Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2=[CH:7][C:8]3[C:23]4[C:22]([C:21]5=[C:24]6[C:17](=[CH:18][CH:19]=[CH:20]5)[CH:16]=[C:15]5[CH:25]=[CH:26][CH:27]=[CH:28][C:14]5=[C:13]6[C:12]=4[CH:11]=[CH:10][CH:9]=3)=[C:5]2[CH:4]=[CH:3][CH:2]=1.[Br:29]Br>C(Cl)(Cl)(Cl)Cl>[Br:29][C:16]1[C:17]2[C:24]3[C:13]([C:12]4[CH:11]=[CH:10][CH:9]=[C:8]5[C:23]=4[C:22]([C:21]=3[CH:20]=[CH:19][CH:18]=2)=[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:6]2=[CH:7]5)=[C:14]2[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=12
Reactant: BrBr
Reactant: c1ccc2c(c1)cc1cccc3c1c2c1cccc2cc4ccccc4c3c21
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c2c3cccc4cc5ccccc5c(c5cccc1c52)c43

Procedure:
After dibenzo[a,j]perylene dissolved in carbon tetrachloride was brominated with cooling for four hours by adding one molar equivalent of bromine, the reaction product was refined in accordance with an ordinary method to obtain 8-bromodibenzo[a,j]perylene. Di-p-tolylamine, potassium carbonate and copper powder were added to the thus obtained 8-bromodibenzo[a,j]perylene and were allowed to react for 30 hours at 20020 C. After the reaction solution was diluted with water, the reaction product was extracted with chloroform. Thereafter, it was refined in accordance with an ordinary method to obtain a target compound expressed in Formula 26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([OH:23])=O)[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:48][NH:49][CH2:50][C:51]1[CH:64]=[CH:63][C:54]([CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)=[CH:53][CH:52]=1>C(Cl)Cl>[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][C:54]2[CH:63]=[CH:64][C:51]([CH2:50][N:49]([CH3:48])[C:21]([C:19]3[N:20]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:17][CH:18]=3)=[O:23])=[CH:52][CH:53]=2)[CH2:57][CH2:58]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(O)CC4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-({[(4-methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)-1,3-oxazole-4-carboxylic acid (35 mg, 0.12 mmol), EDCI (26 mg, 0.14 mmol), HOBt (20 mg, 0.15 mmol) DIPEA (0.035 mL, 0.2 mmol), 1-{4-[(methylamino)methyl]benzyl}piperidin-4-ol dihydrochloride (32 mg, 0.14 mmol) and DCM (10 mL).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Cl-].[Mg+2].[Cl-].[OH:14][C@@:15]([CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH2:24][CH2:25][CH3:26])[CH2:16]C(N1C=CN=C1)=O.Cl>C1COCC1>[OH:14][C@@:15]([CH2:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)([CH2:24][CH2:25][CH3:26])[CH2:16][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCC[C@@](O)(CCc1ccccc1)CC(=O)n1ccnc1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC[C@@](O)(CCc1ccccc1)CC(=O)CC(=O)OCC
Temperature: 40 °C
Reaction time: 2 h
Yield: 67.5 %

Procedure:
Potassium monoethyl malonate (1.080 g, 6.348 mmole) was added to a suspension of magnesium chloride (0.5437 g, 5.713 mmole) and THF (4 mL) and the mixture was stirred at 40° C. for 2 hr. To this suspension was added the total amount of a solution of (R)-3-hydroxy-1-(1-imidazolyl)-3-(2-phenylethyl)hexane-1-one in THF obtained in Reference Example 3 at 40° C., and the mixture was stirred at 60° C. for 6 hr. After cooling to 0° C., 10% aqueous hydrochloric acid (4.4 g) was gradually added in a thin stream and the mixture was stirred at 0° C. for 15 min. After standing still, the mixture was partitioned and the aqueous layer was removed. Saturated brine (4 g) was added to the organic layer and the mixture was stirred for 15 min while maintaining the temperature. After standing still, the mixture was partitioned and the aqueous layer was removed. Anhydrous magnesium sulfate (1 g) was added to the organic layer and dried. Magnesium sulfate was filtered off and the obtained filtrate was concentrated under reduced pressure to give a crude product (1.45 g) of ethyl (R)-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoate. This was purified by silica gel column chromatography to give ethyl (R)-5-hydroxy-3-oxo-5-(2-phenylethyl)octanoate (0.875 g, yield 67.5%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH2:27][OH:28])[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:23]2)=[CH:17][CH:16]=1>[O-2].[O-2].[Mn+4].C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([CH2:21][N:22]2[CH:26]=[C:25]([CH:27]=[O:28])[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:23]2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(CO)c(-c3ccccc3)n2)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(C=O)c(-c3ccccc3)n2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
A mixture of 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-ylmethanol (1.25 g), active manganese dioxide (3.00 g) and ethyl acetate (80 ml) was stirred at room temperature for 3 hours. After manganese dioxide was separated by filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-carboaldehyde (1.20 g, yield 96%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([C:31]5[CH:32]=[CH:33][C:28]([C:37]6[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=6)=[CH:29][CH:30]=5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(-c2ccccc2)cc1

