., to a stirred solution of 0.14 g of 4-(3-aminophenyl)-4,5-dihydro-1,3-thiazol-2-ylamine in 15 cm3 of ethanol. The mixture is stirred for 1 hour at about 0° C. and then for 2 hours at a temperature in the region of 20° C. A further 0.030 g of benzyl ethanimidothioate is added to complete the reaction, after which the mixture is maintained at a temperature in the region of 45° C. for 24 hours. The reaction medium is evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is taken up in 30 cm3 of water and the solution is washed with 30 cm3 of dichloromethane. The aqueous solution is concentrated under the above conditions and the solid obtained is then triturated from diethyl ether, filtered, air-dried and purified by chromatography at atmospheric pressure on a column of silica gel (particle size 40-63μ; mass 63 g), eluting with a dichloromethane/methanol/aqueous ammonia mixture (12/3/0.5 by volume). The fractions containing the expected product are collected. These fractions are combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.100 g of [3-(2-amino-4,5-dihydrothiazol-4-yl)phenyl]-(1-iminoethyl)amine is obtained in the form of a white solid melting at 180° C. 1H NMR spectrum (250 MHz, (CD3)2SO-d6, with addition of a few drops of CD3COOD-d4, δ in ppm): 2.28 (unres. mult.: 3H); 3.18 (dd, J=12.5 and 8.5 Hz: 1H); 3.80 (dd, J=12.5 and 8.5 Hz: 1H); 5.30 (t, J=8.5 Hz: 1H); 7.21 (broad d, J=8.5 Hz: 1H); 7.27 (broad s: 1H); 7.36 (broad d, J=8.5 Hz: 1H); 7.49 (broad t, J=8.5: Hz: 1H).
Reaction SMILES: O[C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C@H:39]([NH2:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C@H:39]([NH:41][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH3:40])[CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: COc1cccc([C@@H](C)N)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc([C@@H](C)NC2CCN(C(=O)OC(C)(C)C)C2)c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of 25 g of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate and 25.9 g of diisopropylethylamine dissolved in 500 ml of methylene chloride was added dropwise 100 ml of a solution of 49 g of anhydrous trifluoromethanesulfonic acid in methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., and then, to the mixture was added dropwise 100 ml of a solution of 24.2 g of (R)-1-(3-methoxyphenyl)ethylamine in methylene chloride at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate. (2) To a solution of 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate dissolved in 30 ml of chloroform was added 300 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 16 hours. The resulting precipitates were collected by filtration, washed with ethyl acetate, and recrystallized from methanol and tetrahydrofuran twice to obtain 8.54 g of (R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.003).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([Si:28]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)Cl)([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11][CH2:12][CH2:13][O:14][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Reaction time: 12 h

Procedure:
(S)-2-tert-Butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl ester (2.5 g) was dissolved in 50 ml DMF and treated with 2.0 ml tert-butyldiphenylchlorosilane, 1.2 ml triethylamine and 95 mg DMAP. After stirring for 12 h equivalent portions of the reagents were added and the mixture stirred for additional 12 h. The mixture was concentrated, the residue was dissolved in ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl and saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 2.0 g.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:37]1[NH:38][CH:39]=[CH:40][N:41]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:38]3[CH:39]=[CH:40][N:41]=[C:37]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CCCCCCCCCCCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (500 mg), 2-undecylimidazole (500 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 4 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (100 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from diethyl ether-hexane to give 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-undecyl-1-imidazolyl)oxazole as pale yellow prisms (100 mg, 13%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12].C([Li])CCC.[B:19](OCC)([O:23]CC)[O:20]CC>C1COCC1>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:19]([OH:23])[OH:20])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)CCOc1ccccc1Br
