Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)[C:10]=23)[CH:5]=[CH:6][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[C:17]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=4)[C:10]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Oc1cccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)c1
Temperature: 80 °C

Procedure:
With the exclusion of air and moisture, a mixture of 0.5 g (1.36 mmol) of 4-(3-chloro-phenylamino)-3-(3-methoxy-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (Example 50), 0.873 g (6.55 mmol) of anhydrous aluminum chloride and 15 ml of benzene is heated at 80° C. for 9 hours. The benzene phase is then decanted off, the resinous residue is partitioned between ethyl acetate and water and the organic phase is washed with water and with a saturated solution of sodium hydrogen carbonate in water, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue is purified by flash chromatography on silica gel having a particle size of 0.04-0.06 mm using methylene chloride/methanol mixtures (50:1 and 20:1). The product-containing fractions are combined and concentrated to a volume of approx. 10 ml, the desired product crystallising out. Filtering and washing the filter residue with diethyl ether yield the title compound; m.p. 265-266° C.; EI-MS: (M)+ =352.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29]C(=O)OC(C)(C)C)[CH2:24]2)=[N:21][CH:22]=1.[Cl:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[C:40]([Cl:53])[C:39]=1[OH:54].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[NH2:29][CH:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:20]2[N:21]=[CH:22][C:17]([NH:16][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:42]5[CH:41]=[C:40]([Cl:53])[C:39]([OH:54])=[C:38]([Cl:37])[CH:43]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[S:12]([CH3:15])(=[O:14])=[O:13])=[CH:18][CH:19]=2)[CH2:24]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(Nc3c(S(C)(=O)=O)cnc4ccc(Br)cc34)cn2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 25 °C
Yield: 12.1 %

Procedure:
To a suspension of tert-butyl 1-(5-(6-bromo-3-(methylsulfonyl)quinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (70 mg, 0.121 mmol), 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (40 mg, 0.142 mmol) and Pd(dppf)Cl2 (9 mg, 0.012 mmol) in dioxane (4 mL) was added Cs2CO3 (182 μL, 2.0 M solution in H2O). N2 gas was bubbled through the reaction mixture, the vessel was sealed and the mixture was then heated microwave irradiation conditions to 140° C. for 30 min. The solution was allowed to cool to rt, then directly subjected to purification by preparatory HPLC. The crude mixture was then treated with TFA to deprotect the pendant amine and reduced to a red-orange residue. This residue was then dissolved in MeOH (2 mL) and treated with a 2.0 M HCl solution in diethyl ether to afford the product (8.2 mg, 10%) as an orange solid: 1H NMR (500 MHz, MeOD) δ 9.03 (s, 1H), 8.27 (d, J=2.7 Hz, 1H), 8.24 (dd, J=8.8, 1.9 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.93 (d, J=1.9 Hz, 1H), 7.74 (dd, J=9.2, 2.7 Hz, 1H), 7.22 (s, 2H), 7.11 (d, J=9.2 Hz, 1H), 4.60 (s, 1H), 4.05 (d, J=13.5 Hz, 1H), 3.45 (s, 3H), 3.26 (m, 3H), 2.19 (d, J=11.1 Hz, 1H), 1.94 (d, J=11.0 Hz, 1H), 1.71 (m, 2H); ESI MS m/z 558, [C26H25Cl2N5O3S+H]+; HPLC 98.9% (AUC), tR=10.14 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH2:6][C:5]12[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]1.[Cl:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>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].O1CCOCC1>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[CH:3]=[C:4]3[C:14](=[CH:15][CH:16]=2)[O:13][C:7]2([CH2:12][CH2:11][CH2:10][O:9][CH2:8]2)[CH2:6][C:5]23[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CC1=NC2(CC3(CCCOC3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC1=NC2(CC3(CCCOC3)Oc3ccc(-c4cccc(Cl)c4)cc32)N=C1N
Temperature: 130 °C
Yield: 30.4 %

