Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[NH:23][N:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]([CH2:30][CH2:31][OH:32])[C:33](=[O:35])[CH3:34])[C:18]=23)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCCNCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)N(CCO)CCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: -15 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
2-({2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl}amino)ethanol (prepared as described in Example 36/30 mg, 0.07 mmol) was dissolved in DMA and the mixture was cooled to −15° C. Acetic anhydride (6 μL, 0.07 mmol) was added and the mixture was stirred for 1 hour. Water was then added and the precipitated solid was filtered and dried to give the title compound (22 mg, 67%); NMR Spectrum (mixture of rotamers): (major isomer) 2.08 (s, 3H), 3.49 (t, 2H), 3.56-3.59 (m, 2H), 3.80 (t, 2H), 4.40 (t, 2H), 4.90 (t, 1H), 5.28 (s, 2H), 7.26 (d, 1H), 7.37 (t, 1H), 7.58 (d, 1H), 7.84-7.98 (m, 2H), 8.16 (d, 1H), 8.28 (s, 1H), 8.30 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 498 (MH+).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[H-].[Na+].[C:15](#[N:17])[CH3:16]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([CH2:16][C:15]#[N:17])=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OC)cc1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CC#N)cc1
Reaction time: 20 h

Procedure:
166.2 grams (1 mole) of 4-methoxybenzoic acid methyl ester and 60 grams (2 moles) of sodium hydride (80 weight % suspension in white oil) were heated to 65° C. in 750 ml of dry toluene. Within 2 hours there were dropped in 82.1 grams (2 moles) of acetonitrile at 85° C. and then stirring was continued for a further 20 hours at 90° C. The precipitate was filtered off with suction, 200 ml of glacial acetic acid slowly stirred in with cooling and subsequently the mixture was added to 1 liter of ice water. The precipitated crystal mass was filtered off with suction, post washed with water and recrystallized from acetone. There were thus obtained 149 grams (85% of theory) of 4-methoxybenzoylacetonitrile having a melting point of 127°-129° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([O:41]CC4C=CC=CC=4)=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].CO.O1CCCC1.C([O-])=O.[NH4+]>>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCc4ccccc4)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(Cc3ccc(O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To a mixture of [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-[3-[(4-benzyloxyphenyl)methyl]-4-methyl-indol-1-yl]tetrahydropyran-2-yl]methyl acetate (1.00 equiv; 1.05 moles; 692.80 g), methanol (85.59 moles; 3.46 L; 2.74 kg), and tetrahydrofuran (42.57 moles; 3.46 L; 3.07 kg) add ammonium formate (5.27 moles; 332.10 g). Purge the reaction vessel with nitrigen and add 5% palladium on charcoal (69.30 g; Johnson Matthey type 87 L, 57.8% moisture content) as a slurry in isopropyl alcohol. Heat the mixture at 38-42° C. for 15 mins (moderate bubbling observed). Remove the heating bath and stir the reaction mixture for 15 minutes whilst cooling. Filter the mixture through diatomaceous earth and concentrate the filtrate under reduced pressure. Partition the residue between ethyl acetate (7.5 L) and water (1 L). Separate the organic layer and wash with brine then dry over MgSO4. Filter, and concentrate under reduced pressure to give the title compound (594 g; 99% yield) mass spectrum (m/z): 568.2 (M+1) and 590.2 (M+23).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][N:41]([C:44](=[O:46])[CH3:45])[CH2:40][CH2:39]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>O1CCOCC1.C(O)CCC>[C:44]([N:41]1[CH2:40][CH2:39][N:38]([C:35]2[CH:36]=[CH:37][C:32]([NH:31][C:2]3[N:3]=[C:4]([NH:21][C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25]([NH2:27])=[O:26])[C:5]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=5)(=[O:12])=[O:13])[C:6]=4[N:7]=3)=[CH:33][CH:34]=2)[CH2:43][CH2:42]1)(=[O:46])[CH3:45]
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(C(N)=O)c4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: C1COCCO1
Product: CC(=O)N1CCN(c2ccc(Nc3nc(Nc4cccc(C(N)=O)c4)c4ccn(S(=O)(=O)c5ccc(C)cc5)c4n3)cc2)CC1
Temperature: 110 °C
Reaction time: 72 h
Yield: 33.7 %

