Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:13](=[O:14])[O:12][CH2:11]2)([OH:7])=O.C(=O)([O-])[O-].[K+].[K+].[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26]O>O1CCCC1.O.C1(C)C=CC=CC=1.CN(C)C(=O)C>[CH3:26][C:25]1([CH3:29])[CH2:28][O:7][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[C:13](=[O:14])[O:12][CH2:11]3)=[N:24]1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc3c(c2)COC3=O)=N1
Temperature: 60 °C
Reaction time: 6 h
Yield: 59.8 %

Procedure:
To a mixture of thionyl chloride (25 ml, 0.344 mol) and N,N-dimethylacetamide (0.2 ml), 5-carboxyphthalide (5 g, 0.028 mol) is added. The stirred mixture is heated 30 minutes at 60° C. and is then brought to reflux (about 80° C.) and kept under these conditions for 6 hours. The thionyl chloride is distilled off in vacuo to an inner temperature of about 90° C. The concentrated mixture is taken up with toluene (25 ml) and distilled in vacuo leaving a residue, which is taken up again twice with of toluene (10 ml) followed by concentration of the solution. The residual acid chloride is taken up with of tetrahydrofuran (25 ml) and the mixture is heated at 60° C. until a complete dissolution is obtained. The solution of the acid chloride in tetrahydrofuran is added dropwise to a mixture of micronized anhydrous potassium carbonate (5 g, 0.036 mol), 2-amino-2-methyl-1-propanol (3.06 ml, 0.032 mol) and of tetrahydrofuran (15 ml), cooled to about 0° C., keeping the temperature at 5-10° C. After about 30 minutes under these conditions, a control by HPLC is performed in order to verify the complete amide formation. The mixture is cooled to 0-3° C. and of thionyl chloride (2 ml, 0.027 mol) is added dropwise to the mixture. At the end of the addition, a control by HPLC confirms that the ring closure of the amide is completed. To the mixture, 50 ml of deionized water is slowly added at 5-10° C. The organic solvents are distilled off in vacuo and the pH is adjusted to 5 with 25% ammonia. The mixture is heated one hour at 50° C., then its temperature is let to decrease to about 20° C., kept at this value for 2 hours, then lowered to 10-15° C. and the mixture is maintained under these conditions for one hour. The mixture is dispersed by stirring, then it is filtered, washed with water and dried in vacuo at 40° C. Yield: 3.87 g of product. Total yield: 59.8%.
Reaction SMILES: Br[C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH3:14][N:15](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[Cl:7][C:6]1[C:2]([C:14]#[N:15])=[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:4][C:5]=1[CH3:8]
Reactant: CCOC(=O)c1[nH]c(C)c(Cl)c1Br
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C#N
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Nitrogen gas was bubbled through a mixture of 1.4 g (5.25 mmol) of ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 192), 470 g (4 mol) Zn(CN)2, 250 mg (0.26 mmol) Pd2(dba)3 and 302 mg (0.26 mmol) dppf in 15 ml DMF for 15 min. The mixture was heated at 130° C. for 1 h. Additional Zn(CN)2 (1 g), Pd2(dba)3 (500 mg) and dppf (604 mg) were added. After bubbling through N2 for 15 min and heating at 130° C. for 2 h, additional Zn(CN)2 (0.5 g), Pd2(dba)3 (250 mg) and dppf (302 mg) were added. Heating was continued at 130° C. for 2h. Solvent was removed and the residue was partitioned between EtOAc and water. The EtOAc was separated and washed with brine. Combined aqueous layers were extracted again with EtOAc, which was washed with brine. Combined EtOAc extracts were dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (100% CH2Cl2 followed by gradient elution to 5% MeOH in CH2Cl2) to afford 750 mg of product as a solid. MS (ES) (MH+): 213 for C9H9ClN2O2; NMR (d6-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.3 (q, 2H), 13.1 (s, 1H).
