Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[CH:12]N(C)C)[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].[H-].[Na+].O>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[N:19][C:18]([NH2:20])=[N:17][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ncc(OCc2ccccc2)cn1
Yield: 65.2 %

Procedure:
2-(Benzyloxy)-3-(dimethylamino)acrylaldehyde (10.95 g, 53.3 mmol) was dissolved in N-methylpyrrolidone (85 mL), the solution was added with guanidine hydrochloride (15.3 g, 160 mmol), and then the mixture was added with sodium hydride (50% in oil, 15.3 g, 320 mmol) with stirring on an ice bath, and stirred on an oil bath at 80° C. for 1 hour. The reaction mixture was added with water on an ice bath to decompose excessive sodium hydride, and then extracted with ether and water, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:acetone=10:1→4:1→2:1→1:1), and the concentrated residue was washed with ether-hexane, and taken by filtration to obtain 5-(benzyloxy)pyrimidin-2-amine (6.99 g, 65%) as pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH2:16].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([F:27])[C:25]=1F)[C:21]#[N:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH:16][C:25]1[C:18]([F:17])=[CH:19][C:20]([C:21]#[N:22])=[CH:23][C:24]=1[F:27]
Reactant: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1N
Reactant: N#Cc1cc(F)c(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1Nc1c(F)cc(C#N)cc1F
Temperature: 210 °C

Procedure:
A mixture of 5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-4-amin (i.e. the product of Step B) (0.25 g, 1.0 mmol), 3,4,5-trifluorobenzonitrile (0.188 g, 1.2 mmol) and cesium carbonate (0.390 g, 1.2 mmol) in acetonitrile (3 mL) was heated at 210° C. in a Biotage Initiator™ microwave apparatus for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a pad of silica gel on a sintered glass frit funnel. The filtrate was concentrated under reduced pressure and the resulting material was purified by silica gel chromatography (30% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.065 g).
Reaction SMILES: [NH2:1][C:2](=[O:43])[CH2:3][C:4]1[CH:42]=[CH:41][CH:40]=[CH:39][C:5]=1[CH2:6][CH2:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[C:21]([F:38])[CH:20]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(Cl)Cl.C1CCCCC1>[F:38][C:21]1[CH:20]=[C:19]([NH:18][C:10]2[N:9]=[C:8]([CH2:7][CH2:6][C:5]3[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=3[CH2:3][C:2]([NH2:1])=[O:43])[C:13]([C:14]([F:17])([F:15])[F:16])=[CH:12][N:11]=2)[CH:24]=[CH:23][C:22]=1[CH:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCCCC1
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)c(F)c2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.5 %

Procedure:
To a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-fluorophenyl)piperidine-1-carboxylate (A32) (0.209 g, 0.347 mmol) in DCM (4 mL) was added TFA (1.0 mL) and the resulting mixture was stirred at room temperature for 16 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (10 mL) and 2 M aqueous NaOH (10 mL). The aqueous layer was extracted with EtOAc (2×10 mL) then the combined organic layers washed with water (10 mL), brine (10 mL) and dried over MgSO4. The volatiles were removed in vacuo to give a yellow solid which was suspended in DCM/cyclohexane and the resulting suspension filtered to give the title compound 7 as a white solid (0.107 g, 61%); 1H NMR (400 MHz, d4-MeOH) δ 8.59 (s, 1H), 7.66 (dd, J=13.2, 2.1 Hz, 1H), 7.39 (dd, J=8.5, 2.1 Hz, 1H), 7.28-7.15 (m, 5H), 3.68 (s, 2H), 3.23-3.14 (m, 4H), 3.10 (dd, J=10.6, 5.4 Hz, 2H), 2.99 (tt, J=11.7, 3.8 Hz, 1H), 2.80 (td, J=12.4, 2.9 Hz, 2H), 1.87-1.68 (m, 4H). LCMS-A: rt 4.851 min; m/z 502.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[SH:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[S:22][C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: Sc1c(Cl)cccc1Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: COC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cccc2Cl)s1