Procedure:
A mixture of 6′-bromo-5-methyl-5″,6″-dihydro-4″H-dispiro[imidazole-2,4′-chromene-2′,3″-pyran]-4-amine (Example 45 Isomer 1, 116 mg, 0.32 mmol), 3-chlorophenylboronic acid (64.7 mg, 0.41 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (26.0 mg, 0.03 mmol), K2CO3 (2 M aq) (0.318 mL, 0.64 mmol) and 1,4-dioxane (2 mL) were added to a microwave vial. The vial was capped, evacuated and filled with argon. The vial was heated in a microwave reactor at 130° C. for 20 min. Brine was added and the residue was extracted with DCM (×3), dried with a phase separator and concentrated under reduced pressure. The crude product was purified by preparative chromatography. The desired fractions were concentrated. Water and DCM were added and the layers separated. The organic phase was dried with a phase separator and concentrated to give isomer 1 of the title compound (38.5 mg, 30% yield) with undetermined configuration: 1H NMR (500 MHz, DMSO-d6) δ ppm 1.44-1.53 (m, 1 H), 1.83-1.92 (m, 3 H), 2.01 (d, 2 H), 2.22 (s, 3 H), 3.41-3.48 (m, 1 H), 3.56 (d, 1 H), 3.67-3.73 (m, 1 H), 3.99 (d, 1 H), 6.58 (s, 1 H), 6.62 (s, 1 H), 6.95 (d, 1 H), 7.31-7.39 (m, 2 H), 7.39-7.47 (m, 3 H); MS (ES+) m/z 396 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=2[O:8][CH2:7][C:6]1=[O:17].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:26]([CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29]>CCCCCCC.CCOC(C)=O>[CH2:26]([CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:32][CH2:31]1)[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(C)c2c(c1)N(CCCCl)C(=O)CO2
Reactant: CCCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(CCCN2C(=O)COc3c(C)cc(C)cc32)CC1
Yield: 72.3 %

Procedure:
4-(3-Chloropropyl)-6,8-dimethyl-4H-benzo[1,4]oxazin-3-one (81MF2237b) (0.96 g, 3.78 mmol), K2CO3 (1.05 g, 7.57 mmol), NaI (1.14 g, 7.57 mmol) and 4-butylpiperidine (0.56 g, 3.97 mmol) were mixed according to GP11. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2237F) (0.98 g, 72%). 1H NMR (CDCl3) δ 6.71 (s, 1H), 6.65 (s, 1H), 4.52 (s, 2H), 3.93 (t, J=7.2, 2H), 2.87 (d, J=11.2, 2H), 2.36 (t, J=7.2 Hz, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 1.81-1.89 (m, 4H), 1.65 (d, J=9.6 Hz, 2H), 1.28-1.17 (m, 9H), 0.87 (t, J=6-8 Hz, 3H); 13C NMR (CDCl3) δ 164.6, 141.4, 131.6, 128.3, 126.3, 126.1, 113.4, 67.8, 56.1, 54.3, 39.8, 36.4, 35.9, 32.7, 29.1, 25.0, 23.0, 21.1, 15.5, 14.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1B(O)O.[O:13]([C:20]([N:22]1[CH2:27][CH:26]=[C:25](OS(C(F)(F)F)(=O)=O)[CH2:24][CH:23]1[CH3:36])=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Li+]>C(COC)OC.C(=O)([O-])[O-].[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:13]([C:20]([N:22]1[CH2:27][CH:26]=[C:25]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[CH2:24][CH:23]1[CH3:36])=[O:21])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1CC(OS(=O)(=O)C(F)(F)F)=CCN1C(=O)Oc1ccccc1
Reactant: OB(O)c1cc2ccccc2o1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Product: CC1CC(c2cc3ccccc3o2)=CCN1C(=O)Oc1ccccc1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A mixture of 2.02 gm (12.5 mMol) benzofuran-2-boronic acid, 3.5 gm (9.6 mMol) 1-phenoxycarbonyl-2-methyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine, 0.443 gm (0.38 mMol) tetrakis [triphenylphosphine]-palladium(0), and 1.22 gm (28.8 mMol) lithium chloride in 55 mL dimethoxyethane and 15 mL 2M aqueous sodium carbonate was stirred at reflux for about 18 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate and aqueous sodium carbonate. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with hexane containing 10% ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 2.87 gm (90%) of the desired compound as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH2:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH:14](O)=O>>[Br:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]2[NH:12][CH:14]=[N:13][C:4]=2[CH:3]=1
Reactant: Nc1cc(Br)c(C(F)(F)F)cc1N
Reactant: O=CO
Product: FC(F)(F)c1cc2[nH]cnc2cc1Br
Temperature: 120 °C
Reaction time: 6 h