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2C=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH2:12][C:11]2=[O:30])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)n2c(C=O)cc3cccnc32)cc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2C(=O)Cc3cccnc32)cc1
Reaction time: 6 h
Yield: 50.2 %

Procedure:
A solution of 1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (24.3 g, Reference Example 73) in dichloromethane (700 mL), under nitrogen and at 5° C., was treated with 3-chloroperbenzoic acid (26.7 g, 70%). After stirring at 5° C. for 16 hours a further aliquot of 3-chloroperbenzoic acid (15 g, 70%) was added and stirring was continued for a further 6 hours at 5° C. The reaction mixture was then treated with sodium sulfite solution (1L, 10%), the organic phase was separated and the aqueous phase was extracted twice with dichloromethane (200mL). The combined organic phase and extracts were washed with water (400 mL), dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting initially with a mixture of ethyl acetate and pentane (1:3, v/v) and then with a mixture of dichloromethane and methanol (95:5, v/v) to give the title compound (11.7 g) as an orange solid.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].FC(F)(F)S(O[CH2:19][C:20]([F:23])([F:22])[F:21])(=O)=O.O>CN(C=O)C.[Cl-].[Na+].O>[F:1][C:2]1[C:9]([O:10][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#Cc1cccc(O)c1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(OCC(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A stirred solution of 2-fluoro-3-hydroxybenzonitrile (800 mg, 5.83 mmol) in DMF (10 mL) at 0° C. was treated portionwise with NaH (280 mg, 7.00 mmol) (60% oil dispersion). The reaction mixture was then stirred for 0.5 h and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1490 mg, 6.42 mmol) was added. The reaction was allowed to warm to rt overnight with stirring. The reaction mixture was then treated with water (40 mL) and brine (5 mL) and extracted with ethyl acetate (˜50 mL). The organic extract was washed with water, dried over anhydrous Na2SO4, filtered and conc. in vacuo to afford a residue which was purified via silica gel chromatography (10% to 30% ethyl acetate/hexanes) to yield the title compound as a white solid (1040 mg, 81%). 1H NMR (400 MHz, MeOD) δ ppm 7.56 (td, 1 H), 7.47-7.38 (m, 1 H), 7.38-7.24 (m, 1 H), 4.73 (q, 2 H); m/z 220.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=1[O:21][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7]
Reactant: COc1ccc(C=O)cc1CCl
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C=O)cc1COc1c(C)cccc1C
Yield: 91.1 %

Procedure:
To a solution of 3-(chloromethyl)-4-methoxybenzaldehyde (300 mg, 1.625 mmol, 1.0 equivalent) and 2,6-dimethylphenol (218 mg, 1.787 mmol, 1.1 equivalent) in 10 ml acetonitrile was added potassium carbonate (1.1 g, 8.12 mmol, 5.0 equivalents). The mixture was heated to 150 C in a microwave for 30 min. Upon completion, the mixture was filtered and dried down to give 3-[(2,6-dimethylphenoxy)methyl]-4-methoxybenzaldehyde (400 mg, 91% yield) as a yellow solid. A portion of which (100 mg, 0.370 mmol, 1.0 equivalent) was taken up in ethanol (4 ml), and to it was added 2-amino-N-(pyridin-3-ylmethyl)benzamide (92 mg, 0.407 mmol, 1.1 equivalent) followed by ytterbium(III) trifluoromethanesulfonate (45.9 mg, 0.074 mmol, 0.2 equivalent). The mixture was heated to 80 C for 2 h. Upon completion, the mixture was dried down and chromatographed on silica gel with 0-30% EtOAc (ethyl acetate)/hexanes gradient elution to give the desired 2-{3-[(2,6-dimethylphenoxy)methyl]-4-methoxyphenyl}-3-(pyridin-3-ylmethyl)-2,3-dihydroquinazolin-4(1H)-one (110 mg, 62.0% yield) as a tan solid. 