Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[O:21][CH2:20][CH2:19][CH2:18]3)O1.Br[C:27]1[C:28]([C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:29]([CH3:33])[S:30][C:31]=1[CH3:32]>O.CN(C)C=O.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.[Pd]>[O:21]1[C:22]2[CH:23]=[CH:24][C:15]([C:27]3[C:28]([C:34](=[O:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:29]([CH3:33])[S:30][C:31]=3[CH3:32])=[CH:16][C:17]=2[CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)C(=O)c1c(C)sc(C)c1Br
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Temperature: 110 °C
Yield: 37.7 %

Procedure:
Under a nitrogen atmosphere, sodium carbonate (78 mg, 0.7 mmol), palladium tetrakis(triphenylphosphine) (81 mg, 0.07 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (182 mg, 0.7 mmol) were added to a solution of ethyl (4-bromo-2,5-dimethyl-thiophen-3-yl)-oxo-acetate (17c) (200 mg, 0.69 mmol) in a mixture of water (3.5 mL) and N,N-dimethylformamide (11 mL). The mixture was heated at 110° C. for 1 hour. The mixture was then cooled at room temperature, concentrated in vacuo and water (30 mL) was added. The aqueous layer was extracted with ethyl acetate (2×30 mL). The organic layer was washed with brine (30 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 80/20) to afford the desired product (17d) as a white solid (90 mg, 0.26 mmol, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][CH3:13])[CH2:10][CH3:11].CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14][CH2:24][O:25][CH3:26])([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCC(O)(CC)c1ccc(C)cc1Br
Reactant: COCCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)(OCOC)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 11 h
Yield: 57 %

Procedure:
To a stirring solution of 3-(2-bromo-4-methylphenyl)pentan-3-ol (6.0 g, 23.3 mmol) in DCM (20 mL) at rt were successively added DIPEA (8.1 mL, 47.4 mmol) and MOMCl (2.7 mL, 35.5 mmol) over a 10 min period. The solution was stirred 11 h at rt followed by addition of aqueous NH4Cl solution (100 mL). The aqueous phase was segregated, and the organic one was washed with water (100 mL), brine, dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(3-(methoxymethoxy)pentan-3-yl)-4-methylbenzene (4.0 g, yield 57%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:20]([F:27])([F:26])C(OCC)=O>CN(C=O)C.CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:20]([F:27])[F:26])=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)(C)c1cc(Br)ccc1O
Reactant: CCOC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(Br)ccc1OC(F)F
Temperature: 80 °C
Yield: 33.2 %

Procedure:
step 1—To a mixture of 4-bromo-2-tert-butyl-phenol (640 mg, 2.795 mmol) and potassium carbonate (1.20 g, 8.682 mmol) in DMF (8 mL) was added ethyl chlorodifluoroacetate (1.1 mL, 8.687 mmol). The reaction was heated to 80° C. overnight then cooled to RT, and diluted with EtOAc and water. The organic layer was washed with water, with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 column eluting with hexane to afford 259 mg (33%) of 4-bromo-2-tert-butyl-difluoromethoxy-benzene (20) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:3][CH2:4][CH2:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[Br:24][CH:25](Br)[CH3:26].O>C(COC)OC>[Br:24][CH2:25][CH2:26][C:6]([CH2:5][CH2:4][CH2:3][C:2]([F:21])([F:1])[C:17]([F:18])([F:19])[F:20])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(Br)Br
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(CCBr)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Diethyl 2-(4,4,5,5,5-pentafluoropentyl)propane-1,3-dioate (51 0 mg, 1.592 mmol) was dissolved in anhydrous dimethoxyethane (5 ml). Sodium hydride (60%. 88 mg, 2.2 mmol) was added to the solution and then stirred at room temperature for 1 h under nitrogen atmosphere. Dibromoethane (0.82 ml, 9.55 mmol) was added to the mixture and then stirred at 70° C. for 5 h under nitrogen atmosphere. When the reaction was completed, the mixture was cooled to room temperature. Water was added to reaction solution which was then extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to column chromatography (n-hexane:dichloromethane=3:1) to obtain 489 mg (yield: 72° C.) of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:59])[C:33]([CH3:58])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][CH2:51][C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:29][O:30][C:31]1[C:32](=[O:59])[C:33]([CH3:58])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][CH2:51][C:52]3[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=3)=[C:45]([CH:49]=2)[C:46]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2cc(CC3=C(C)C(=O)C(OC)=C(OC)C3=O)ccc2OCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 7 %

