Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:24][C:23]([C:25]([O:27]C)=[O:26])=[CH:22][C:21](=[O:29])[C:4]=2[C:5]([C:17]([F:20])([F:19])[F:18])=[C:6]2[C:11]=1[NH:10][C:9]([C:12]([O:14]C)=[O:13])=[CH:8][C:7]2=[O:16].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[C:11]2[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][C:7](=[O:16])[C:6]=2[C:5]([C:17]([F:19])([F:18])[F:20])=[C:4]2[C:3]=1[NH:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][C:21]2=[O:29]
Reactant: COC(=O)c1cc(=O)c2c(C(F)(F)F)c3c(=O)cc(C(=O)OC)[nH]c3c(Cl)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(=O)c2c(C(F)(F)F)c3c(=O)cc(C(=O)O)[nH]c3c(Cl)c2[nH]1
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
A mixture of 1.65 grams (0.0058 mole) of dimethyl 10-chloro-1,4,6,9-tetrahydro-4,6-dioxo-5-(trifluoromethyl)pyrido[3,2-g]quinoline-2,8-dicarboxylate and 20 ml. of water is stirred and to the mixture is added a 5% sodium hydroxide solution until solution occurs (3ml.). The solution is stirred for 15 minutes and then acidified by the addition of a dilute HCl solution. The resulting tan precipitate is removed by filtration and washed with water. There is obtained 1.11 gram of material melting above 300°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[CH:12]=O.Cl.[NH2:15]O.C(OC(=O)C)(=O)C.[OH-].[Na+].Cl>O1CCCC1.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[C:12]#[N:15]
Reactant: O=Cc1c[nH]c2cc(F)c(F)cc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: N#Cc1c[nH]c2cc(F)c(F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
To a solution of 5,6-difluoro-1H-indole-3-carbaldehyde (1.0 g) in tetrahydrofuran (15 ml) were added hydroxylamine hydrochloride (0.81 g) and pyridine (1.9 g), and this mixture was stirred at 80° C. for 8 hours. Acetic anhydride was added to reaction mixture and this mixture was stirred at 80° C. for 8 hours. After cooling to ambient temperature, 2 mol/L aqueous sodium hydroxide solution was added to this mixture and resulting mixture was stirred for 30 minutes. This mixture was poured into 2 mol/L hydrochloric acid and the precipitated solid was collected by filtration, and washed with water and n-hexane. The solid was dissolved in ethyl acetate and this residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.95 g).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH3:13]>CO>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH2:13])[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: N
Solvent: CO
Product: Nc1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.6 %

Procedure:
To stirred neat 2,4-dichloro-5-(trifluoromethyl)pyrimidine (F-1) (5.0 g, 23.04 mmol) under argon, ammonia in methanol (7N solution, 15 mL) is added dropwise and the resulting mixture is stirred at RT for 2 h. The reaction mixture is quenched with water and then extracted with ethyl acetate (200 mL×2). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography on silica gel eluting with 0-20% ethyl acetate/hexanes to afford the product, 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (F-2) (1.03 g, 22.6% yield). The other regio-isomer, 2-chloro-5-(trifluoromethyl)pyrimidin-4-amine (F-3), can also be isolated.
Reaction SMILES: [Cl:1][C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][O:14][C:15]1[CH:30]=[CH:29][C:18]3[O:19][CH2:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[CH:23](O)[C:17]=3[CH:16]=1)=[N:7]2.[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:34]([CH2:33][CH2:32][S:31][CH:23]1[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[CH2:20][O:19][C:18]2[CH:29]=[CH:30][C:15]([O:14][CH2:13][C:6]3[CH:5]=[CH:4][C:3]4[C:8](=[CH:9][CH:10]=[C:11]([F:12])[C:2]=4[Cl:1])[N:7]=3)=[CH:16][C:17]1=2)([OH:36])=[O:35]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4c(Cl)c(F)ccc4n3)cc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4c(Cl)c(F)ccc4n3)cc21

Procedure:
2-(5-Chloro-6-fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:13][CH:12]1[CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[OH-].[Li+]>>[CH2:14]([CH:12]1[CH2:13][CH:11]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:22])=[O:2])/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCC/C=C\CC1CC1CCCCCCCC(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCCCC/C=C\CC1CC1CCCCCCCC(=O)O