Procedure:
A mixture of 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (85 mg, 0.19 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (105 mg, 0.480 mmol) and trimethylsilyl chloride (0.030 mL, 0.24 mmol) in dioxane (1 mL) and nBuOH (1 mL) was stirred at 110° C. for 72 h. It was concentrated in vacuo. The residue was purified by HPLC to give 3-(2-(4-(4-acetylpiperazin-1-yl)phenylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzamide (40 mg).
Reaction SMILES: BrN1C(=[O:7])CCC1=O.[Cl:9][C:10]1[CH:11]=[C:12]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]3[NH:31][C:30](=[O:32])[O:29][C:28]([CH3:34])([CH3:33])[C:27]=3[CH:35]=2)[CH:13]=[CH:14][C:15]=1[Cl:16].O>CO>[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]3[NH:31][C:30](=[O:32])[O:29][C:28]([CH3:33])([CH3:34])[C:27]=3[CH:35]=2)=[O:7])[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Solvent: O
Solvent: CO
Product: CC1(C)OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
One gram (0.0056 mol) of N-bromosuccinimide is gradually added to a solution of 2.13 gm (0.005 mol) of 6-[4-(3,4-dichlorophenylmercapto)-butoxy]-4,4-dimethyl-4H-3,1-benzoxazin-2-one in 50 ml of methanol, under stirring. After reaction for 24 hours, 500 ml of water at 80° C. is added, and the precipitate is subjected to suction filtration after stirring for two hours. By recrystallization from isopropanol/diisopropylether, crystals are obtained, melting point: 136°-139° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
Under nitrogen bubbling, a mixture of 2-(4-chlorophenyl)-3H-imidazo [4,5-b]pyridine-3-acetic acid (4.0 g, 0.014 mole) and 1,1'-carbonyldiimidazole (2.27 g, 0.014 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 3 hours. Cyclohexylamine (2.77 g, 0.028 mole) was added and the reaction mixture was allowed to stir at room temperature overnight. The tetrahydrofuran was evaporated to dryness and the residue was treated with water. The solid was collected by filtration, washed with water, and dried under high vacuum over the weekend. The solid was recrystallized from isopropyl alcohol-95% ethanol, collected by filtration, washed with water, and dried under high vacuum at 50° C. overnight to give 3.75 g (73%) of crystal, mp 240°-241° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][N:7]([C:15]1[C:20]([N+:21]([O-])=O)=[CH:19][N:18]=[C:17]([Cl:24])[N:16]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][N:7]([C:15]1[C:20]([NH2:21])=[CH:19][N:18]=[C:17]([Cl:24])[N:16]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1([CH3:14])[CH3:13])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCCC1(C)C
Yield: 78.9 %

Procedure:
A mixture of 3.3 g (0.0093 mole) of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propionic acid ethyl ester (IV-59) in 30 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration under reduced pressure gave 2.5 g of (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-59). This material was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:4][C:3]2[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=2[Br:1])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1cc(F)ccc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(F)ccc2Br)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-bromo-5-fluoro-benzaldehyde (3.00 g, 14.8 mmol), piperazine-1-carboxylic acid tert-butyl ester (2.75 g, 14.8 mmol) and sodium triacetoxyborohydride (4.38 g, 20.7 mmol) was prepared in DCE (80 mL) and stirred at RT for 3 hours. The reaction mixture was diluted with DCM (100 mL), and then washed with a mixture of saturated aqueous solution of Na2CO3 (100 mL) and water (50 mL). The aqueous layer was extracted with DCM (100 mL). The organic layers were combined, dried (Na2SO4) and concentrated under vacuum. After purification by filtration through a silica pad (EtOAc), the title compound was obtained as a white powder (5.12 g, 93%). 1H NMR (300 MHz, CDCl3) δ 7.48 (dd, J=8.8, 5.3 Hz, 1H), 7.26 (dd, J=9.6, 3.1 Hz, 1H), 6.85 (ddd, J=8.8, 7.8, 3.1 Hz, 1H), 3.56 (s, 2H), 3.49-3.42 (m, 4H), 2.50-2.42 (m, 4H), 1.46 (s, 9H). HPLC (max plot) 94.1%; Rt 2.73 min. UPLC/MS: (MS+) 373.1 and 375.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[NH2:44][C:45]1[S:46][C:47]2[C:53]([N:54]([CH3:58])[C:55](=[O:57])[CH3:56])=[CH:52][CH:51]=[C:50]([O:59][CH3:60])[C:48]=2[N:49]=1>C1COCC1>[C:55]([N:54]([CH3:58])[C:53]1[C:47]2[S:46][C:45]([NH:44][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:49][C:48]=2[C:50]([O:59][CH3:60])=[CH:51][CH:52]=1)(=[O:57])[CH3:56]
Reactant: COc1ccc(N(C)C(C)=O)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C)C(C)=O)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 2 h
Yield: 24.3 %