Procedure:
4-Bromo-5-trifluoromethyl-benzene-1,2-diamine (200 mg, 0.785 mmol) was dissolved in formic acid (3 ml), and the mixture was stirred at 120° C. for six hours. The reaction solution was concentrated, and water was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-bromo-6-trifluoromethyl-1H-benzimidazole (201 mg) as a crude compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]1[C:13]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH:20]=2)=[N:12][C:11]([CH2:32][NH2:33])=[N:10]1>N1C=CC=CC=1>[CH3:8][N:9]1[C:13]([NH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:20]=2)=[N:12][C:11]([CH2:32][NH:33][C:1](=[O:3])[CH3:2])=[N:10]1
Reactant: Cn1nc(CN)nc1NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCc1nc(NCCCOc2cccc(CN3CCCCC3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
A solution of acetic anhydride (0.089 g) in dry pyridine (1 ml) was added dropwise to a solution of 1-methyl-5-[[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanamine (A) (0.31 g) at 5°. The solution was stirred at room temperature for 0.5 h, and the solvent was removed under reduced pressure to leave a yellow oil which was triturated with light petroleum b.p. 60°-80° to give the title compound as a white solid (0.27 g), m.p. 123°.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH:23]3[CH2:25][O:24]3)[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]([F:31])([F:32])[C:3]([C:12]1[CH:27]=[CH:26][C:15]([O:16][C:17]2[CH:18]=[C:19]([CH2:23][CH2:25][OH:24])[CH:20]=[CH:21][CH:22]=2)=[C:14]([CH2:28][CH2:29][CH3:30])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:5])([F:7])[F:6]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(C2CO2)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1cccc(CCO)c1
Yield: 45.8 %

Procedure:
To a solution of 2-(3-(4-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-2-propylphenoxy)phenyl) oxirane (550 mg, 1.18 mmol) in tetrahydrofuran (10 mL), boron trifluoride diethyl ether complex (400 μl) and sodium cyanoborohydride (222 mg) were added at 0° C. under an argon atmosphere, and the resultant mixture was stirred. After completion of the reaction, the reaction solution was added with a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and then concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate) and the title compound (252 mg, yield 46%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:6]=1)[CH:2]=[CH2:3].C(N(CC)CC)C.[C:28](Cl)(=[O:37])[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:30]([O:29][C:28]([N:18]1[CH2:17][CH2:16][N:15]([C:7]2[N:6]=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:20][CH2:19]1)=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCOc1nc(N2CCNCC2)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCOc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
To a solution of 4-[(2-propen-1-yl)oxy]-2-(1-piperazinyl)quinazoline (1.80 g) in dry methylene chloride (18 ml) is added triethylamine (1.88 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (1.04 ml) in dry methylene chloride (3 ml). The mixture is stirred under ice-cooling for 2 hours. The reaction mixture is diluted with chloroform, washed with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(2-propen-1-yl)oxy]quinazoline (1.76 g) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[S:16]([C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([S:16](=[O:17])(=[O:18])[NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.4 %