Procedure:
Prepared according to the procedure described for step A of example 18 from methyl 5-chloro-4-nitrothiophene-2-carboxylate (5 g, 22.7 mmol) and 2,6-dichlorothiophenol (4.4 g, 24.8 mmol), The titled product was obtained as an off-white solid (5.5 g, 67% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.17 (1H, s), 7.83 (2H, m), 7.62 (1H, m), 3.77 (3H, s). MS m/z: 363.92, 365.93 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:18](=[O:27])[C:19]([CH3:26])=[C:20]([CH3:25])[C:21](=[O:24])[C:22]=2[CH3:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl.C(Cl)(=O)C(Cl)=O.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:17]2[C:18](=[O:27])[C:19]([CH3:26])=[C:20]([CH3:25])[C:21](=[O:24])[C:22]=2[CH3:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:29][OH:30])=[O:15])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)O)c2ccc(F)cc2)=C(C)C1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1=C(C)C(=O)C(C(CCCCCC(=O)NO)c2ccc(F)cc2)=C(C)C1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
7-(4-Fluorophenyl)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-heptanoic acid (0.8 g, 2.2 mmol) was dissolved in dichloromethane (20 ml), to which oxalyl chloride (0.5 ml) was added at room temperature. The reaction mixture was stirred at 50° C. for 1 hour, and the solvent was evaporated under reduced pressure The resultant residue was dissolved in THF (5 ml), which was added dropwise at room temperature to a mixture of hydroxylamine hydrochloride (0.5 g, 7 mmol) in THF (10 ml) and saturated solution of aqueous sodium hydrogencarbonate (10 ml). After being stirred at room temperature for 1 hour, ethyl acetate (20 ml) was added to the reaction mixture. The organic layer was washed with water, dried, and concentrated under reduced pressure, and the resultant residue was recrystallized from isopropylether, to give 7-(4-fluorophenyl)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-heptanohydroxamic acid (0.7 g, 85%). The physical properties are shown in the column of Compound No.6 in Table 1. In the similar manner, Compounds Nos. 2, 3, 5, 7, 9, and 18 were synthesized.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[C:17]([C:22](=[O:34])[NH:23][C:24]2[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=2)[CH:16]=3)=[C:8]([CH3:35])[CH:7]=1.O.[OH-].[Li+].C1COCC1.CO.O.Cl>O>[CH3:12][C:10]1[CH:11]=[C:6]([CH2:5][CH2:4][C:3]([OH:36])=[O:2])[CH:7]=[C:8]([CH3:35])[C:9]=1[C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([C:22](=[O:34])[NH:23][C:24]1[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=1)[CH:16]=2
Reactant: COC(=O)CCc1cc(C)c(-c2cc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(CCC(=O)O)cc(C)c1-c1cc2ccc(C(=O)Nc3ccc4ccccc4n3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-{3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-indol-2-yl]-phenyl}-propionic acid methyl ester (100 mg, 210 μmol) and lithium hydroxide monohydrate (26 mg, 620 μmol) in 5:5:2 THF/MeOH/H2O (10 mL) was stirred at ambient temperature for 18 h. The solution was concentrated to remove the organic solvents, then was diluted with water and neutralized with one equivalent of 1N HCl. The mixture was stirred vigorously for 30 min and the precipitate was filtered and washed with water. The solid was triturated with water and refiltered, then dried at 50° C. under reduced pressure to give the title compound. 1H NMR (DMSO-d6, 400 MHz): δ 12.15 (s, broad, 1H), 11.56 (s, 1H), 10.99 (s, 1H), 8.39 (s, 2H), 8.16 (s, 1H), 7.95 (d, J=7.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.79 (dd, J=8.3, 1.4 Hz, 1H), 7.73 (m, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.52 (t, J=7.1 Hz, 1H), 7.06 (s, 2H), 6.41 (d, J=1.4 Hz, 1H), 2.82 (t, J=7.4 Hz, 2H), 2.57 (t, J=7.6 Hz, 2H), 2.11 (s, 6H). MS (m/z) 464.3 (M+1); Retention time=1.36 min (Method 10).
Reaction SMILES: [Br:1][C:2]1(Br)[CH2:16][CH2:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]1=[O:17].C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([NH:12][CH2:13][CH3:14])=[O:11])[S:8][C:4]=2[C:3]=1[OH:17]
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)C(Br)(Br)CC2
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)Nc1nc2ccc(Br)c(O)c2s1
Temperature: 20 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
A suspension of 1-(6,6-dibromo-7-oxo-4,5,6,7-tetrahydro-2-benzothiazolyl)-3-ethyl-urea 5 (7.78 g, 19.6 mmol) in THF (50 mL) was treated with DBU (8.79 mL, 58.8 mmol, 3.0 eq) dropwise at about 20° C. A dark green suspension was obtained while heat was generated upon addition of DBU. It was stirred at about 20° C. for about 18 hours. The reaction mixture was concentrated and the residue was treated with saturated NH4Cl (aq) solution to neutral. A light brown colored precipitate was obtained. It was filtered off and washed with H2O (2×50 mL), small amount of MeOH and CH2Cl2, and finally dried under vacuum to give 4.83 g (78%) of the desired compound 6. 1H NMR (DMSO) δ 10.68 (br s, 1H, NH), 7.43 (d, 1H, J=8.5 Hz, ArH), 7.08 (d, 1H, J=8.5 Hz, ArH), 6.70 (br s, 1H, NH), 3.18 (m, 2H, CH2), 1.09 (t, 3H, J=7.2 Hz, CH3). LC/MS 316 (MH+); RP-HPLC RT 2.80 minutes.
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:10]=2)[N:5]=[CH:6][N:7]=1.[CH2:25]([OH:27])[CH3:26].[H-].[Na+]>O1CCCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2[N:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:10]=[C:3]3[C:2]([O:27][CH2:25][CH3:26])=[N:7][CH:6]=[N:5][C:4]=23)=[CH:19][CH:20]=1
Reactant: CCO
Reactant: Clc1ccc(-c2c3ncnc(Cl)c3nn2-c2ccccc2Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidine (I-2A-1c; 50 mg, 0.133 mmol) and ethanol (0.016 ml, 0.27 mmol) in tetrahydrofuran (1.5 ml) was added NaH (60% dispersion in oil, 14 mg, 0.33 mmol). After stirring for 1 hour, the reaction was extracted from saturated aqueous NaHCO3 with ethyl acetate, the combined organic layers were dried (MgSO4), concentrated and purified on a Biotage® Flash 12M column using a solvent gradient of 0-20% ethyl acetate in hexanes as eluant to afford 12A-1 (46 mg, 92%) as a colorless solid: +ESI MS (M+1) 385.4; 1H NMR (400 MHz, CD2Cl2) δ 8.56 (s, 1H), 7.58-7.46 (m, 6H), 7.34 (d, J=8.7 Hz, 2H), 4.70 (q, J=7.1 Hz, 2H), 1.53 (t, J=7.1 Hz, 3H).
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[O:31]>>[O:17]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]2[C:14]([F:15])=[CH:13][C:11]([NH:12][C:30](=[O:31])[O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:10][C:9]=2[F:16])[CH2:4][CH2:3]1
Reactant: Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cc(F)c(N2CCS(=O)(=O)CC2)c(F)c1
Temperature: 45 °C