Procedure:
The title compound, white solid (93 mg, 73%), MS (ISP) m/z=511.6 [(M+H)+], mp 232° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and biphenyl-4-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[N:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[OH:12])[CH3:3].[H-].[Na+].[CH2:15]([N:17]=[C:18]=[O:19])[CH3:16]>O1CCCC1>[CH2:15]([NH:17][C:18]([O:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:5]=[CH:4][N:2]([CH3:1])[CH3:3])=[O:19])[CH3:16]
Reactant: CCN=C=O
Reactant: CN(C)C=Nc1ccncc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNC(=O)Oc1cnccc1N=CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a warm solution of 4-[[(dimethylamino)methylene]amino]-3-pyridinol (7.12 g) in dry tetrahydrofuran (150 mnL) were added sodium hydride (173 mg) and ethyl isocyanate (3.59 mL). The reaction mixture was stirred at room temperature overnight, cooled in an ice bath and filtered, and the solid was washed with diethyl ether. The solid was distributed between methylene chloride (250 mL) and saturated ammonium chloride (30 mL) and extracted twice more with methylene chloride (100 mL). The solution was dried (MgSO4) and concentrated, and the solid was recrystallized from ethyl acetate to yield 5.7 g of needles, m.p. 138° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][C:14]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C(=O)([O-])[O-:30].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]([NH2:18])=[O:30])=[CH:15][C:14]=2[C:21]2[C:22]([O:27][CH3:28])=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: O=C([O-])[O-]
Reactant: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(OC(C)C)c(Cl)c1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ncccc1-c1cc(C(N)=O)ccc1Oc1cnc(OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-[(5-chloro-6-isopropoxypyridin-3-yl)oxy]-3-(2-methoxypyridin-3-yl)benzonitrile (Preparation 26, 534 mg, 1.35 mmol) in DMSO (10.0 mL) was added potassium carbonate (560 mg, 4.05 mmol) and a 30% aqueous solution of hydrogen peroxide (690 μL, 6.74 mmol). The reaction was stirred at room temperature for 1 hour. Water (50 mL) was added to the reaction mixture resulting in the formation of a white precipitate. The precipitate was filtered, washed with water (50 mL) and dried in vacuo to obtain the title compound as a colourless solid (436 mg, 85%), which was used without further purification in the next step.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH:17]([NH2:19])[CH3:18])=[N:9][C:10]3[C:15]([CH:16]=2)=[N:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25](Cl)[N:24]=[CH:23][N:22]=1.CCN(C(C)C)C(C)C>CCCCO>[NH2:20][C:21]1[C:26]([C:27]#[N:28])=[C:25]([NH:19][CH:17]([C:8]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][N:14]=3)[N:9]=2)[CH3:18])[N:24]=[CH:23][N:22]=1
Reactant: CC(N)c1nc2cccnc2cc1-c1ccccc1
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc(N)c1C#N)c1nc2cccnc2cc1-c1ccccc1
Temperature: 25 °C