Procedure:
To a stirred solution of 31 mg (0.22 mmol) 4-fluoro-benzoic acid in 2 ml THF were added 89 mg (0.23 mmol) HATU and 0.07 ml (0.44 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 2 h. 28 mg (0.11 mmol) N-(2-amino-4-methoxy-benzothiazol-7-yl)-N-methyl-acetamide was then added and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (dichloromethane/methanol 50/1) followed by trituration in ether afforded 10 mg (24%) N-[7-(acetyl-methyl-amino)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide as a white crystalline solid. ES-MS m/e (%o): 374 (M+H+, 100).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:14])=[CH:2]1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCCc1c[nH]c2ccccc12)OCc1ccccc1
Reaction time: 4 h
Yield: 94.1 %

Procedure:
To a solution of 3-indolebutyric acid (25 g) and potassium carbonate (20 g) in dimethylformamide (150 ml) was added benzylbromide (21 g) at room temperature. After stirring for 4 hours, the mixture was poured into ice and diluted hydrochloric acid (300 ml). The organic layer was extracted with ethyl acetate (150 ml), and the extract was washed with water (150 ml×3) and dried over magnesium sulfate. After the solvent was removed in vacuo, the residue was crystallized from n-hexane to give a solid of benzyl 4-(3-indolyl)butyrate (33.9 g).
Reaction SMILES: [C:1]([NH:4][C:5]([NH2:7])=[S:6])(=[O:3])[CH3:2].[Cl:8][CH2:9][C:10]([CH2:12]Cl)=O>CC(C)=O.C(OCC)(=O)C>[Cl:8][CH2:9][C:10]1[N:7]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][CH:12]=1
Reactant: CC(=O)NC(N)=S
Reactant: O=C(CCl)CCl
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C

Procedure:
A mixture of acetylthiourea (591 mg, 5 mmol) and 1,3-dichloroacetone (667 mg, 5.25 mmol) in acetone (15 mL) was heated at reflux for 7 hours, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by column chromatography to give the title compound. MS (DCI) m/e 191 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 12.21 (s, 1H), 7.22 (s, 1H), 4.70 (s, 2H), 2.13 (s, 3H).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].CN(C=O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:17][CH:16]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 130 °C
Yield: 96.3 %

Procedure:
Compound 4 was prepared as follows: a mixture of carbazole (6.30 g, 37.7 mmol), 1-bromo-4-iodobenzene (15.99 g, 56.52 mmol), copper powder (4.79 g, 75.4 mmol), K2CO3 (20.83 g, 150.7 mmol) and anhydrous DMF (100 mL) was degassed with argon for about 1 h while stirring. The stirring reaction mixture was then maintained under argon at about 130° C. for about 42 h. Upon confirming consumption of the starting material by TLC (SiO2, 4:1 hexanes-dichloromethane), the mixture was cooled to RT, filtered, the filtrant washed copiously with EtOAc (ca. 200 mL) and the resulting filtrate concentrated in vacuo. Purification of the crude product by flash chromatography (SiO2, hexanes) afforded compound 4 (11.7 g, 96% yield) as a pale yellow solid. (See Xu, H.; Yin, K.; Huang, W. Chem. Eur. J., 2007, 13(36), 10281-10293.)
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([C:8]([OH:10])=O)=[CH:6][N:7]=1)[CH3:2].Cl.[NH2:12][C@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)=[CH:25][CH:24]=1)[CH2:14][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Cl:35][C:31]1[CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][C@@H:13]([NH:12][C:8]([C:5]3[O:4][C:3]([CH2:1][CH3:2])=[N:7][CH:6]=3)=[O:10])[CH2:14][CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:24][CH:25]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: CCc1ncc(C(=O)O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(CC)o1
Reaction time: 2 h
Yield: 100.5 %