Procedure:
To a 400 L glass-lined reactor containing the 4-(1,1-dioxido-4-thiomorpholinyl)-3,5-difluoroaniline/tetrahydrofuran solutions (Step 3, 12.6 kg, 48 moles, 1.0 eq) was added 47% potassium carbonate solution (14.1 kg, 48 moles, 1.0 eq). The mixture was heated to approximately 45° C., and isobutyl chloroformate (7.2 kg, 53 moles, 1.1 eq) was added while maintaining a reaction temperature between 45° C. and 55° C. The reaction was stirred at 45°-55° C. Once deemed complete, the reaction was quenched by slowly adding water (45 L) over 15 minutes. The reaction mixture was cooled to 25° C. and the phases are separated. The tetrahydrofuran solution was swapped to an isopropanol (150 L)/water (50 L) suspension, and the slurry was slowly cooled to 5° C. The yellow slurry was then filtered and the cake washed with cold isopropanol (2×30 L). The yellow solids are dried with 60° C. nitrogen to give the title compound, 1H NMR (CDCl3) (δ): 7.02 (m, 2H), 6.81 (s, 1H), 3.95 (d, 2H), 3.60 (m, 4H), 3.17 (m, 4H), 1.97 (m, 1H), 0.94 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][CH2:13][CH2:14][CH2:15]Br.[OH-].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]#[N:10])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: BrCCCCBr
Reactant: N#CCc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#CC1(c2ccccc2Cl)CCCC1
Reaction time: 1 h
Yield: 61.5 %