1H nuclear magnetic resonance (400 MHz, DMSO-d6) δ ppm 8.39-8.45 (m, 2 H), 7.60-7.67 (m, 2 H), 7.48 (d, J=2.35 Hz, 1 H), 7.15-7.35 (m, 4 H), 6.94-7.02 (m, 3 H), 6.84-6.93 (m, 1 H), 6.60-6.69 (m, 2 H), 5.82 (d, J=2.35 Hz, 1 H), 5.07 (d, J=15.65 Hz, 1 H), 4.64 (d, J=2.74 Hz, 2 H), 3.99 (d, J=15.45 Hz, 1 H), 3.73 (s, 3 H), 2.12 (s, 6 H); liquid chromatography mass spectrometry: (electrospray+ve), m/z 480.2 (MH)+ (mass of molecular weight plus 1); HPLC: tR=5.05 min, UV254=100%. High-resolution mass spectroscopy (electrospray ionization): m/z calculated for C30H30N3O3 [M+H]+480.2282, found 480.2291.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([CH:12]=[O:13])=[CH:10][N:11]=2)=[N:3]1.[CH2:14]([Mg]Br)[CH3:15].C(OCC)C.CO.C(Cl)Cl>C1COCC1>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([CH:12]([OH:13])[CH2:14][CH3:15])=[CH:10][N:11]=2)=[N:3]1
Reactant: CC[Mg]Br
Reactant: Cn1ccc(-c2ncc(C=O)s2)n1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1cnc(-c2ccn(C)n2)s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a solution of 2-(1-methyl-1H-pyrazol-3-yl)thiazole-5-carbaldehyde (0.1 g, 0.51 mmol) in THF (10 mL) at 0° C. was slowly added 3.0 M ethyl magnesium bromide in diethyl ether (0.5 mL, 0.15 mmol), and the reaction mixture was stirred at 0° C. for 3 h. After completion of reaction by monitoring with TLC (5% MeOH\DCM), the reaction mixture was quenched with sat'd. NH4Cl (50 mL) solution. The reaction mixture was then extracted with EtOAc (3×50 mL), washed with water (2×50 mL), dried over Na2SO4 and concentration in vacuo and to provide a yellow solid (0.09 g, 81% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.82 (s, 1H), 7.50 (s, 1H), 5.60 (d, 1H), 4.70 (q, 1H), 3.86 (s, 3H), 1.69 (m, 2H), 0.844 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:18]2[CH:22]=[C:21]([NH2:23])[CH:20]=[N:19]2)[CH:6]=[CH:7][C:8]=1B1OC(C)(C)C(C)(C)O1.Cl[C:25]1[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]2[CH2:37][C:36]([CH3:39])([CH3:38])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]2)=[CH:27][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[NH2:23][C:21]1[CH:20]=[N:19][N:18]([C:5]2[CH:6]=[CH:7][C:8]([C:25]3[N:30]=[N:29][C:28]([N:31]([CH3:42])[CH:32]4[CH2:37][C:36]([CH3:38])([CH3:39])[NH:35][C:34]([CH3:41])([CH3:40])[CH2:33]4)=[CH:27][CH:26]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=1
Reactant: COc1cc(-n2cc(N)cn2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(c1ccc(Cl)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-n2cc(N)cn2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Temperature: 100 °C

Procedure:
To a microwave vial was added 1-(3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrazol-4-amine (92 mg, 0.29 mmol), 6-chloro-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine Intermediate 1-1 (75 mg, 0.27 mmol), potassium phosphate (169 mg, 0.78 mmol), Pd2(dba)3 (12.14 mg, 0.01 mmol), and SPhos (10.89 mg, 0.03 mmol), followed by addition of 1,4-dioxane (1 mL)/H2O (0.2 mL). The vial was purged with N2 for 10 minutes and the reaction mixture was heated at 100° C. in a microwave reactor for one hour. The reaction mixture was concentrated in vacuo, then the crude material was adjusted to pH 3 using 1 M HCl aqueous solution, then loaded on an SCX column. The column was washed with methanol then eluted with 2 N ammonia in methanol. The product-containing fractions concentrated to afford 6-(4-(4-amino-1H-pyrazol-1-yl)-2-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (100 mg, MS: 436.4 [M+H+].).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.CCCCCCCC(C([NH3+])(C(CCCCCCC)=O)C(CCCCCCC)=O)=O.[Cl-]>ClCCl.O>[OH:11][C@H:10]1[CH2:9][CH2:8][C@H:7]2[C@H:6]3[C@H:5]([CH2:4][CH2:3][C@:2]12[CH3:1])[C@@H:20]1[C@@H:14]([CH2:15][C:16](=[O:17])[CH2:18][CH2:19]1)[CH2:13][CH2:12]3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: CCCCCCCC(=O)C([NH3+])(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@H]4CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reaction time: 8 h
Yield: 107 %

Procedure:
A solution of 19-nortestosterone (10.0 g, 35.5 mmol) in dichloromethane (100.0 ml) was mixed with the catalyst previously prepared from RhCl3.H2O (380 mg) and Aliquat-336® (800 mg) in water (10.0 ml) and dichloromethane (22.0 ml). The mixture was hydrogenated overnight at 20 psi. The product was washed twice with water (40 ml) and dried on Na2SO4. The catalyst was removed by flash-chromatography on silica gel with CH2Cl2 as eluant to give 10.5 g (92% yield) the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]>C(O)C.[Rh]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[C:10]=1[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16]
Reactant: CC(=O)NCCCc1c(Cl)ccc2occc12
Agent: [Rh]
Solvent: CCO
Product: CC(=O)NCCCc1c(Cl)ccc2c1CCO2
Yield: 52 %

Procedure:
A solution of N-[3-(5-chloro-benzofuran-4-yl)-propyl]-acetamide (0.25 g) in ethanol (15 ml) was hydrogenated over 5% rhodium on carbon (80 mg) for 18 h. The catalyst was filtered off and the filtrate evaporated. The residue was purified by column chromatography on silica, eluting with dichloromethane/methanol 40:1 gave the title compound as a colourless solid (131 mg) mp 91-92
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=1.[C:27]([C:29]1[CH:30]=[C:31]([NH:35][C:36]([C:38]2[N:42]([CH3:43])[N:41]=[C:40]([CH3:44])[CH:39]=2)=[O:37])[CH:32]=[CH:33][CH:34]=1)#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:43][N:42]1[C:38]([C:36]([NH:35][C:31]2[CH:30]=[C:29]([C:27]#[C:28][C:2]3[CH:3]=[C:4]([C:8]([N:10]=[S@:11]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:12])=[O:9])[CH:5]=[N:6][CH:7]=3)[CH:34]=[CH:33][CH:32]=2)=[O:37])=[CH:39][C:40]([CH3:44])=[N:41]1
Reactant: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(NC(=O)c2cc(C)nn2C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)CCCC[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3cc(C)nn3C)c2)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the flame-dried 100 mL round bottom flask containing (S)-Methyl 5-{N-[(5-bromopyridin-3-yl)carbonyl]-S-phenylsulfonimidoyl}pentanoate (609 mg, 1.39 mmol), N-(3-ethynylphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (0.50 g), triethylamine (0.77 mL), bis(triphenylphosphine)palladium(II) dichloride (97.3 mg), and triphenylphosphine (9.1 mg) under nitrogen/hydrogen (1:1) atmosphere at room temperature was added copper(I) iodide (52.8 mg). The resulting reaction mixture was heated and stirred at 60° C. for 1 hour. It was then diluted with EtOAc, washed sequentially with saturated aqueous NaHCO3 (2×), brine (1×), and finally dried with anhydrous sodium sulfate. The solution was decanted and concentrated with silica gel. Chromatography (EtOAc-Hex from 1:2 to 3:2) yielded the title compound as white foam in amount of (712 mg, 86%).
Reaction SMILES: C([N:4]1[CH2:12][CH:11]2[C:6]([C:22]3[S:23][C:24]([F:27])=[CH:25][CH:26]=3)([N:7]=[C:8]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9][CH2:10]2)[CH2:5]1)C=C>C(Cl)(Cl)Cl.ClCCl.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:27][C:24]1[S:23][C:22]([C:6]23[CH2:5][NH:4][CH2:12][CH:11]2[CH2:10][S:9][C:8]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7]3)=[CH:26][CH:25]=1
Reactant: C=CCN1CC2CSC(NC(=O)c3ccccc3)=NC2(c2ccc(F)s2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(NC1=NC2(c3ccc(F)s3)CNCC2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92 %

Procedure:
Through a stirred solution of racemic N-[6-allyl-7a-(5-fluoro-2-thienyl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (163 mg, 0.406 mmol) in chloroform (4.1 mL) is passed a stream of nitrogen for 20 minutes. N,N-Dimethylbarbituric acid (380 mg, 2.44 mmol) is added and degassing is continued for a further 5 minutes. Tetrakis(triphenylphosphine)palladium (70 mg, 0.061 mmol) is added and the mixture is stirred under nitrogen at room temperature for 45 minutes. The mixture is diluted with dichloromethane (approximately 15 mL) and extracted twice with 1 M hydrochloric acid (10 mL). The pH of the combined aqueous acid extracts is adjusted with 5 M sodium hydroxide (5 mL). The aqueous solution is extracted three times with dichloromethane (20 mL) and the combined dichloromethane extracts are dried over sodium sulfate, filtered, and concentrated to give the title compound (135 mg, 92%). ES/MS (m/e): 361 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:23]=[N:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:27][C:17]([F:16])([F:26])[C:18]1[N:19]=[CH:20][C:21]([CH2:24][CH2:25][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[N:22][CH:23]=1