Procedure:
1-(3-Phenyl-1,5-naphthyridin-2-yl)ethanamine (46 mg, 0.19 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (28.5 mg, 1.0 eq) and Hunig's base (39 μL, 1.2 eq) in n-BuOH (2 mL) was heated to 130° C. for 4 h. The mixture was cooled to rt, filtered and washed with small amount of EtOH to give a white solid as 4-amino-6-(1-(3-phenyl-1,5-naphthyridin-2-yl)ethylamino)pyrimidine-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (1H, dd, J=8.0, 4.0 Hz), 8.44 (1H, dd, J=8.0, 4.0 Hz), 8.21 (1H, s), 7.97 (1H, s), 7.84 (1H, dd, J=8.0, 4.0 Hz), 7.61-7.47 (6H, m), 7.30 (1H, br, s), 5.63 (1H, t, J=8.0 Hz)), 1.31 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 368 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][PH:4]([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2].[C:10](#[N:13])[CH:11]=[CH2:12].[Na].C(O)(=O)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:12][CH2:11][C:10]#[N:13])([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])[CH3:2]
Reactant: CCCC[PH](=O)OCC
Reactant: C=CC#N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCP(=O)(CCC#N)OCC
Temperature: 25 °C

Procedure:
15.0 g of n-butylphosphinic acid ethyl ester and 5.3 g of acrylonitrile are dissolved under argon in 25 ml of ethanol. The solution is cooled to 10°, and a solution of 1.15 g of sodium in 50 ml of ethanol is added dropwise, whereupon the exothermic reaction takes place. The mixture is then heated under reflux for one hour and cooled to room temperature, and 3.3 g of glacial acetic acid are added. The solvent is removed and the residue is taken up in dichloromethane. The resulting solution is washed with water, dried over sodium sulfate and concentrated by evaporation. The oil that remains is distilled, yielding 2-cyanoethyl(n-butyl)phosphinic acid ethyl ester having a boiling point of 120° (10-1 bar).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:4][C:5]([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Fc1cc(-c2ccc(C(F)(F)F)cc2)c(Cl)cn1
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4cccnc4c3)ncc2Cl)cc1

Procedure:
This compound could be prepared by the method described in Example 6(d) from 5-chloro-2-fluoro-4-(4-trifluoromethyl-phenyl)-pyridine and 7-aminoquinoline by microwave in a Smith Synthesizer (Personal Chemistry) at 180° C. for 20 min. The product will be isolated using flash chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[C:24](Cl)=[O:25]>>[O:15]=[C:13]1[NH:12][C:8]2=[N:9][CH:10]=[CH:11][C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]4[CH:27]=[C:28]([Cl:30])[CH:29]=[C:21]([C:20]([F:32])([F:19])[F:31])[CH:22]=4)[CH:18]=[CH:17][CH:16]=3)=[C:7]2[NH:14]1
Reactant: O=C(Cl)c1cc(Cl)cc(C(F)(F)F)c1
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)c1cc(Cl)cc(C(F)(F)F)c1
Yield: 29.8 %

Procedure:
Method H was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]-pyridin-2(3H)-one and 3-trifluoromethyl-5-chlorobenzoyl chloride to afford the title compound (28 mg, 29.8%). 1H-NMR (δ, ppm, DMSO-d6): 6.50 (d, 1H, HPy,5, J=5.9 Hz), 6.94-6.96 (m, 1H, Harom), 7.45 (t, 1H, Harom-5, J=8.2 Hz), 7.59 (s, 1H, Harom-2), 7.63-7.65 (m, 1H, Harom), 7.81 (d, 1H, HPy,6, J=5.9 Hz), 8.12 (s, 1H, Harom′), 8.22 (s, 1H, Harom′), 8.30 (s, 1H, Harom′), 10.60 (s, 1H, NHamide), 11.20 (s, 1H, NHPy7), 11.39 (s, 1H, NHPy9). LC-MS, tR=5.07 minutes, m/z: 448.06 (M+H)+, calculated for C20H13N4O3F3Cl. HRMS (EI): m/z [M+H] calculated for C20H13N4O3F3Cl: 449.0628; found: 449.0619.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:15](Cl)(=O)[C:16](Cl)=O.C(O)C.C([O-])(O)=O.[Na+]>ClCCl.CN(C)C=O>[CH2:15]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([F:12])=[C:10]([F:11])[C:2]=1[F:1])[CH3:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 96.8 %