Procedure:
A solution of 4-fluoroaniline (484 μL, 5.11 mmol) and pyridine (688 μL, 8.52 mmol) in DCM (20 mL) was treated with methyl 4-(chlorosulfonyl)benzoate (1.00 g, 4.26 mmol) and stirred at room temperature for 3 hours. The mixture was diluted with DCM, washed with 1 N aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Triturating with pentane gave 4-(4-fluoro-phenylsulfamoyl)-benzoic acid methyl ester (1.02 g, 77%). 1H NMR (300 MHz, CDCl3) δ 8.10 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.07-6.99 (m, 2H), 6.98-6.88 (m, 2H), 6.75 (br s, 1H), 3.94 (s, 3H). LCMS (m/z, Method A) ES+ 310.0 [M+1]+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:36][CH2:35][C:18]3([C:22](=[O:23])[N:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:36][CH2:35][C:18]3([C:22](=[O:23])[N:21]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]([F:32])([F:34])[F:33])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cccc(OCc3ccccc3)n1)CC2
Agent: [Pd]
Solvent: CO
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cccc(O)n1)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.5 %

Procedure:
To a solution of 8-(6-benzyloxy-pyridin-2-yl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (58 mg, 0.12 mmol) in methanol (2 mL) was added palladium (0) (4 mg). The reaction mixture was stirred at room temperature under an atmospheric pressure of H2 for 4 h and subsequently filtered. The filtrate was concentrated in vacuo and the crude residue was purified by flash column chromatography to yield the title compound (11 mg, 23%) as a white solid. MS (ESI): 408.3 (MH+)
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:27]=[C:26]([CH2:38][CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[N:27]=[C:26]([CH2:38][CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCN(C)CC2)n1
Agent: [Pd]
Solvent: CO
Product: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCN(C)CC2)n1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A mixture of ((2R)-2-(cyclopentylmethyl)-3-{2-[2-ethyl-5-fluoro-6-(4-methyl-1-piperazinyl)-4-pyrimidinyl]hydrazino}-3-oxopropyl)[(phenylmethyl)oxy]formamide (17.1 g, 31.61 mmol) and 10% Pd/C (4 g) suspended in MeOH (400 mL) was stirred under a balloon of H2 gas. After 2 h, and additional 2 g of fresh 10% Pd/C was added. The resulting suspension was stirred for another 1.5 h under a hydrogen atmosphere until the staring material was consumed. The Pd/C was removed by filtration through Celite, washing with MeOH and CH2Cl2. The filtrate was concentrated in vacuo. As the evaporation proceeded, the product crystallized out from the remaining solution. The evaporation continued until only ˜50 mL of liquid remained. The crystals were then collected by filtration to provide the product as a white solid (10.0 g). The filtrate was further evaporated to give a second crop of crystals (1.5 g) as the pure product. In the same way, a third crop was collected. The combined yield of ((2R)-2-(cyclopentylmethyl)-3-{2-[2-ethyl-5-fluoro-6-(4-methyl-1-piperazinyl)-4-pyrimidinyl]hydrazino}-3-oxopropyl)hydroxyformamide was 86% (12.2 g). LCMS: (M+H)+: 452.1.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@H:9]([CH3:33])[CH2:10][N:11]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13].[CH:34]1[C:43]2[C:38](=[CH:39][C:40]([S:44](Cl)(=[O:46])=[O:45])=[CH:41][CH:42]=2)[CH:37]=[CH:36][N:35]=1>ClCCl>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:11]([CH2:10][C@H:9]([NH:8][S:44]([C:40]1[CH:39]=[C:38]2[C:43](=[CH:42][CH:41]=1)[CH:34]=[N:35][CH:36]=[CH:37]2)(=[O:45])=[O:46])[CH3:33])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:13])=[O:14]
Reactant: C[C@@H](N)CN(CCc1ccccc1Cl)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(Cl)c1ccc2cnccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CN(CCc1ccccc1Cl)S(=O)(=O)c1ccccc1[N+](=O)[O-])NS(=O)(=O)c1ccc2cnccc2c1
Reaction time: 6 h
Yield: 73 %