Procedure:
In the same manner as in Example 1(2) using 8-(2-(2-(Z)-octenyl)cyclopropyl)octanoic acid methyl ester and 0.5N lithium hydroxide instead of 1N lithium hydroxide, 8-(2-(2-(Z)-octenyl)cyclopropyl)octanoic acid was obtained as an oil (56.3 mg).
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=C1)[CH2:7]3.C([OH:14])C=C>>[CH:8]12[CH2:7][CH:6]([CH:10]=[CH:9]1)[CH2:5][CH:4]2[CH2:3][OH:14]
Reactant: C=CCO
Reactant: C1=CC2C3C=CC(C3)C2C1
Product: OCC1CC2C=CC1C2
Temperature: 210 °C
Yield: 52 %

Procedure:
397 g (3 mol) of dicyclopentadiene (DCPD) (produced from Aldrich Inc.) and 331 g (5.7 mol) of allyl alcohol (produced from Aldrich Inc.) were added to a 2 L high-pressure reactor and the temperature of the 2 L high-pressure reactor was increased to 210° C. The resulting mixture was reacted for one hour, stirring at 300 rpm. When the reaction was completed, the reactant was cooled and loaded into a distillation device. The reactant was distilled twice at a reduced pressure of 1 torr using a vacuum pump to attain a product at 56° C. (Yield: 52%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[N:2]=1.[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24](Br)=[N:23][C:22]([CH3:26])=[CH:21][N:20]=2)(=[O:17])=[O:16])=[CH:12][CH:11]=1>>[Cl:9][C:10]1[S:14][C:13]([S:15]([NH:18][C:19]2[C:24]([O:8][CH2:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[N:23][C:22]([CH3:26])=[CH:21][N:20]=2)(=[O:16])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(Br)n1
Reactant: OCc1cccnn1
Product: Cc1cnc(NS(=O)(=O)c2ccc(Cl)s2)c(OCc2cccnn2)n1

Procedure:
Prepared by the method of Example 20b using pyridazine-3-methanol and 5-chloro-N-(3-bromo-5-methyl-2-pyrazinyl)-2-thiophenesulphonamide (Example 23a).
Reaction SMILES: [C:1]([C:6]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][C:10]3[O:18][CH2:17][O:16][C:11]=3[CH:12]=2)[CH:7]1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)([O:3][CH2:4][CH3:5])=[O:2].BrN1C(=[O:42])CCC1=O>>[C:31]([C:6]1([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:15][C:14](=[O:42])[C:13]2[C:8](=[CH:9][C:10]3[O:18][CH2:17][O:16][C:11]=3[CH:12]=2)[CH:7]1[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1)([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2cc3c(cc2C1c1cc(OC)c(OC)c(OC)c1)OCO3
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)c2cc3c(cc2C1c1cc(OC)c(OC)c(OC)c1)OCO3

Procedure:
In a small Pyrex tube equipped with a spin bar was added 50 mg of 2,2-dicarbethoxy-1-(3',4',5'-trimethoxyphenyl)-6,7-methylenedioxytetralin (XIV-b; R2 = ethyl) and 72 mg (4.0 eq) of N-bromosuccinimide (recrystallized from water). Dioxane (2 ml) was distilled in (from (Na/benzophenone), and the tube was sealed and placed under nitrogen. The mixture was irradiated for 2 min with a sunlamp while cooling with a cold water stream. Water (+μl) was then syringed in and irradiation and cooling was maintained for 18 to 20 min. The reaction mixture was then poured into saturated sodium bisulfite and extracted three times with chloroform. The organic layer was washed twice with 2N sodium hydroxide, twice with water, once with saturated brine, and was dried over sodium sulfate. Filtration and evaporation gave the title product (XV; R2 = ethyl) plus the ring bromination product at C-2' (<10%). One crystallization from methanol gave 46 mg (90%) pure title product, mp 152°-153°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[O:33]C)[C:6]([NH:8][C:9]1[S:10][C:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)=[O:7].B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][C:32]=1[OH:33])[C:6]([NH:8][C:9]1[S:10][C:11]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:13]=1)=[O:7]
Reactant: COc1ccc(C(=O)Nc2nc(-c3ccccc3)c(Cc3ccc([N+](=O)[O-])cc3)s2)cc1OC
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccccc2)c(Cc2ccc([N+](=O)[O-])cc2)s1)c1ccc(O)c(O)c1
Yield: 62.8 %