Procedure:
Ethyl 4-aminobenzoate (0.248 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.2115 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.020 g, 0.0351 mmol, 7%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2.O>CN(C)C1C=CN=CC=1.CC1C=CC=CC=1C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2cc(Oc3ccnc4cc(OC)c(OC)cc34)ccc2[nH]1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (362 mg), ethyl 5-hydroxy-1H-2-indolecarboxylate (277 mg), and 4-dimethylaminopyridine (195 mg) were suspended in o-xylene, and the suspension was heated under reflux overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using ethyl acetate-hexane on silica gel to give the title compound (161 mg, yield 30%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:14]([SH:15])=[N:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([OH:3])=O.[CH:16]([NH:18][NH:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[SH:15][C:14]1[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[NH:24][C:23]3[CH:22]=[CH:21][C:20]([NH:19][NH:18][CH:16]=[O:17])=[CH:26][CH:25]=3)[CH:5]=2)[N:11]=[N:12][N:13]=1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Reactant: Nc1ccc(NNC=O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=CNNc1ccc(NC(=O)c2cccc(-n3nnnc3S)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.4 %

Procedure:
In 50 ml of dimethylformamide were dissolved 11.1 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole and 7.6 g of 4-(2-formylhydrazino)aniline, and a solution of 10.3 g of dicyclohexylcarbodiimide in 10 ml of dimethylformamide was added dropwise to the solution at 0° C. in a nitrogeneous atmosphere over about 30 minutes. After the addition, the mixture was stirred at room temperature for 3 hours. The precipitated dicyclohexylurea was separated by filtration, and the filtrate was added to 500 ml of ice-water while stirring. The thus precipitated crystals were filtered, washed with water and dispersed in 100 ml of hot methanol. The dispersion was allowed to cool to room temperature and filtered. The filtrate was washed with methanol to obtain 4.5 g of the desired compound. Melting point: 202° C. (with decomposition).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][CH:20]([CH3:66])[C:21]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([C:57]3[N:58]=[N:59][NH:60][C:61]=3[Si](C)(C)C)[CH:53]=2)[CH:48]=1)([C:23]1[N:24]=[CH:25][N:26](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:27]=1)[OH:22]>C1COCC1.O>[NH:26]1[CH:27]=[C:23]([C:21]([C:47]2[CH:56]=[CH:55][C:54]3[C:49](=[CH:50][CH:51]=[C:52]([C:57]4[N:58]=[N:59][NH:60][CH:61]=4)[CH:53]=3)[CH:48]=2)([OH:22])[CH:20]([CH3:19])[CH3:66])[N:24]=[CH:25]1
Reactant: CC(C)C(O)(c1ccc2cc(-c3nn[nH]c3[Si](C)(C)C)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)(c1ccc2cc(-c3c[nH]nn3)ccc2c1)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 166.6 %

Procedure:
A solution of tetrabutylammonium fluoride in THF (1M:3 mL) was added to a solution of 2-methyl-1-(6-(5-trimethylsilyl-1H-1,2,3-triazol-4-yl)-2-naphthyl)-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (820 mg) in THF (3 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The residue was purified by column chromatography (eluent; hexane:THF=4:1) and crystallized from ethyl acetate-hexane to give the titled compound (703 mg) as a colorless powder.
Reaction SMILES: N1[CH:5]=[CH:4]N=C1.B([O-])[O-].[C:9](O)([C:11](F)(F)F)=O>CO>[C:11]1([C:5]2[CH:4]=[CH:11][CH:9]=[CH:11][CH:9]=2)[CH:9]=[CH:4][CH:5]=[CH:5][CH:4]=1
Reactant: O=C(O)C(F)(F)F
Reactant: c1c[nH]cn1
Agent: [O-]B[O-]
Solvent: CO
Product: c1ccc(-c2ccccc2)cc1