Procedure:
0.3 mL of triethylamine and 280 mg of (R)—N-(2-aminopropyl)-N-(2-chlorophenethyl)-2-nitrobenzenesulfonamide prepared in Reference Example 6 were added with stirring at room temperature to a dichloromethane solution of isoquinoline-6-sulfonyl chloride prepared in Reference Example 1, and the mixture was then stirred for 6 hours. The reaction solution was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 300 mg of the title compound (73%).
Reaction SMILES: [F:1][C:2]1([F:37])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]2[C:29]3[CH:28]=[C:27]([C:30]4[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=4)[N:26]=[CH:25][C:24]=3[CH:23]=[N:22]2)[N:16]=1.O1CCOCC1.Cl>>[F:37][C:2]1([F:1])[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[C:15]1[N:16]=[C:17]([N:21]2[C:29]3[CH:28]=[C:27]([C:30]4[CH:35]=[N:34][CH:33]=[C:32]([CH3:36])[N:31]=4)[N:26]=[CH:25][C:24]=3[CH:23]=[N:22]2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CN(C(=O)OC(C)(C)C)CCC3(F)F)n2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3CNCCC3(F)F)n2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
To a solution of tert-butyl 4,4-difluoro-3-[6-[6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]piperidine-1-carboxylate (50 mg, 0.099 mmol) in 1,4-DIOXANE (2.00 mL, 23.4 mmol) was added hydrogen chloride (4 mol/l) in 1,4-dioxane (1.00 mL, 4.00 mmol). The reaction was stirred at RT 18 h. The reaction was concentrated and submitted for reverse phase HPLC to give 259 17 mg 42% yield. MS (ESI) m/z: 408.1. 1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 9.46 (s, 1H), 9.36 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 8.04 (t, J=7.8 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H), 3.60-3.42 (m, 2H), 3.18 (d, J=12.8 Hz, 1H), 2.87 (t, J=12.6 Hz, 1H), 2.67 (s, 3H), 2.36 (d, J=18.3 Hz, 1H), 2.21-2.09 (m, 1H), 1.99 (d, J=34.4 Hz, 1H).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[CH:28]1[C:37]2[C:32](=[C:33]([NH:38][NH2:39])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1>>[CH:28]1[C:37]2[C:32](=[C:33]([N:38]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[CH:16][C:17]([S:20]([C:23]([F:25])([F:24])[F:26])(=[O:22])=[O:21])=[CH:18][CH:19]=5)[N:8]=4)=[CH:4][CH:3]=[N:39]3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][N:29]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc2cnccc12
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2cnccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and isoquinolin-5-yl-hydrazine according to the method described for example 43. MS: M=498.0 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10](=O)[NH:9]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10](=[S:29])[NH:9]1
Reactant: O=C1COCCC(c2ccccc2F)(C(F)(F)F)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Fc1ccccc1C1(C(F)(F)F)CCOCC(=S)N1
Temperature: 25 °C
Yield: 180.6 %

Procedure:
To a solution of 5-(2-fluoro-phenyl)-5-trifluoromethyl-[1,4]oxazepan-3-one (1.19 g, 4.29 mmol) in 15 mL THF was added Lawesson's reagent (955 mg, 2.36 mmol). The reaction mixture was stirred at room temperature over night. The mixture was then partitioned between aqueous Na2CO3 solution (2 mol/L) and TBME. The layers were separated, washed with aqueous Na2CO3 solution (2 mol/L), brine and TBME. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was purified on a silica gel column by eluting with hexane/EtOAc 95/5->90/10 to give 1.25 g of the title compound as a yellow resin.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH2:4][CH2:5][NH2:6].[Cl-].[NH4+].[CH2:9](O)[CH3:10]>>[ClH:1].[CH3:2][N:3]1[CH2:4][CH2:5][N:6]=[C:10]1[CH2:9][Cl:1]
Reactant: CCO
Reactant: CNCCN
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CN1CCN=C1CCl
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A solution of chloracetimidoethylether, hydrochloride (1.58 g, 10 mmol) and N-methyl-ethylenediamine (0.74 g, 10 mmol) in 10 ml absolute ethanol is stirred at 0° C. and under a nitrogen atmosphere for one hour. A solution of hydrogen chloride in absolute ethanol (6.3 ml, 10 mmol) is added and the mixture is heated to 40° C. and stirred for additional two hour. After cooling to room temperature a precipitate of ammonium chloride is filtered of and the filtrate is concentrated in vacuo yielding the title compound as a yellow oil.