Procedure:
A solution of 2,3,4-trifluoro-5-methoxybenzoic acid (Hayashi et al., Bull. Chem. Soc. Jap., 1972; 45(9):2909–2914, 3.443 g, 16.7 mmol) in dichloromethane (100 mL) at 0° C. is treated with oxalyl chloride (7 mL, 80 mmol) followed by N,N-dimethylformamide (4 drops). The mixture is stirred at room temperature for 3.5 hours, concentrated to near dryness, and co-evaporated with benzene. The acid chloride is then diluted with dichloromethane, cooled to 0° C., and treated with absolute ethanol (10 mL, 170 mmol). The resulting solution is stirred at room temperature for 20 hours, poured into saturated NaHCO3 solution, and extracted with dichloromethane. The organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to afford the title compound (3.785 g). 1H NMR (200 MHz, CDCl3): δ 7.36–7.29 (m, 1H), 4.42 (q, 2H), 3.93 (s, 3H), 1.44 (t, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:21]1[CH:26]=[C:25]([CH:27]=[CH2:28])[CH:24]=[CH:23][C:22]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:13][C:8]=2[N:7]=[C:6]1[C:21]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(-n2cncn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Reaction time: 12 h
Yield: 30.7 %

Procedure:
To a solution of 5-[1-tert-butyl-2-(2-1,2,4-triazol-1-yl-5-vinyl-phenyl)-1H-benzimidazol-5-yl]-pyrimidin-2-ylamine (100 mg, 0.23 mmol) in EtOH (5 mL) is added 10% Pd/C (10 mg) at room temperature. The reaction vessel is de-gased and is filled with H2 using a balloon. The mixture is stirred at the same temperature for 12 hours. The mixture is filtered and the filtrate is concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (31 mg, 31%) as a pale brown foam. LCMS (ESMS): m/z 439.73 (M++1)
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:14](=[O:35])[N:15]([CH3:34])[C:16]2[C:21]([CH:22]=1)=[CH:20][N:19]=[C:18]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N+:30]([O-])=O)[C:17]=2[CH3:33]>C(OCC)(=O)C>[NH2:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:18]1[C:17]([CH3:33])=[C:16]2[C:21]([CH:22]=[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])[C:14](=[O:35])[N:15]2[CH3:34])=[CH:20][N:19]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4ccccc4[N+](=O)[O-])c(C)c3n(C)c2=O)c1Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c(Cl)c(-c2cc3cnc(Nc4ccccc4N)c(C)c3n(C)c2=O)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a solution of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1,8-dimethyl-7-(2-nitrophenylamino)-1,6-naphthyridin-2(1H)-one (100 mg, 0.2 mmol) in ethyl acetate (20 mL) was added stannous chloride (150 mg, 0.8 mmol), and the mixture was stirred at 80° C. for 1 h. LCMS monitored the reaction was completed. The solid was filtered off, and the filtrate was concentrated. The residue was purified by Prep-HPLC to get the title compound (38.6 mg, 41%) as a yellow solid. MS (ES+) C24H22Cl2N4O3 requires: 484, 486. found: 485, 487 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.24 (s, 1H), 7.76 (s, 1H), 7.67 (s, 1H), 7.03 (d, 1H, J=7.5 Hz), 6.97 (s, 1H), 6.92-6.89 (m, 1H), 6.75-6.73 (m, 1H), 6.57-6.54 (m, 1H), 4.77 (s, 2H), 3.95 (s, 6H), 3.66 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:11]=[N:10][NH:9][C:8]=2[C:12]2[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.[CH3:30]NN.S(=O)(=O)(O)O>C(O)C>[CH3:30][N:10]1[CH:11]=[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)=[N:9]1
Reactant: CNN
Reactant: c1ccc2nc(COc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 2-[-4-(4-Pyridin-4-yl-2H-pyrazol-3-yl)-phenoxymethyl}-quinoline (1.72 g) in ethanol (20 ml) was added methyl hydrazine (3.5 ml, 1.5 eq.) and concentrated sulfuric acid (0.1 ml). The reaction mixture was stirred 1 h at ambient temperature and solvent evaporated. The reaction mixture was partitioned between methylene chloride and saturated sodium bicarbonate. The layers were separated and the organic layer dried magnesium sulfate, filtered and concentrated. Preparative HPLC chromatography provided the title compound (major isomer) as a clear oil (0.97 g, 56%). 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J=5.0 Hz, 2H), 8.17 (d, J=8.7 Hz, 1H), 8.05 (d, J=8.3 Hz, 1H), 7.81 (d, J=7.9 Hz, 1H), 7.70 (m, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.54 (s, 1H), 7.53 (m, 1H), 7.37 (d, J=8.7 Hz, 2H) 7.15 (d, J=5.0, 2H), 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 3.93 (s, 3H); MS: (M+H m/z=393.3).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10].[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>O1CCCC1.[Cl-].[Na+].O.CCOC(C)=O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1/[C:9](=[N:18]\[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH3:10]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(F)c1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C/C(=N/[S@](=O)C(C)(C)C)c1cccc(F)c1Cl
Temperature: 65 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 1-(2-chloro-3-fluorophenyl)ethanone (31.21 g, 181 mmol) in tetrahydrofuran (500 mL) was added (R)-2-methylpropane-2-sulfinamide (32.9 g, 271 mmol) and titanium(IV) isopropoxide (111 mL, 371 mmol). The mixture was heated to 65° C. overnight. LCMS showed 25% starting material remaining. Additional 16 g sulfinamide and 30 mL Ti(OPr)4 was added and the reaction was continued at 70° C. overnight. The mixture was diluted with brine (600 mL), and EtOAc. The solid was filtered through a pad of celite and washed with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (330 g, 0-60% EtOAc-hexane in 20 min) to give (R,Z)-N-(1-(2-chloro-3-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (40.8 g, 82% yield) as yellow oil. MS m/z=276 [M+H]+. Calculated for C12H15ClFOS: 275.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[N:8][N:9]([C:11]2[C:16](Br)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])[CH3:2].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH:27]1(B(O)O)[CH2:29][CH2:28]1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[N:8][N:9]([C:11]2[C:16]([CH:27]3[CH2:29][CH2:28]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(-c2ncccc2Br)nc1C
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn(-c2ncccc2C2CC2)nc1C
Temperature: 100 °C
Yield: 107.2 %