Procedure:
Example 1-4-d was prepared from 1-4-c and 1b in similar fashion to the preparation of 1d from 1b and 1c. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.99-1.60 (m, 18 H) 1.75-2.11 (m, J=73.24 Hz, 6 H) 2.12-2.32 (m, 2 H) 3.32-3.41 (m, 2 H) 3.56 (s, 2 H) 4.63-5.02 (m, 2 H) 6.98-8.28 (m, 10 H) 11.67-12.33 (m, 2H); LC conditions: Phenomenex Luna 3.0×5.0 mm S10, Solvent A—0.1% TFA in 10% MeOH/90% H2O, Solvent B—0.1% TFA in 90% MeOH/10% H2O, 0 to 100% B over 2 min, Stop time=3 min, Flow rate=4 ml/min, Wavelength=220 nm, LC/MS (M+H)+=625.32. Retention time=1.438 min Additional Biphenyl Analogs were Prepared Similarly.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([Cl:8])=[N:6][CH:7]=1.B(F)(F)[F:11].CCOCC.C(ON=O)(C)(C)C.CCCCCC>ClCCl>[Cl:8][C:5]1[C:4]([Cl:9])=[CH:3][C:2]([F:11])=[CH:7][N:6]=1
Reactant: FB(F)F
Reactant: Nc1cnc(Cl)c(Cl)c1
Agent: CC(C)(C)ON=O
Solvent: CCCCCC
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1cnc(Cl)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
5-Amino-2,3-dichloropyridine (0.80 g) in dichloromethane (10 ml) was added to boron trifluoride etherate (0.92 ml) at -15° C. under nitrogen. Dichloromethane (15 ml) was added followed by t-butylnitrite (0.71 ml) in dichloromethane (5 ml). After 15 minutes the mixture was allowed to warm to -5° C. over 20 minutes. Hexane was added and the resulting solid was filtered, air-dried and washed with ether and stored at approximately -20° C. overnight. The solid was then heated until gas evolution had ceased and the product kugelrohr distilled to give 2,3-dichloro-5-fluoropyridine (0.104 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:9][C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1)[CH3:19]
Reactant: O=C(O)COc1ccc(F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 50 g (0.29 moles) of p-fluorophenoxy acetic acid in one liter of absolute ethanol is added 10 ml of sulfuric acid. The mixture is heated to reflux for 18 hours, cooled to room temperature, and evaporated under vacuum. It is then poured onto 300 g of ice, extracted twice with 500 ml of ether, washed twice with 250 ml of a saturated solution of sodium bicarbonate, 100 ml of saturated sodium chloride solution, dried with magnesium sulfate, filtered and evaporated under vacuum giving 58 g of an oil. This is crystallized from 50 ml of hexane at -25° C. to give 55 g (90%) of the subject product as colorless crystals, mp 32°-33° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[CH2:9][O:8]1.Cl.[NH:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:16]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[OH:8][CH:7]([CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[CH2:9][N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[NH:24][C:23]2=[O:31])[CH2:16]1
Reactant: O=c1[nH]c2ccccc2n1CC1CCCNC1
Reactant: COc1ccccc1OCC1CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1OCC(O)CN1CCCC(Cn2c(=O)[nH]c3ccccc32)C1
Yield: 22 %

Procedure:
A mixture of 3.6 parts of 2-(2-methoxyphenoxymethyl)oxirane, 5.3 parts of 1,3-dihydro-1-(3-piperidinylmethyl)-2H-benzimidazol-2-one monohydrochloride, 6 parts of sodium carbonate and 80 parts of ethanol is stirred and refluxed for 6 hours. The reaction mixture is cooled, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding 1.8 parts (22%) of 1,3-dihydro-1-{1-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-3-piperidinylmethyl}-2H-benzimidazol-2-one; mp. 158.1° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[CH3:27])[CH:20]=[CH:19][CH:18]=1>>[CH2:13]([O:12][C:10]([C:2]1[N:1]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[CH3:27])[CH:20]=[CH:19][CH:18]=2)[C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Cc1cccc2cccc(CBr)c12
Product: CCOC(=O)c1cc2ccccc2n1Cc1cccc2cccc(C)c12

