Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:4]=[CH:3]1.C([Li])CCC.[CH:20]1([C:23](Cl)=[O:24])[CH2:22][CH2:21]1>C1COCC1.CCCCCC>[CH:20]1([C:23]([C:3]2[N:2]([CH3:1])[C:14]3[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=[CH:6][C:5]=3[N:4]=2)=[O:24])[CH2:22][CH2:21]1
Reactant: Cn1cnc2cnc3ccccc3c21
Reactant: O=C(Cl)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1c(C(=O)C2CC2)nc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 36.5 %

Procedure:
In the same manner as in Ex. 1, to a solution containing 550 mg of 1-methyl-1H-imidazo[4,5-c]quinoline (II-2) in 25 ml of THF and a mixture of 2.2 ml of 1.6M solution of n-butyl lithium in hexane-2 ml of THF was added 0.75 g of cyclopropanecarbonyl chloride. The reaction mixture was gradually warmed to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous ammonia. The organic layer was washed with water and brine, and then dried. The ethyl acetate was removed by evaporation, and the residue was chromatographed on a column of silica gel for purification. The fraction eluted with ethyl acetate was concentrated and the residue was crystallized from n-hexane to give 275 mg (yield: 36%) of the titled compound (Ia-1). This was recrystallized from ethyl acetate n-hexane to give colorless crystals melting at 156°~158° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([F:19])[CH:13]=[C:12](F)[C:11]=1[F:21].[CH3:22][O-:23].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([F:19])[CH:13]=[C:12]([O:23][CH3:22])[C:11]=1[F:21]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1c(F)cc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(F)c([N+](=O)[O-])c(Nc2ccc(I)cc2F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 456.4 %

Procedure:
To a solution of 2-fluoro-N-(2,3,5-trifluoro-6-nitrophenyl)-4-iodobenzeneamine (2.55 g, 6.16 mmol) in THF (40 mL), was slowly added NaOMe solution (25% in MeOH, 1.4 mL, 0.62 mmol) at −78° C. The mixture becomes dark in color immediately. After the addition was complete, the reaction mixture was warmed to rt and stirred overnight. It was then diluted with ethyl acetate and washed with water, brine and then dried. After removal of volatiles, the crude product was purified by silica gel flash column using 2-10% ethyl acetate/hexanes as eluent to produce the desired product as yellow powder (1.2 g, 48%). Unreacted starting material 2-fluoro-N-(2,3,5-trifluoro-6-nitrophenyl)-4-iodobenzeneamine (1 g) was also recovered.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:28]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:26]=[C:25](Cl)[N:24]=3)=[O:22])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(OCC)(=O)C.C(N(CC)CC)C.[Pd]>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([C:23]3[CH:28]=[C:27]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:26]=[CH:25][N:24]=3)=[O:22])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(N2CCOCC2)nc(Cl)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cc(N2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.9 %

Procedure:
To a mixture of 2-chloro-6-morpholin-4-yl-pyrimidine-4-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide (95 mg) and 10% Pd/C (10 mg) in ethyl acetate (4 ml) is added a few drops of triethylamine. The mixture is then shaken at room temperature under hydrogen at 50 psi for 8 h. The solvent is then removed under reduced pressure and the residue purified by column chromatography on silica gel eluted with ethyl acetate:hexane (1:1) to 100% ethyl acetate to provide 6-morpholin-4-yl-pyrimidine-4-carboxylic acid [4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-amide as a solid (22 mg).
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1>C1(C)C(C)=CC=CC=1>[C:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: Cc1ccccc1C
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 125 °C
Reaction time: 1 h

Procedure:
116.3 g (0.61 mol) of decanoyl chloride were heated in 300 ml of xylene to 125° C. and over the course of 6 hours 69.1 g (0.5 mol) of 4-hydroxybenzoic acid were introduced in portions. The batch was stirred at 125° C. for 1 hour thereafter, cooled to room temperature, and filtered with suction, and the filter product was washed three times with 45 ml of xylene. The yield after drying under reduced pressure at 100° C. was 108.4 g (74% of theory). According to HPLC and NMR measurement, the product was free from decanoic acid and from unreacted para-hydroxybenzoic acid, but contained 0.4% by weight of byproducts such as dimers and trimers of the para-hydroxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[NH2:34][CH2:35][CH:36]([OH:43])[CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[OH:43][CH:36]([CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:35][NH:34][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: NCC(O)CN1CCCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCC(O)CN1CCCC1

Procedure:
5-[5-(2,6-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was coupled with 1-amino-3-pyrrolidin-1-yl-propan-2-ol to give the titled compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:19][CH3:20])(=[O:18])[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:13]([C:12]([O:19][CH3:20])=[O:18])[C:14]([O:16][CH3:17])=[O:15])([O-:3])=[O:2]
Reactant: COC(=O)CC(=O)OC
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)OC
Yield: 96 %