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)CCOc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of 1-bromo-2-(isopentyloxy)benzene (9.68 g, 40 mmol) in THF (160 mL) under N2 atmosphere at −78° C. was added dropwise n-butyl lithium (1.6 M in hexanes, 26.3 mL, 42 mmol, Aldrich) over 30 min period. The reaction mixture was stirred for an additional 1 hour at −78° C., followed by the drop wise addition of triethyl borate (5.86 mL, 51 mmol). The cooling bath was removed, and the reaction was allowed to warm up to the room temperature then stirred for an additional 18 h at room temperature. The reaction mixture was acidified with 2 N HCl (20 mL) and water (50 mL). The resulting slurry was extracted with 5 of 80 mL portions of Et2O. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 6.30 g (77%) of 2-(isopentyloxy)-phenylboronic acid. 1H NMR (400 MHz, CDCl3): 7.83 (d, 1H), 7.43 (dd, 1H), 7.03 (t, 1H), 6.93 (t, 1H), 6.05 (s, 1H), 4.10 (t, 2H), 1.85-1.75 (m, 3H), 1.02 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.C(N(CC)CC)C.[CH2:28]([OH:31])[C:29]#[CH:30]>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: C#CCO
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cc(C#CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of the 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (140 mg, 0.374 mmol), Pd(PPh3)4 (10 mg, 0.009), and CuI (30 mg, 0.158 mmol) in N,N-dimethylformamide (3 mL) was treated with triethylamine (1 mL, 726 mg, 7 mmol). The reaction mixture was cooled to 0° C. and treated with propargyl alcohol (56 mg, 1 mmol). The mixture was stirred at ambient temperature 5 hours and then filtered through a short plug of silica gel, washing with ethyl acetate. The organic solution was concentrated in vacuo. Silica gel chromatography afforded 20 mg (18%) of 3-(2-pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole: 1H-NMR (MeOH-d4), δ ppm: 8.80 (d, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.30 (d, 1H), 8.10 (m, 2H), 7.60 (m, 1H), 4.5 (s, 2H).
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[Cl:22][C:23]1[N:28]=[CH:27][C:26](/[CH:29]=[CH:30]\[C:31]#[N:32])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]2[CH:30]=[C:31]([NH2:32])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)=[CH:25][CH:24]=1
Reactant: N#C/C=C\c1ccc(Cl)nc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Product: Nc1cc(-c2ccc(Cl)nc2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):323 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-(6-chloro-pyridin-3-yl)-acrylonitrile.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C=C(S(N)(=O)=O)C=CC=1>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=3)=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(-c2cccc(S(N)(=O)=O)c2)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c1
Yield: 91 %

Procedure:
3-(2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)benzenesulfonamide. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (75 mg, 0.113 mmol) and 3-bromobenzenesulfonamide following General Procedure A. Flash chromatography (10-30% EtOAc/hexanes) yielded the title compound as a white solid (55 mg, 91%): 1H NMR (CD3OD, 500 MHz) δ 8.24 (m, 1H), 7.92 (d, 1H, J=8.0 Hz), 7.74 (d, 1H, J=8.0 Hz), 7.64 (t, 1H, J=7.6 Hz), 7.58 (s, 1H), 7.24-7.20 (m, 2H), 7.14-7.13 (m, 3H), 4.88 (ex s, 2H), 3.32-3.31 (m, 1H), 2.58 (t, 2H, J=7.6 Hz), 1.98-1.86 (m, 2H), 1.69-1.60 (m, 2H), 1.38-1.34 (m, 6H), 0.90 (s, 9H), 0.12 (s, 3H), 0.00 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.9, 150.3, 142.7, 130.7, 128.9, 128.8, 128.6, 128.2, 128.2, 128.0, 125.4, 124.7, 122.3, 36.1, 35.6, 31.4, 28.9, 28.8, 28.0, 25.0, 24.9, 17.8, −6.0, −6.1.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:18])[C:7]=2[C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:27][C:28](=[O:46])/[CH:29]=[CH:30]/[C:31]1[CH:45]=[CH:44][C:34]2[N:35]([CH3:43])[C:36]([C:38]3([NH2:42])[CH2:41][CH2:40][CH2:39]3)=[N:37][C:33]=2[CH:32]=1)C>>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][C:11]([C:15]([NH:42][C:38]4([C:36]5[N:35]([CH3:43])[C:34]6[CH:44]=[CH:45][C:31](/[CH:30]=[CH:29]/[C:28]([OH:27])=[O:46])=[CH:32][C:33]=6[N:37]=5)[CH2:39][CH2:40][CH2:41]4)=[O:16])=[CH:12][CH:13]=3)[N:8]([CH3:18])[C:7]=2[C:19]2[CH:24]=[N:23][CH:22]=[CH:21][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cn1c(-c2cnccn2)c(C2CCCC2)c2ccc(C(=O)O)cc21