Procedure:
A procedure similar to that in Example 7 was used. 3,4-dimethoxy-N-[5-(4-nitro-benzyl)-4-phenyl-thiazol-2-yl]-benzamide prepared in Example 29 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone and ethyl acetate to give a product as a white solid in a yield of 62.8%, mp: 244└(Dec.). 1H-NMR (DMSO-d6, 400 MHz) δ: 4.42 (2H, s, CH2), 6.81 (1H, d, J=8.40 Hz, ArH), 7.38 (1H, t, J=7.60 Hz, ArH), 7.44˜7.55 (6H, m, ArH), 7.64 (2H, d, J=8.44 Hz, ArH), 8.20 (2H, d, J=8.68 Hz, ArH), 9.32 (1H, br, OH), 9.81 (1H, br, OH), 12.38 (1H, br, CONH); EI-MS m/e (%): 447.1 (M+, 16), 311.1 (100); HREI-MS Calcd. for C23H17N3O5S: 447.0889. found: 447.0887.
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[O-]S([O-])(=O)=O.[Na+].[Na+]>[C:16]1([CH:15]([OH:22])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: Br[Mg]Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(Cc1ccccc1)c1ccccc1
Temperature: -10 °C

Procedure:
To 100 mL (0.10 mol) of 1.0 M BnMgBr in THF 9.50 g (90 mmol) of benzaldehyde (2) was added with vigorous stirring at −10° C. This mixture was slowly warmed to room temperature and then stirred for 2 hr at this temperature. The mixture was added to 300 mL of saturated aqueous Na2SO4. The organic layer was separated and washed with saturated aqueous NH4Cl. The aqueous layer was extracted with 2×100 mL of diethyl ether. The combined organic extracts were evaporated to dryness, and the residue was dissolved in 100 mL of dichloromethane. The obtained solution was dried over Na2SO4 and evaporated to dryness. This crude product was further used without an additional purification. Yield 12.0 g (67%) of the title compound.
Reaction SMILES: C(O[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[C:14](/[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[CH:15]/[CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:9]=1)(=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>C1COCC1.O.[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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N:17]1([CH2:16]/[CH:15]=[C:14](/[C:10]2[N:9]=[C:8](/[CH:7]=[CH:6]/[CH2:5][N:29]=[N+:30]=[N-:31])[CH:13]=[CH:12][CH:11]=2)\[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC/C=C/c1cccc(/C(=C/CN2CCCC2)c2ccc(C)cc2)n1
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(/C(=C\CN2CCCC2)c2cccc(/C=C/CN=[N+]=[N-])n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
A solution of 3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-en-1-yl acetate (136 mg, 0.365 mmol) in a mixture of THF/water (5:1, 5 ml) was treated with sodium azide (28 mg, 0.44 mmol) and tetrakis(triphenylphosphine) palladium(0) (17 mg, 0.015 mmol). The reaction was stirred at room temperature for 18 hours. Solvent was removed under reduced pressure to leave a dark brown residue. The product was purified by column chromatography on silica-gel eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed under reduced pressure to yield {3-(6-[3-pyrrolidino-1-{4-tolyl}-prop-1E-enyl]-pyridin-2-yl)-prop-2E-enyl}-azide as a brown gum (110 mg, 85%). 1H-NMR; δ (CDCl3), 7.67 (1H, m), 7.56 (1H, m), 7.40 (2H, m), 7.24 (2H, d, J=8.2 Hz), 7.19 (1H, t, J=6.8 Hz), 7.10 (2H, m), 6.91 (1H, dt, J=15.8, 6.6 Hz), 6.73 (2H, m), 4.02 (2H, d, J=8.8 Hz), 3.35 (2H, m), 2.70 (2H, m), 2.41 (3H, s) and 1.82 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:25])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:24].[CH3:27][NH2:28]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:28][CH3:27])=[C:4]([F:25])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[CH:9]=[C:8]([C:21]([OH:23])=[O:22])[C:7]2=[O:24]
Reactant: CN
Reactant: COc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(OC)c3)c2c1Cl
Temperature: 25 °C
Reaction time: 27 h
Yield: 88.1 %