Procedure:
75.5 g (500 millimoles) of 3-nitrobenzaldehyde and 73 g (550 millimoles) of dimethyl malonate were stirred for 4 hours at 60° C., similarly to Example 9. After the addition of 5 ml of glacial acetic acid, the mixture was worked up in a conventional manner. The product of melting point 78°-80° C. was obtained in 96% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:10])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:37])C(=O)C1>CN(C=O)C>[Br:37][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([CH3:10])[CH3:1]
Reactant: CC(C)=CCCCCCO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)=CCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 7-methyl-oct-6-en-1-ol (1.00 g, 7.04 mmol) in DMF (18 mL) was added triphenylphosphine (2.06 g, 7.85 mmol). The solution was cooled to 0° C. and NBS (1.35 g, 7.58 mmol) was added in portions. After stirring for 30 min at room temperature, the reaction was quenched with methanol (1 mL). The solution was diluted with ether (100 mL), washed with water, saturated aqueous NaHCO3 and brine successively. The organic layer was dried and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexane to afford 8-bromo-2-methyl-oct-2-ene (1.11 g, 77%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 5.10 (1H, m), 3.40 (2H, t, J=6.9 Hz), 1.98 (2H, m), 1.86 (2H, m), 1.68 (3H, d, J=0.9 Hz), 1.60 (3H, d, J=0.3 Hz), 1.42 (2H, m), 1.41 (4H, m); 13C NMR (75 MHz, CDCl3) δ 132.08, 124.81, 34.59, 33.44, 29.64, 28.49, 28.44, 26.36, 18.35.
Reaction SMILES: [CH:1]1([NH:4][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH3:6])[CH2:3][CH2:2]1.[CH2:13]([C:15]1[C:20](=[O:21])[NH:19][C:18]([CH3:22])=[C:17]([C:23]2[S:27][C:26]([S:28](Cl)(=[O:30])=[O:29])=[CH:25][CH:24]=2)[CH:16]=1)[CH3:14]>ClCCl>[CH:1]1([N:4]([CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH3:6])[S:28]([C:26]2[S:27][C:23]([C:17]3[CH:16]=[C:15]([CH2:13][CH3:14])[C:20](=[O:21])[NH:19][C:18]=3[CH3:22])=[CH:24][CH:25]=2)(=[O:29])=[O:30])[CH2:3][CH2:2]1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CC(NC1CC1)c1ccccn1
Solvent: ClCCl
Product: CCc1cc(-c2ccc(S(=O)(=O)N(C3CC3)C(C)c3ccccn3)s2)c(C)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.3 %

