Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([OH:18])=O)[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl.C[O:22][C:23](=[O:27])[C@@H:24]([CH3:26])[NH2:25]>>[CH:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:19])=[C:10]([C:16]([NH:25][C@H:24]([CH3:26])[C:23]([OH:27])=[O:22])=[O:18])[N:11]=[C:12]2[Cl:15])=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)N[C@H](C)C(=O)O)nc(Cl)c2c1

Procedure:
Analogously to Example A-56, 0.040 g of 7-isopropoxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid were allowed to react with D-Alanine methyl ester hydrochloride. The intermediate ester product was hydrolyzed as in Example A-56 to give 0.042 g of a white solid: MS-(−)-ion, M−1=353.0 amu.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH:7]=[N:8][C:4]=2[C:3]=1[O:17][CH3:18].[CH:19](/B(O)O)=[CH:20]\[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O>[CH3:18][O:17][C:3]1[C:4]2[N:8]=[CH:7][N:6]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[C:5]=2[CH:15]=[CH:16][C:2]=1[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1c(Br)ccc2c1ncn2C1CCCCO1
Reactant: OB(O)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C=Cc2ccccc2)ccc2c1ncn2C1CCCCO1
Temperature: 100 °C
Reaction time: 6 h
Yield: 77.9 %

Procedure:
A 1 L three-necked round bottom flask fitted with an overhead stirrer was dried and cooled under a stream of nitrogen then charged with 5-bromo-4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (30 g, 0.096 mol, 1.0 equiv.) in 1,4-dioxane (300 mL) and water (60 mL). The mixture was degassed with nitrogen. To the degassed solution at RT was added sequentially trans-β-styrene boronic acid (14.26 g, 0.096 mol, 1.0 equiv.), Cs2CO3 (62.82 g, 0.19 mol, 2.0 equiv.), Pd(II)Cl2(PPh3)2 (3.38 g, 0.004 mol, 0.05 equiv.) then the reaction was heated with stirring at 100° C. for 6 h. The reaction mixture was quenched with ice cold water (1 L) and extracted with EtOAc (2×1 L). The organic layers were combined, washed with brine solution (500 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (40-50% EtOAc) to afford 4-methoxy-5-styryl-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (25 g, 77%) as a brown solid.
Reaction SMILES: C(Cl)(=O)C.[CH2:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])=[CH:11][CH:12]=2)[CH2:7][NH:6]1.NC1C=C2C(=CC=1)CN(C(NC1C=C[C:42]([C:45](=[O:50])NCCC)=[CH:41][CH:40]=1)=O)C2>>[C:45]([N:6]1[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[C:10]([NH:14][C:15]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)=[O:16])[CH:9]=2)[CH2:5]1)(=[O:50])[CH2:42][CH2:41][CH3:40]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: O=C(Nc1ccc2c(c1)CNC2)N1Cc2ccccc2C1
Solvent: CC(=O)Cl
Product: CCCC(=O)N1Cc2ccc(NC(=O)N3Cc4ccccc4C3)cc2C1

Procedure:
The title compound was prepared as described in Example 278, substituting butyryl chloride for acetyl chloride and N-(isoindolin-5-yl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (s, 1H), 7.59-7.61 (bs, 1H), 7.43-7.48 (m, 1H), 7.30-7.41 (m, 4H), 7.22 (t, J=7.7 Hz, 1H), 4.77 (d, J=13.9 Hz, 2H), 4.77 (s, 4H), 4.55-4.60 (m, 2H), 2.33 (td, J=7.3, 3.7 Hz, 2H), 1.54-1.63 (m, 2H), 0.93 (td, J=7.3, 1.4 Hz, 3H); MS (ESI(+)) m/e 350 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C>CC(OC)(C)C>[CH3:14][C:12]1[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[N:9]=[C:8]([C:4]2[CH:3]=[C:2]([B:30]([OH:35])[OH:31])[CH:7]=[CH:6][CH:5]=2)[CH:13]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)c1
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(B(O)O)c2)c1
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 2-(3-bromo-phenyl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example E.90) (1.23 g, 3.13 mmol) in TBME (80 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 3.2 mL, 5.0 mmol) keeping the internal temperature below −60° C. (ca. 3 min), stirring was continued at −78° C. for 25 min, then triisopropyl borate (1.5 mL, 6.27 mmol) was added quickly, causing the internal temperature to rise to −60° C., stirring was continued at −78° C. for 20 min. The mixture was quenched by addition of 1M NaH2PO4.2H2O-solution, the cooling bath was removed and the mixture was allowed to warm to 0° C. and stirred at 0° C. for 10 min. Diluted with EtOAc and brine, extracted three times with EtOAc, dried the combined organic layers over Na2SO4. Removal of the solvent in vacuum left the title compound as a light brown foam (1.20 g, 70.5%, purity: 65.8%), which was used without further purification. MS (ISP) 358.2 [(M+H)+].
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][N:8]=2)(=O)[CH3:2].O.[NH2:23][NH2:24]>C(O)(=O)C>[CH3:2][C:1]1[C:4]2[C:5](=[O:21])[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[NH:24][N:23]=1
Reactant: NN
Reactant: CC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 25 °C
Yield: 44.3 %