Procedure:
Using general procedure A (Exp. 1.3.), 1,8-dimethyl-naphthalene was reacted with N-bromosuccinimide to give 1-bromomethyl-8-methyl-naphthalene as white solid. MS: 234.1 ([M]+). Using general procedure B, ethyl 2-indole carboxylate was coupled with 1-bromomethyl-8-methyl-naphthalene to give 1-(8-methyl-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a white solid. MS: 314.4 ([M−H]−).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34]N)=[CH:30][CH:29]=1.CCN(CC)CC>C(O)C>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:30][CH:29]=1
Reactant: COc1ccc(NN)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nccc2-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-methoxyphenylhydrazine hydrochloride (262 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (154 mg, 37%).
Reaction SMILES: [CH2:1]([C:15]1[CH:19]=[CH:18][S:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C>[Br:27][C:16]1[S:17][CH:18]=[CH:19][C:15]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCCCc1ccsc1
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccsc1Br
Reaction time: 8 h

Procedure:
3-Tetradecylthiophene (5.6 g, 20 mmol) was dissolved in 30 mL of dry DMF. NBS (3.56 g, 20 mmol) was dissolved in 20 mL of DMF. At room temperature, the NBS solution was add to the 3-tetradecylthiophene solution dropwise. The reaction mixture was stirred in dark overnight. The reaction mixture was then poured onto ice, and then extracted with tert-butyl methyl ether (50 mL×3). The organic layer was collected and washed with half-brine (5×100 mL). After the organic layer was dried by MgSO4, the solvent was removed by rotary evaporation. The organic solution thus formed was dried by vacuum pump to give 2-bromo-3-tetradecylthiophene as a colorless oil. The product was used as is in the next step without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[C:6]1[NH:17][C:18]1[S:19][C:20]2[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=2[N:22]=1)[CH:2]([CH3:4])[CH3:3].[CH2:32]([NH2:34])[CH3:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:32]([NH:34][C:14]([C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:7][C:8]=2[CH:13]=1)=[O:16])[CH3:33]
Reactant: CCN
Reactant: CC(C)Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2CC(C)C

Procedure:
1-Isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid ethylamide (47.0 mg) was prepared by following General Procedure F starting from 1-isobutyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid (100.0 mg), ethylamine (2.0 M solution in THF, 0.5 mL), HBTU (130.0 mg) and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 479 and 1H NMR (DMSO-d6, 400 MHz): δ 8.43 (1H, m), 8.09 (1H, m), 7.91 (1H, m), 7.73 (1H, m), 7.54 (1H, m), 7.37-7.35 (1H, m), 4.04-4.00 (2H, m), 3.32 (2H, m), 2.28 (1H, m), 1.16-1.13 (3H, t), 0.95-0.91 (6H, m), 2 —NH proton signals were not observed.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>C(#N)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)Cl
Reactant: c1ccc(Oc2ccc(NCc3cccnc3)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A 2.8 g. portion of 3-(4-phenoxyphenylaminomethyl)pyridine was dissolved in 100 ml. of acetonitrile, and to it were added 2 g. of potassium carbonate and 1.3 g. of ethanesulfonyl chloride. The mixture was stirred at ambient temperature for 2 days, and it was then filtered and concentrated under vacuum. The oily residue was chromatographed on silica gel, eluting with 4.1 toluene:acetone. The product-containing fractions were evaporated under vacuum, and the residue was taken up in diethyl ether. Upon standing, a precipitate formed, which was shown to be 2.0 g. of the desired product, m.p. 79°-80°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.I[C:20]1[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].Cl>[Cu]Br.CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)[C:6]([C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: FC(F)(F)c1cccc(I)c1
Agent: [Cu]Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN1CCCC1=O
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2n1-c1cccc(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
A mixture of 1-(5-chloro-1H-indol-2-yl)heptan-1-one (9.14 g) synthesized above, 3-iodobenzotrifluoride (1.97 mL), copper (I) bromide (327 mg), potassium carbonate (2.36 g) and N-methyl-2-pyrrolidone (30 mL) was deaerated, and the mixture was stirred under argon atmosphere at 180° C. for 1 day. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to give the title object compound (0.78 g, 17%) as a brown oil.
Reaction SMILES: [CH:1]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:16]O>>[CH:1]1([C:8]([O:10][CH3:16])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCCCCC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCCCCC1

Procedure:
To a solution of 25.0 g cycloheptanecarboxylic acid in methanol (300 mL) was added concentrated H2SO4 (0.5 g) and the mixture was stirred at reflux overnight. The reaction mixture was concentrated under vacuum and the residue was diluted with ethyl ether (500 mL). The mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.