Procedure:
A mixture of cyclopropyl(1-pyridin-2-yl)ethylamine (73.5 mg, 0.453 mmol), 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride (144 mg, 0.453 mmol), PS-piperidinomethyl (155 mg, 0.542 mmol, beads) and dichloromethane (5 mL) is stirred at room temperature overnight. The reaction mixture is filtered and the filtrate is evaporated. The residue is purified by chromatography on an ISCO Redisep 10 g cartridge eluting with ethyl acetate-5% methanol to afford 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonic acid cyclopropyl(1-pyridin-2-yl)ethylamide (85 mg, 43% yield) as a white solid. A hydrochloride salt is prepared by dissolving the amine (85 mg, 0.192 mmol) in methanol (2 mL), adding 1 M ethereal hydrochloric acid (0.3 mL), some methanol is removed, more ether added and the hydrochloride salt is collected by filtration (50 mg, 54% yield as an off white solid). RT=2.93 min; m/e=444; 1H NMR (δ, ppm): 11.84 (1H, br s), 8.6 (1H, d), 8.02 (1H, m), 7.69 (1H, d), 7.61 (1H, d), 7.50 (1H, m), 7.37 (1H, s), 5.24 (1H, d), 5.27 (2H, m), 2.40 (2H, m), 2.33 (3H, s), 1.53 (3H, d), 1.13 (3H, t), 0.6-0.96 (4H, m).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:35][C:36](Cl)=[O:37].[OH-].[K+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=2)[O:11][CH2:35][C:36]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCOc1ccc(C(O)CNCc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)C(=O)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22.50 g; 63.3 mmol) and Et3N (9.7 mL; 69.6 mmol) in CH2Cl2 (500 mL) was added dropwise a solution of chloroacetyl chloride (5.5 mL; 69.6 mmol) in CH2Cl2 (25 mL), at 0° C. After 1 hour at 0° C. the reaction mixture was quenched with 1M aqueous HCl (200 mL). The layers were separated and the organic layer washed with a 5% aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in 2-propanol (250 mL) and KOH (4.26 g; 76 mmol) was added. The resulting mixture was stirred at RT for 1 hour and subsequently concentrated in vacuo. The crude product was partitioned between EtOAc and 0.5 M aqueous HCl. The layers were separated and the organic layer was washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) and evaporated in vacuo to afford 4-benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one (22.30 g) which was used as such in the next step.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].S([O-])(O)(=O)=O.[K+]>CN(C)C=O>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cccc(I)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
To a solution of m-iodophenol (1.22 g, 5.55 mmol) in N,N-dimethylformamide (15 ml) were added potassium carbonate (1.40 g, 10.1 mmol) and t-butyl bromoacetate (1.22 ml, 6.25 mmol), and the mixture was stirred for 3 hours at 50° C. Thereto was added an aqueous 5% potassium hydrogensulfate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=4:1) to give the subject compound (1.85 g, 100%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>O1CCCC1>[C:24]([S:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[CH:10]=[C:9]2[C:14]2[CH:19]=[CH:18][C:17]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1)(=[O:26])[CH3:25]
Reactant: Cc1cc(-c2ccc(S(N)(=O)=O)cc2)n(-c2ccc(S)cc2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Sc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
0.90 g (2.6 mmol) of 1-(4-mercaptophenyl)-4-methyl-2-(4-sulfamoylphenyl)-pyrrole (prepared as described in Example 129) was dissolved in 15 ml of tetrahydrofuran, and 0.27 ml (2.9 mmol) of acetic anhydride was added to the resulting solution. 0.53 ml (6.5 mmol) of pyridine was then added to the mixture, which was then stirred at room temperature overnight. The reaction mixture was then concentrated by evaporation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue. The resulting mixture was then extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. The residue thus obtained was applied to a silica gel chromatography column and eluted with a 3:2 by volume mixture of hexane and ethyl acetate, to give 0.44 g (yield 43%) of the title compound as a white powder, melting at 149-152° C.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]CC)=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO.C(#N)C>[F:29][C:2]([F:1])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC#N
Product: O=C(O)/C=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To (E)-ethyl 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)acrylate (C17) (1.95 g, 4.83 mmol) in methanol (25 mL) was added sodium hydroxide (2 N, 10 mL, 20.0 mmol) and the solution was stirred at room temperature overnight. The methanol was evaporated off under reduced pressure, the reagents were diluted with acetonitrile, and additional sodium hydroxide (2 N, 20 mL, 40.0 mmol) was added. The reaction was stirred at room temperature for 5 hours and then acidified with hydrogen chloride (2 N). The white precipitate was vacuum-filtered to afford the title compound as a white solid (1.72 g, 94%): mp 239-241° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 9.44 (s, 1H), 8.14 (d, J=8.4 Hz, 2H), 8.12-8.05 (m, 2H), 7.85 (d, J=8.4 Hz, 2H), 7.69-7.59 (m, 3H), 6.61 (d, J=16.0 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 376 ([M+H]+).
Reaction SMILES: FC1C=CC([N:8](CC2C=CC=CN=2)[C:9](=O)[C:10]2[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=2)=CC=1.[SH2:25].[Na]>CN(C)C=O.C(OCC)(=O)C>[C:9]([NH2:8])(=[S:25])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1
Reactant: S
Reactant: O=C(c1ccc(Cl)nc1)N(Cc1ccccn1)c1ccc(F)cc1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=S)c1cccnc1
Reaction time: 1 h
Yield: 82 %

Procedure:
In a round bottom flask, N-(4-fluoro-phenyl)-N-pyridin-2-ylmethyl-6-chloro-nicotinamide intermediate X (1.078 g, 3.16 mmol) and anhydrous sodium hydrogen sulfide (0.354 g, 6.32 mmol) was suspended in anhydrous dimethylformamide (10 mL). The suspension was heated to reflux, and the reaction mixture turned a deep green color. After 1 h, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (20 mL). The aqueous layer was back extracted with ethyl acetate (2×20 ml), and the organic layers combined and washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and evaporated by rotary evaporation to yield 0.88 g (82%) of thionicotinamide intermediate XI as a dark yellow oil. TLC (EtOAc/hexanes, 2:1) Rf=0.1; ESI-MS m/z=339.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][C@@H:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].Cl[C:26]1[N:30]([CH2:31][C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[C:29]2[CH:37]=[CH:38][CH:39]=[CH:40][C:28]=2[N:27]=1>C(Cl)Cl.[Cu]>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:26]2[N:30]([CH2:31][C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:29]3[CH:37]=[CH:38][CH:39]=[CH:40][C:28]=3[N:27]=2)[CH2:9][C@@H:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: Clc1nc2ccccc2n1Cc1cccs1
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@H](N)C[C@@H]2Cc2ccccc2)c1
Agent: [Cu]
Solvent: ClCCl
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](Nc3nc4ccccc4n3Cc3cccs3)C[C@@H]2Cc2ccccc2)c1
Yield: 94 %