Procedure:
Compound 102 in an amount of 1.2 g (4.3 millimoles) was suspended in 10 ml of glacial acetic acid, and 0.46 ml (9.4 millimoles) of hydrazine monohydrate was added to the suspension. Thereafter, the mixture was heated under reflux for 3 hours. The reaction solution was cooled to room temperature, and the precipitate was collected by filtration and recrystallized from DMF-water to give 530 mg (yield: 44.3%) of Compound 2.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[K+].[Br-].C[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:1]([O:4][CH2:5][C:2]1[C:1](=[O:3])[O:4][C:5]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:6]=2)[CH3:2]
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: [Br-]
Agent: [K+]
Product: CCOCc1cc2ccccc2oc1=O

Procedure:
(0.15 g, 73%); m.p.: 95-96° C., Rf=0.38 (ethyl acetate:n-Hexane=1:5); IR (KBr cm−1): 2970, 2924, 2863, 2341, 1717, 1605, 1574, 1447, 1384, 1283, 1172, 1116, 1061, 919, 756, 630; 1H-NMR (400 MHz, CDCl3) δ/ppm: 1.31 (3H, t, J=7.0 Hz, OCH2CH3), 3.68 (2H, q, J=7.0 Hz, OCH2CH3), 4.46 (2H, d, J=1.6 Hz, CH2OCH2CH3), 7.28 (1H, td, J=7.6, 1.2 Hz, ArH), 7.34 (1H, d, J=8.0 Hz, ArH), 7.48-7.52 (2H, ArH), 7.81 (1H, t, J=1.6 Hz, H-4); 13C-NMR (100 MHz, CDCl3) δ/ppm: 15.2, 66.9, 66.9, 116.5, 119.2, 124.4, 126.4, 127.7, 131.0, 138.1, 153.1, 160.5; MS (EI) m/z: 175 ([M-(C2H5)]+, 53%), 160 (100%), 132 (51%), 131 (42%); Anal. calcd for C12H12O3 (204.22): C, 70.57; H, 5.92. found: C, 70.60; H, 5.95.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=[N:19]2)=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH2:25]([O:24][C:22]([C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([NH:11][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1])[CH:21]=2)=[O:23])[CH3:26]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CCOC(=O)c1cnc2cc(N)ccc2c1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3Br)ccc2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A solution of 2-bromobenzoyl chloride (5.38 g, 24.5 mmol) in 100 ml chloroform was added dropwise at room temperature to a solution of ethyl 7-aminoquinoline-3-carboxylate (2.65 g, 12.25 mmol), 4-N,N-dimethylaminopyridine (150 mg, 1.23 mmol) and pyridine (3.96 ml, 49 mmol) in 100 ml chloroform. The resulting solution was heated under reflux for 4 hr, then cooled to room temperature. The chloroform solution was then washed sequentially with dilute aqueous hydrochloric acid solution, water and brine, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. The residue was chromatographed on silica gel, eluting with 60:40 hexane/ethyl acetate to yield the title product as a solid foam (2.45 g 50% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:16]=[CH:15][C:14]=3[F:24])=[CH:11][N:10]([CH3:25])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.[CH2:26]([OH:30])[CH2:27][C:28]#[CH:29]>O1CCCC1.C(N(CC)CC)C.[Cu]I>[CH2:22]([S:19]([C:17]1[CH:16]=[CH:15][C:14]([F:24])=[C:13]([C:12]2[C:4]3[C:5](=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:29]#[C:28][CH2:27][CH2:26][OH:30])[CH:3]=3)[N:10]([CH3:25])[CH:11]=2)[CH:18]=1)(=[O:21])=[O:20])[CH3:23]
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c3c(OC)nc(Br)cc23)c1
Reactant: C#CCCO
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c3c(OC)nc(C#CCCO)cc23)c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 68.4 %