Reactant: C=Cc1cnc(C(F)(F)F)cn1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C(F)(F)F)cn2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 2-(trifluoromethyl)-5-vinylpyrazine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]2[N:28]3[CH:29]=[CH:30][N:31]=[C:32]([N:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[C:27]3=[N:26][CH:25]=2)[N:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C>C(O)C.Cl>[CH3:39][N:36]1[CH2:35][CH2:34][N:33]([C:32]2[C:27]3[N:28]([C:24]([C:20]4[N:19]=[C:18]([NH:17][CH:10]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH2:9][CH2:8][NH2:7])[CH:23]=[CH:22][CH:21]=4)=[CH:25][N:26]=3)[CH:29]=[CH:30][N:31]=2)[CH2:38][CH2:37]1
Reactant: CN1CCN(c2nccn3c(-c4cccc(NC(CCNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2nccn3c(-c4cccc(NC(CCN)c5ccccc5)n4)cnc23)CC1

Procedure:
The solution of (3-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-3-phenyl-propyl)-carbamic acid tert-butyl ester (44 mg, 0.08 mmol) in ethanol (4 mL) and concentrated HCl (4 mL) was stirred at room temperature for 15 hours. The reaction mixture was then concentrated under reduced pressure. The residue was suspended in CH2Cl2 and concentrated under reduced pressure to give N1-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-yl}-1-phenyl-propane-1,3-diamine; hydrochloride. (Yield 25 mg). 1H NMR (300 MHz, CD3OD): δ 8.39 (s, 1H), 8.15 (s, 1H), 7.61 (t, 1H, J=5.7 Hz), 7.40-7.48 (m, 7H), 6.78 (brs, 1H), 5.39 (brs, 1H), 5.01 (brs, 1H), 3.81-3.66 (m, 4H), 3.37 (brs, 2H), 3.12-2.91 (m, 7H), 2.16-2.14 (m, 2H). LC-MS: [M+H]+ 443.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[CH:4][C:5]([CH2:8][N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:6][CH:7]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cn2)CC1
Reactant: OB(O)c1cccc(F)c1
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: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cccc(F)c3)cn2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen then charged with tert-butyl 4-[(5-bromopyridin-2-yl)methyl]piperazine-1-carboxylate (1.00 g, 2.81 mmol, 1.00 equiv), (3-fluorophenyl)boronic acid (0.790 g, 5.65 mmol, 2.00 equiv), Tetrakis(triphenylphosphine)palladium (0.325 g, 0.280 mmol, 0.10 equiv), potassium carbonate (1.17 g, 8.47 mmol, 3.00 equiv), dioxane (24 mL), and water (4 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/1) to provide 0.955 g (92% yield) of tert-butyl 4-[[5-(3-fluorophenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 372 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[CH2:12]([O:14]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:13].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([C:12](=[O:14])[CH3:13])=[CH:11][CH:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc2nccnc2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2nccnc2c1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A solution of 6-bromo-quinoxaline (261 mg, 1.25 mmol), 1-ethoxyvinyltri-n-butyltin (0.47 mL, 1.4 mmol), palladium(II) acetate (16 mg) and tri-t-butylphosphonium tetrafluoroborate (41 mg) in anhydrous DMF (4 mL) under a nitrogen atmosphere was heated at 120° C. for 1 hr. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate (25 mL) and H2O (10 mL). The organic extraction was washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was chromatographed on silica gel eluting with ethyl acetate:hexanes (1:1) to provide 110 mg of the title compound. 1H NMR (300 MHz, CDCl3) δ 2.79 (s, 3 H), 8.18 (d, J=9 Hz, 1 H), 8.36 (dd, J=9 Hz, J=3 Hz, 1 H), 8.70 (d, J=3 Hz, 1 H), 8.95 (s, 2 H); MS (DCl/NH3) m/z 173 (M+H)+.