Procedure:
(±)-cis-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinamine (1.2 g), 2-chloro-1-(2-thienylmethyl)-1H-benzimidazole (2.24 g) and copper (0.6 g) were stirred at 150° C. for 5 hours. The mixture was taken up in CH2Cl2 and filtered. The filtrate was washed with diluted NH4OH and stirred. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 97/3). The pure fractions were collected and the solvent evaporated. The residue was crystallized from CH3CN, yielding 1.87 g (35%) of (±)-cis-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-N-[1-(2-thienylmethyl)-1H-benzimidazol-2-yl]-4-piperidinamine (comp. 76; mp. 201.4° C.).
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH:12]=[C:13]([F:15])[CH:14]=2)[C:10]#[N:11])=[CH:4][CH:3]=1.C[Sn](C)(C)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>C1(C)C=CC=CC=1.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>[F:15][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([C:5]2[O:6][C:2]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:3][CH:4]=2)[CH:14]=1)[C:10]#[N:11]
Reactant: N#Cc1cc(F)cc(-c2ccc(Br)o2)c1
Reactant: C[Sn](C)(C)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)cc(-c2ccc(-c3ccccn3)o2)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 43.4 %

Procedure:
Pd(PPh3)4 (10 mg, 0.009 mmol) was added to a solution of 3-(5-bromofuran-2-yl)-5-fluoro-benzonitrile (180 mg, 86% purity, 0.59 mmol) and 2-trimethylstannylpyridine (193 mg, 0.80 mmol) in toluene (2.5 mL) under argon. The resulting solution was stirred at 110° C. for 48 h. After cooling to room temperature, the solvent was removed in vacuo. Flash chromatography (silica gel, 35-100% dichloromethane in hexane) afforded 67.7 mg (43%) of 3-fluoro-5-(5-(2-pyridyl)-2-furyl)-benzonitrile. 1H-NMR (CDCl3), δ (ppm): 8.64 (d, 1H), 7.76-7.83 (m, 3H), 7.66 (m, 1H), 7.24 (m, 2H), 7.19 (d, 1H), 6.92 (d, 1H).
Reaction SMILES: Cl[C:2]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1)=O.O.[NH2:27][NH2:28]>N1C=CC=CC=1>[C:12]([C:10]1[CH:11]=[C:6]([C:4]2[C:3]3[C:2](=[N:24][C:23]([CH3:25])=[CH:22][CH:21]=3)[NH:28][N:27]=2)[CH:7]=[C:8]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:9]=1[OH:16])([CH3:15])([CH3:13])[CH3:14]
Reactant: NN
Reactant: Cc1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(Cl)n1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc2c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n[nH]c2n1
Yield: 81.2 %

Procedure:
The similar procedures in Example 1 by using 15.5 g of 4-(2-chloro-6-methylnicotinoyl)-2,6-di-tertiary butylphenol, 9.7 g of hydrazine hydrate and 85 ml of pyridine are carried out, and then the obtained crude crystals are recrystallized from ethanol to give 11.8 g of 3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine as white crystals, melting at 239°-240° C.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:14]2[NH:13][C:12](=[O:15])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CN(C)C=O.O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:13]1[C:14]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[CH:9][C:10]=2[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:12]1=[O:15])[CH3:35]
Reactant: CCC(CC)c1cccc2c1[nH]c(=O)n2C(=O)OC(C)(C)C
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(C(=O)OC(C)(C)C)c2cccc(C(CC)CC)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-(1-ethylpropyl)-2-oxo-2,3-dihydro-1H-benzimidazole-1-carboxylate (Reference Example 7; 4.94 g, 16.2 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (2.47 g, 17.9 mmol) and ethyl bromoacetate (1.98 mL, 17.9 mmol), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-20% ethyl acetate/n-hexane gradient mixture to give the title compound (6.17 g, 15.8 mmol, 98%) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH3:13])[O:10][N:9]=2)=[CH:4][CH:3]=1.B([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=1)(O)O>>[CH3:13][C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)[N:12]=1
Reactant: Cc1nc(-c2ccc(Br)cc2)no1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)O)cc3)cc2)no1

Procedure:
The title compound was prepared from 1-bromo-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzene [EP 0533268A1] (0.58 g) and 4-boronobenzoic acid (0.4 g) as described in Description 11 as a white solid (0.64 g, 97%).