Procedure:
A mixture of Example 126A (300 mg, 0.702 mmol), but-3-yn-1-ol (63.8 μl, 0.843 mmol), Pd(dppf)CH2Cl2 (57.3 mg, 0.070 mmol), and copper(I) iodide (13.4 mg, 0.070 mmol) in tetrahydrofuran (9 mL) and triethylamine (3 mL) was purged with nitrogen and then stirred at 70° C. in a sealed tube for 2.5 hours. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified on silica gel column (0-8% MeOH in dichloromethane) to give the title compound (200 mg, 68.4% yield)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[C:14]([NH2:20])[CH:13]=2)[CH:10]=1)=[O:4].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=S)=[CH:24][CH:23]=1.CI>CO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]3[N:18]([CH3:19])[C:29]([NH:28][C:25]4[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=4)=[N:20][C:14]=3[CH:13]=2)[CH:10]=1)=[O:4]
Reactant: CNc1ccc(Oc2cncc(C(=O)OC)c2)cc1N
Reactant: S=C=Nc1ccc(Br)cc1
Solvent: CO
Solvent: CI
Product: COC(=O)c1cncc(Oc2ccc3c(c2)nc(Nc2ccc(Br)cc2)n3C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the methyl5-[3-amino-4-(methylamino)phenoxy]pyridine-3-carboxylate (1 eq) in methanol (8 ml) was treated with 4-bromophenylisothiocyanate (1 eq) and stirred at 60° C.-65° C. for 2 hours. The reaction mixture was cooled down to room temperature and methyl iodide (1 eq) was added and stirred overnight at 60° C. The reaction was cooled down to room temperature, evaporated, taken up in ethyl acetate and washed with water and brine, dried, evaporated under reduced pressure. Column chromatography yielded methyl5-{2-[(4-bromophenyl)amino]-1-methylbenzimidazol-5-yloxy}pyridine-3-carboxylate. MS: MH+=452
Reaction SMILES: [C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)(=[O:3])[NH2:2].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=1[O:36][CH3:37]>O1CCOCC1.C(OCC)(=O)C.[Ag-]=O>[C:1]([CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15](=[O:23])[NH:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:12][CH:13]=2)[C:8]([CH2:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][C:27]=2[O:36][CH3:37])=[CH:7]1)(=[O:3])[NH2:2]
Reactant: NC(=O)CCn1ccc2cc(C(=O)NCC3CCCC3)ccc21
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=[Ag-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(Cc2cn(CCC(N)=O)c3ccc(C(=O)NCC4CCCC4)cc23)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 38.8 %