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)nc(C1(N)CCC1)n2C
Product: Cn1c(C2(NC(=O)c3ccc4c(C5CCCC5)c(-c5cnccn5)n(C)c4c3)CCC2)nc2cc(/C=C/C(=O)O)ccc21

Procedure:
3-cyclopentyl-1-methyl-2-pyrazin-2-yl-1H-indole-6-carboxylic acid 5-1 (prepared using procedures described in WO 03/010141) and (E)-3-[2-(1-aminocyclobutyl)-1-methyl-1H-benzimidazol-5-yl]acrylic acid ethyl ester 4-2 were coupled, followed by saponification of the ethyl ester, using analogous procedures to those described in Example 4 to give (E)-3-(2-{1-[(3-Cyclopentyl-1-methyl-2-pyrazin-2-yl-1H-indole-6-carbonyl)amino]cyclobutyl}-1-methyl-1H-benzimidazol-5-yl)acrylic acid 5-2 (compound 4003, Table 4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17]C(=O)C)=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(=O)Oc1ccc(C=Cc2cc(F)cc(F)c2)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Oc1ccc(C=Cc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
To a solution of 3,5-difluoro-4′-acetoxystilbene (0.69 g, 2.5 mmol) in MeOH (10 ml) was added 5 mL 4M HCl in 1,4-dioxane. The mixture was stirred for 20 minutes at ambient temperature. After purification by flash column, 3,5-difluoro-4′-hydroxystilbene (0.51 g, 88%) was obtained. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.40 (m, 2H), 7.05-6.83 (m, 6H), 6.67 (tt, 1H), 4.88 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 164.49 (d), 162.47, 156.01, 141.29, 130.90, 128.53, 124.74, 115.96, 109.03 (t), 102.53 (t); 19F NMR (CDCl3, 282 MHz) δ −31278.95 (t, J=1720.2 Hz); HRMS (EI+) found 232.0715 M+, calcd 232.0700 for C14H10F2O.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[OH-].[Na+].C(OCC)(=O)C.CCCCCC.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1ccc(C(=O)C(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
A solution of ethyl 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetate (12 g, 0.49 mol) in toluene (120 mL, 10 times) was heated to 50° C. 3M NaOH solution (2.23 g, 1.2 eq) was added drop wise at 50° C. and the contents were allowed to reflux for 3 h at 60° C. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.1). On completion of the reaction, toluene was distilled off and the residue obtained was taken in ice cold water. Then the contents were acidified with diluted HCl at 0° C. and allowed to stir for 1 h at room temperature. The precipitate was filtered and dried to yield 2-(3-chloro-4-(methylthio)phenyl)-2-oxoacetic acid as an yellow colored solid (10 g, 93%).
Reaction SMILES: [CH2:1]([N:5]([CH3:24])[C:6]([C:8]1[CH:9]=[C:10]([C:21]([OH:23])=O)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1)=[O:7])[CH:2]([CH3:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[NH2:48][C@@H:49]([C:52]1[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=1)[CH2:50][OH:51].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:51][CH2:50][C@@H:49]([NH:48][C:21]([C:10]1[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=[C:8]([C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:24])=[O:7])[CH:9]=1)=[O:23])[C:52]1[CH:53]=[N:54][C:55]([O:58][CH3:59])=[CH:56][CH:57]=1
Reactant: COc1ccc([C@H](N)CO)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N(C)CC(C)C)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc([C@@H](CO)NC(=O)c2cc(C(=O)N(C)CC(C)C)cc(-c3ccc(C)cc3)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(isobutyl(methyl)carbamoyl)-4′-methylbiphenyl-3-carboxylic acid (35 mg, 0.11 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (41 mg, 0.22 mmol), 1-hydroxybenzotriazole hydrate (16 mg, 0.11 mmol), CH2Cl2 (3 mL) were added (S)-2-amino-2-(6-methoxypyridin-3-yl)ethanol (27 mg, 0.16 mmol) (WO 2008/130481) and N,N-diisopropylethylamine (28 pt, 0.16 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to yield a white solid.