Procedure:
A mixture of 2-chlorophenylacetonitrile (20 g), 1,4-dibromobutane (28.5 g) and dimethyl sulphoxide (100 ml) was added dropwise to a stirred suspension of powdered potassium hydroxide (26 g) in dry dimethylsulphoxide (300 ml). The mixture was stirred for one hour, then poured onto ice/water and extracted with ethyl acetate. The extracts yielded an oil which was distilled under vacuum (b.p. 112°-116° C./1 mbar) to give 1-(2-chlorophenyl)cyclopentanecarbonitrile (16.7 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].Br[C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[C:35]([NH:37][CH:38]3[CH2:40][CH2:39]3)[N:34]=[C:33]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)[CH:32]=2)[CH:28]=[N:29][CH:30]=1.C(Cl)Cl>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:38]1([NH:37][C:35]2[N:34]=[C:33]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[N:42]=3)[CH:32]=[C:31]([C:27]3[CH:28]=[N:29][CH:30]=[C:25]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)[CH:10]=4)[CH:26]=3)[CH:36]=2)[CH2:40][CH2:39]1
Reactant: Cc1cccc(-c2cc(-c3cncc(Br)c3)cc(NC3CC3)n2)n1
Reactant: CN1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1cccc(-c2cc(-c3cncc(-c4cccc(CN5CCN(C)CC5)c4)c3)cc(NC3CC3)n2)n1

Procedure:
To a solution of 3-((4-Methyl-piperazin-1-yl)methyl)-phenyl boronic acid (Intermediate B1) (1.2 eq, 0.157 mmol, 0.037 g) and 2M Na2CO3 (2.0 eq, 0.262 mmol, 0.1 ml) in DME (1 ml) is added (5″-Bromo-6-methyl-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 2.36; step1) (1 eq, 0.131 mmol, 0.05 g) followed by [1,1′-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II), complex with DCM (0.1 eq, 0.013 mmol, 9.6 mg). The reaction mixture is heated using microwave radiation at 90° C. for 1 hour 30 mins. The reaction mixture is dissolved in EtOAc and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-30% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 491.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:15]=[CH:14][N:13]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Cc1ccccc1S
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1Sc1ccnc(Cl)c1
Yield: 88.7 %