Procedure:
8-Chloro-6,7-difluoro-1-(4-fluoro-3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (160 mg) and an aqueous solution (about 40%; 400 mg) of methylamine were added to pyridine (1,000 mg), and the mixture was stirred at room temperature for 27 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (145 mg) as a colorless powder
Reaction SMILES: [OH:1][P:2]([CH2:5][CH:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([OH:9])=O)([CH3:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:30]1([NH:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:43])[CH3:42])[NH2:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1.C(OCC)(=O)C>[C:30]1([NH:36][C:37](=[O:44])[C@H:38]([CH2:40][CH:41]([CH3:42])[CH3:43])[NH:39][C:7](=[O:9])[CH:6]([CH2:5][P:2]([OH:1])([CH3:4])=[O:3])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)C[C@H](N)C(=O)Nc1ccccc1
Reactant: CP(=O)(O)CC(CCc1ccccc1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)C(CCc1ccccc1)CP(C)(=O)O)C(=O)Nc1ccccc1
Temperature: 25 °C
Yield: 94.1 %

Procedure:
A portion (313 mg) of the crude 2-((hydroxy(methyl)phosphinyl)methyl)-4-phenylbutanoic acid from Step B was dissolved in tetrahydrofuran (3.0 mL) and 4 Å molecular sieves (0.40 g) were added. The mixture was stirred at room temperature and 1,1'-carbonyldiimidazole (215 mg, 1.33 mmol) was added, followed 15 min later by L-leucine N-phenylamide (297 mg, 1.44 mmol).7After 22 h, the mixture was diluted with ethyl acetate (30 mL) and washed with 2N aqueous hydrochloric acid (2×15 mL) and saturated aqueous sodium chloride (15 mL). The organic layer was dried (sodium sulfate) decanted, and evaporated to give 511 mg of colorless foam. The two diastereomers of a portion (145 mg) of the crude product were separated by high pressure liquid chromatography on a 22 mm×25 cm reverse phase column (Whatman ODS-3, Partisil 10) eluting with 60% methanol/40% water/0.05% trifluoroacetic acid (flow rate of 25 mL/min, detection at 250 nm). This yielded the more mobile isomer (43 mg, 31% yield for Steps B-C) and the less mobile isomer (51 mg, 36% yield for Steps B-C), both obtained as brittle films.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20][OH:21])=[C:11]([NH:22][C:23]([C:25]2[NH:26][C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH3:35])=[C:29]([O:36][CH3:37])[C:28]=3[O:38][CH3:39])=[O:24])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH3:47][S:48]([O:21][CH2:20][CH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][C:11]=1[NH:22][C:23]([C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH3:35])=[C:29]([O:36][CH3:37])[C:28]=2[O:38][CH3:39])=[O:24])(=[O:50])=[O:49]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCO)[nH]c2c(OC)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2cc(C(=O)Nc3cc(OCc4ccccc4)c4ccccc4c3CCOS(C)(=O)=O)[nH]c2c(OC)c1OC
Reaction time: 1 h
Yield: 121.3 %