Procedure:
A mixture of 1-(3-bromo-pyridin-2-yl)-3-methyl-pyrazole-4-carboxylic acid ethyl ester (1.5 g, 5.5 mmol), potassium phosphate (4.0 g, 19.2 mmol), cyclopropyl boronic acid (0.7 g, 8.2 mmol) and toluene/water (2:1, 15 mL) is degassed with nitrogen and tricylohexylphosphene (0.153 g, 0.54 mmol) and palladium acetate (0.061 g, 0.27 mmol) are added. The mixture is degassed again with nitrogen and the reaction vessel is sealed and heated at 100° C. for 16 h. The reaction mixture is concentrated, diluted with water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture is purified by chromatography on silica gel eluting with hexane/ethyl acetate (85:15) to yield 1.6 g (93%) of 1-(3-cyclopropyl-pyridin-2-yl)-3-methyl-pyrazole-4-carboxylic acid ethyl ester. MS (m/z): 272 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[N:31]=[N:30][N:29](COCC[Si](C)(C)C)[C:28]=4[CH:27]=[C:26]([C:41]([F:44])([F:43])[F:42])[CH:25]=3)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[C:32]4[NH:31][N:30]=[N:29][C:28]=4[CH:27]=[C:26]([C:41]([F:44])([F:42])[F:43])[CH:25]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3c2nnn3COCC[Si](C)(C)C)(c2ccc(F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C2(COCc3cc(C(F)(F)F)cc4nn[nH]c34)CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((6-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-yl)methoxy)methyl)piperidine-1-carboxylate (120 mg, 0.188 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 2 mL) and stirred at room temperature for 4 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted using 2M ammonia in methanol and concentrated to give 75 mg (98%) as an amorphous solid. LC/MS (HPLC method 4): tR=2.28 min, 409.15(MH)+.