Procedure:
Using the method of Example 3, Step A, 2-methylbenzenethiol (0.783 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 12.6 mmol) to provide 2-chloro-4-(o-tolylthio)pyridine (1.32 g, 89% yield) as an oil. 1H NMR (CDCl3) δ 8.09 (d, 1H), 7.55 (d, 1H), 7.37-7.44 (m, 2H), 7.29 (t, 1H), 6.81 (s, 1H), 6.75-6.78 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Reactant: C1CNCCN1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCNCC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-piperazin-1-yl-nicotin-amide was prepared starting from intermediate E and piperazine. MS calcd. for C26H24ClN5O2 [(M+H)+] 474.2, obsd. 474.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][N:12]1[C:16]([CH3:17])=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][N:12]1[C:16]([CH3:17])=[C:15]([C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH:14]=[N:13]1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cnn1C
Reactant: O=Cc1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc(F)c(C=O)c2)cnn1C
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.1 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (200 mg, 0.99 mmol) in DMF (5 mL) and H2O (1 mL) are added 1,5-dimethyl-1H-pyrazole-4-boronic acid pinacol ester (328 mg, 1.5 mmol), Pd(PPh3)4 (113 mg, 0.099 mmol) and K2CO3 (204 mg, 1.5 mmol) at room temperature. The solution is heated to 100° C. for 1 hour in a microwave reactor. The solution is cooled down and 3-mercaptopropyl-functionalized silica gel (500 mg) is added. The solution is stirred for 15 minutes and is filtered. The filtrate is washed with H2O (10 mL) and is extracted with EtOAc (3×10 mL). The combined organic layer is dried with MgSO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash chromatography with 20% EtOAc in Hepthane as the eluent to afford 5-(1,5-dimethyl-1H-pyrazol-4-yl)-2-fluoro-benzaldehyde (160 mg, 74%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1>[C:12]([C:11]1[C:2]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2C#N)CC1

Procedure:
0.5 g of the product from Example 1 and 0.48 g of N-methylpiperazine are boiled in 8 ml of dioxane for 3 hours. The mixture is then concentrated in vacuo, water is added to the residue and the solution formed is rendered neutral. The solid which has precipitated out is isolated, washed and dried.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1)[CH:8]=[CH:7]2)([O-])=O>CO.[Ni]>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[CH:8]2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(-n2ccc3cc([N+](=O)[O-])ccc32)cn1
Agent: [Ni]
Solvent: CO
Product: Nc1ccc2c(ccn2-c2ccc(N)nc2)c1
Yield: 79 %

Procedure:
A solution of compound 75 (200 mg, 0.79 mmol) in methanol (10 mL) was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad washed with methanol (20 mL). The filtrate was concentrated and the residue was subjected to silica gel chromatography (CH2Cl2 to MeOH:CH2Cl2, 1:9) to give compound 76 (140 mg, 79.1%) as an off-white solid. 1H NMR (DMSO-d6) δ 8.01 (d, J=2.7 Hz, 1H), 7.51 (dd, J=2.9, 6.1 Hz, 1H), 7.27 (d, J=3.0 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.1 Hz, 1H), 6.59 (s, 1H), 6.56 (s, 1H), 6.55 (dd, J=2.1, 6.8 Hz, 1H), 6.33 (d, J=3.0 Hz, 1H), 6.10 (brs, 2H), 4.61 (brs, 2H); ESI-MS (m/z, %): 225 (M+1, 100%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:27])(=O)[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:27][C:6]1[C:5]2[N:4]=[C:1]([CH3:2])[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1c(Cl)cccc1NCc1ccc(Sc2ccc(C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(Sc2ccc(Cn3c(C)nc4c(Cl)cccc43)cc2)cc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A mixture of 2-acetamido-1-chloro-3-[4-(4-methylthiophenoxy)benzylamino]benzene (0.413 g), p-toluenesulfonic acid (0.040 g) and toluene (150 ml) was heated under reflux while removing the by-produced water therefrom through a Dean-Stark trap. After the by-production of water ceased, the reaction mixture was cooled to room temperature, washed with a saturated sodium carbonate solution and water and distilled under reduced pressure to remove toluene. The residue was purified by silica gel column chromatography to give 4-chloro-2-methyl-1-[4-(4-methylthiophenoxy)benzyl]benzimidazole (0.375 g) as a colorless liquid. nD22.0 1.6341.