Procedure:
To a solution of 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethanol (80 mg, 0.15 mmol) and triethylamine (0.09 mL, 0.61 mmol) in CH2Cl2 (2 mL) was added methanesulfonyl chloride (0.05 mL, 0.61 mmol) with ice bath, and then the mixture was stirred for 1 h. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with H2O (10 mL) and saturated aqueous NaCl (20 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield as a brown oil 2-[4-benzyloxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl methanesulfonate (0.11 g, quant); 1H NMR (CDC3, 500 MHz) δ 9.24 (s, 1H), 8.47 (s, 1H), 8.41 (d, 8.0, 1H), 7.85 (d, 8.5, 1H), 7.71 (dd, 3.5, 5.5, 1H), 7.60 (t, 7.0, 1H), 7.48-7.56 (m, 3H), 7.44 (t, 8.0, 2H), 7.37 (t, 7.5, 1H), 7.18 (s, 1H), 6.88 (s, 1H), 5.28 (s, 2H), 4.63 (t, 6.5, 2H), 4.09 (s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.56 (t, 6.5, 2H), 2.86 (s, 3H); EIMS m/z 509 (M−CH3SO3H+); IR (neat) νmax 3330, 3099, 2933, 2874, 1725, 1649, 1592, 1537, 1502, 1466, 1411, 1369, 1306, 1238, 1174, 1127, 1076, 1048, 998, 972, 951, 833, 796, 751, 702 cm−1.
Reaction SMILES: [C:1]1([CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][OH:9])[CH:2]=1.N1C=CN=C1.Cl[Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21]>CN(C)C=O.O>[CH:20]([Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[O:12][CH2:11][CH2:10][C:1]1[CH:2]=[C:3]([CH2:7][CH2:8][OH:9])[CH:4]=[CH:5][CH:6]=1)([CH3:22])[CH3:21]
Reactant: OCCc1cccc(CCO)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCc1cccc(CCO)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
2,2′-(1,3-Phenylene)diethanol (0.430 g, 2.59 mmol) and imidazole (0.176 g, 2.59 mmol) were dissolved in anhydrous N,N-dimethylformamide (15 mL) and cooled to 0° C. in an ice bath. Chlorotriisopropylsilane (0.22 mL) was slowly added and the reaction mixture was kept stirring at 0° C. for 3 h, and then diluted with water (5 mL), extracted with ethyl acetate (15 mL×2), and washed with brine (10 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue so obtained was purified by column chromatography eluting with 1:10 of ethyl acetate-hexanes to give the desired compound as a colorless oil. Yield 35%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Br[C:13]([CH3:16])([CH3:15])[CH3:14].CO.[OH-].[K+]>CS(O)(=O)=O>[C:13]([C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)Br
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Methyl 4-hydroxybenzoate (3.00 g) was dissolved in methanesulfonic acid (15 mL), and 2-bromo-2-methylpropane (11.1 mL) was added to the solution, and then the mixture was stirred at 70° C. for 16 hours. To the reaction solution, methanol (20 mL) was added, and then the reaction mixture was stirred at 50° C. for 3 hours. 1N potassium hydroxide was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% potassium carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (1.83 g) as a pale yellow crystal.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33](=[O:40])([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH2:34].O.O.O.[O-]C1C=CC=CC=1.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([NH:34][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])=[CH:21][CH:20]=3)[N:13]=[C:12]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccc(Br)cc3)c2CC1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
A mixture of 1-(4-bromo-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 113; 0.04 mmol), tert-butyl carbamate (0.05 mmol), sodium phenoxide trihydrate (0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.001 mmol), and tri-tert-butylphosphine (0.05 mmol) in anhydrous toluene (3 mL) was heated under N2 at 100° C. for 6 h, 70° C. for 15 h and 100° C. for 2.5 h. After cooling to RT, the reaction mixture was purified directly by preparative TLC (2:1 hexanes/EtOAc) to yield 0.008 g of 1-(4-tert-butoxycarbonylamino-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester, which was then diluted with DMF (1 mL) and treated with NaH (60%, 1.5 equiv.). After 15 min, methyl iodide (1.5 equiv.) was added. After 1 h, the reaction was quenched with H2O and the mixture was extracted with EtOAc (2×). The combined organic layers were dried over Na2SO4 and concentrated. The resulting semi-solid was then dissolved in CH2Cl2/MeOH (9:1, 1 mL) and treated with HCl (1 N in Et2O, 4 mL). The mixture was stirred at RT for 3 h, then was concentrated. The resulting oil was purified by preparative TLC (10% 2 M NH3 in MeOH/CH2Cl2) to yield 0.002 mg of the title compound as a white solid. MS (ESI): exact mass calculated for C21H23ClN4, 366.16; found, m/z 367.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.32 (m, 4H), 6.84 (d, J=8.6 Hz, 1H), 6.48-6.45 (m, 2H), 5.12 (s, 2H), 2.84-2.81 (m, 4H), 2.79-2.77 (m, 2H), 2.69-2.66 (m, 2H), 2.63 (s, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1)(=[O:27])[CH3:26].[Cl:40][C:41]1[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43][N:44]([CH2:47][C:48](O)=[O:49])[C:45]=1[CH3:46]>>[C:25]([C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:35][CH2:36][N:37]([C:48](=[O:49])[CH2:47][N:44]3[C:45]([CH3:46])=[C:41]([Cl:40])[C:42]([C:51]([F:54])([F:53])[F:52])=[N:43]3)[CH2:38][CH2:39]2)=[CH:32][CH:33]=1)(=[O:27])[CH3:26]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(=O)c1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Acetyl-phenyl)piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.80 (d,1H), 6.98 (d, 2H), 5.38 (s, 2H), 3.61 (m, 4H), 3.48 (m, 2H), 3.39 (m, 2H), 2.46 (s, 3H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=429.1, found=429.0.