Procedure:
To a solution of 2-ethyloxazole-5-carboxylic acid (95 mg, 0.68 mmol) in DMF (2 mL) and DCM (2 mL) is added (4S)-ethyl 4-amino-5-(3′-chlorobiphenyl-4-yl)-2-methylpentanoate hydrochloride (215 mg, 0.56 mmol), HATU (321 mg, 0.84 mmol), and TEA (392 μL, 2.81 mmol). After stirring for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O(0.1% TFA)/CH3CN) to give (4S)-ethyl 5-(3′-chlorobiphenyl-4-yl)-4-(2-ethyloxazole-5-carboxamido)-2-methylpentanoate (264 mg), HPLC retention time=0.71 minutes (condition B); MS (m+1)=469.3.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Cl[CH2:18][C:19]([CH3:22])([OH:21])[CH3:20]>>[OH:21][C:19]([CH3:22])([CH3:20])[CH2:18][N:3]1[C:4]2[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: CC(C)(O)CCl
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(C)(C)O

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 120) and 1-chloro-2-methyl-2-propanol: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.5 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 6.60 (s, 1H), 4.12 (s, 2H), 2.52 (s, 3H), 1.30 (s, 6H); MS (ES) m/z 297 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:17]=[C:16]([O:29][CH2:30][CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])[CH:15]=2)=[CH:9][C:8]=1[CH3:36])C.[OH-].[Na+].Cl>C(O)C>[CH2:34]([CH:31]([CH2:32][CH3:33])[CH2:30][O:29][C:16]1[CH:15]=[C:14]([S:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])=[C:8]([CH3:36])[CH:9]=2)[CH:19]=[C:18]([C:20]#[C:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:17]=1)[CH3:35]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCN3CCOCC3)cc(OCC(CC)CC)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CC)COc1cc(C#CCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(C)c2)c1
Reaction time: 16 h

Procedure:
{4-[3-(2-Ethyl-butoxy)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (210 mg; 0.40 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h. acidified with 1 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness and purified by prep HPLC (method B). Yield: 144 mg (73%). HPLC-MS: m/z: 498.2 (M+H)+; Rt: 1.97 min.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1ccc(-c2nc(-c3cccnc3)no2)c(F)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,3,4-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.37-7.48 (m, J=9.3, 9.3, 7.1, 2.4 Hz, 1 H), 7.64 (ddd, J=7.9, 5.0, 1.0 Hz, 1 H), 8.08-8.18 (m, 1 H), 8.56 (dt, J=8.0, 1.9 Hz, 1 H), 8.75 (dd, J=5.0, 1.8 Hz, 1 H), 9.30 (dd, J=2.0, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=5)[C:19]([C:33](O)=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN.O1CCCC1.C[CH2:44][N:45](CC)CC.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:29]([CH3:30])[CH3:31])=[O:32])=[CH:24][CH:23]=5)[C:19]([C:33]([NH:45][CH3:44])=[O:34])=[CH:18][CH:17]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C(=O)N(C)C)cc1
Reaction time: 3 h
Yield: 10.3 %

Procedure:
5-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-4′-(dimethylcarbamoyl)biphenyl-2-carboxylic acid (47 mg, 0.10 mmol) and 75 μl of a 2.0 M solution of methylamine in tetrahydrofuran (0.15 mmol) were dissolved in DMF (1.0 mL) containing Et3N (28 μL, 0.20 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) was added to the mixture and the resulting solution was allowed to stir for 3 hours. The mixture was filtered and purified by reverse phase HPLC to yield 5-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane-carboxamido)-N2,N4′,N4′-trimethylbiphenyl-2,4′-dicarboxamide (5.0 mg, 10%). ESI-MS m/z calc. 485.5. found 486.5 (M+1)+; retention time 2.54 minutes.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8].[CH2:9]([O:16][CH2:17]Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>ClCCl.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:9]([O:16][CH2:17][N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][C:2]1=[O:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCOCc1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: ClCCl
Product: O=c1ccn(COCc2ccccc2)c(=O)[nH]1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
After N,O-bis(trimethylsilyl)acetoamide (18.5 ml, 74.8 mmol) was added dropwise to a suspension of pyrimidine-2,4-dione (3.36 g, 30.0 mmol) in dichloromethane (90 ml) at room temperature, the mixture was stirred for 2 hours. Tetra-n-butyl ammonium iodide (1.12 g, 3.0 mmol) was added to the reaction mixture, and benzyloxymethyl chloride (4.4 ml, 31.7 mmol) was further added to it. This mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with water and a saturated aqueous solution of sodium hydrogencarbonate, and it was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium thiosulfate and with water successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid residue was washed with diisopropyl ether and collected by filtration to give the title compound (6.00 g, yield 86%) as a white powder.