Procedure:
Silver(I) oxide (0.17 g) was added to a solution of 1-(2-carbamoylethyl)-5-(N-cyclopentylmethylcarbamoyl)indole (0.70 g) and methyl 4-bromomethyl-3-methoxybenzoate (B) (0.19 g) in 1,4-dioxane (10 ml). The mixture was protected from light and stirred at 80° C. under an atmosphere of nitrogen for 12 hours. The mixture was then diluted with 1:1 v/v ethyl acetate:ether (50 ml) and filtered. The filtrate was washed sequentially with water and brine, dried (MgSO4), and evaporated. The residual yellow gum was purified by flash chromatography on silica gel (500 ml), eluting with 5:95 v/v methanol:chloroform to give the title compound (0.14 g, 39%) as a white solid; mp 189°-191° C. (d); NMR (250 MHz, DMSO-d6):
Reaction SMILES: [C:1]1([N:7]2[C:22]([OH:23])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].Cl>CN(C=O)C>[C:1]1([N:7]2[C:22]([O:23][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[C:10]3[N:11]=[CH:12][N:13]=[C:14]([S:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]3=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCBr
Reactant: CCOC(=O)CSc1ncnc2c(O)n(-c3ccccc3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCOc1c2ncnc(SCC(=O)OCC)c2nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 g of 2-phenyl-3-hydroxy-7-ethoxycarbonylmethylthio-pyrazolo[4,3-d]pyrimidine was dissolved in 10 ml of DMF, and 0.5 g of anhydrous potassium carbonate and 0.65 g of bromoheptane were added thereto. The mixture was stirred at room temperature for 48 hours. Then, after confirming the completion of the reaction by means of TLC, an aqueous hydrochloric acid solution was added. The reaction mixture was extracted with chloroform. The chloroform layer was washed with an aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and then chloroform was distilled off. The residue was purified by silica gel chromatography (60% chloroform-hexane), whereby the desired product was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.[H-].[Na+].[F:19][C:20]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[C:22](F)[N:21]=1>CN(C)C=O>[F:19][C:20]1[N:21]=[C:22]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)[CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:27])[F:28]
Reactant: Fc1ccc(C(F)(F)F)c(F)n1
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(F)n2)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (1.008 mmol; 213.0 mg) in Dimethylformamide (10 mL) at 0° C. was added sodium hydride (60% in mineral oil; 1.210 mmol; 48.40 mg). The resulting mixture was stirred for 10 min. 2,6-difluoro-3-(trifluoromethyl)pyridine (1.008 mmol; 184.6 mg) was then added. The reaction was stirred and allowed to warm to room temperature and stirred for 4 hours. The mixture was quenched with water, and extracted with EtOAc. The organic layer was washed with brine, and then concentrated. The residue was purified on silica eluted with 0 to 100% EtOAc in Heptane. 1-[6-fluoro-5-(trifluoromethyl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine was obtained as the most abundant isomer (173.6 mg, 46%).
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][C@H:10]2[O:19][CH3:20])=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.N.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][C@H:10]2[O:19][CH3:20])=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: [H][H]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC#N)C[C@H]1OC
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Yield: 13 %

Procedure:
A mixture of 3 parts of cis-4-amino-5-chloro-N-[1-(2-cyanoethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide and 200 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at 20° C. with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 0.4 parts (13%) of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide; mp. 174.8 (interm. 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:39])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[C:31]([F:38])[CH:30]=1.CCN(CC)CC>ClCCCl>[CH3:24][O:25][C:26](=[O:39])[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:37])=[C:31]([F:38])[CH:30]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: COC(=O)COc1ccc(N=C=O)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)COc1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (example 9.1) was reacted with (3-fluoro-4-isocyanato-phenoxy)-acetic acid methyl ester (example 24.1) in 1,2-dichloroethane in the presence of Et3N (2.2 eq.) for 3 days under reflux conditions to give the title compound as brown gum. MS: m/e=551.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH:9]([NH:16][CH3:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:3]=1.ClC(Cl)(O[C:22](=[O:28])OC(Cl)(Cl)Cl)Cl.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][C:22](=[O:28])[N:16]([CH3:17])[CH:9]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CNC(c1ccccn1)c1cc(Br)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)Nc2ccc(Br)cc2C1c1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of crude 4-Bromo-2-(methylamino-pyridin-2-yl-methyl)-phenylamine (500 mg) in THF (20 mL) is added triphosgene (493 mg, 1.87 mmol), then the mixture is stirred at room temperature for 2 h. TLC showed the reaction is completed. Water (20 mL) is added and the mixture is extracted with EtOAc, the organic layer is dried over Na2SO4 and concentrated to give the desired compound as a crude mixture. This is used in next step with no further purification.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:10]([CH:12](CCCC)[C:13]([O-:15])=[O:14])[CH3:11].[Sn+2].C(C(CCCC)C([O-])=[O:25])C>>[CH2:1]([O:9][C:11](=[O:25])[CH2:10][CH2:12][C:13]([OH:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCC(CC)C(=O)[O-]
Reactant: CCCCCCCCO
Agent: [Sn+2]
Product: CCCCCCCCOC(=O)CCC(=O)O
Temperature: 140 °C
Reaction time: 2 h
Yield: 5513 %

Procedure:
A mixture containing 4.1 g (31.5 mmol) of 1-octanol, 100 mg of tin(II) 2-ethylhexanoate and 3.0 g (30 mmol) of succinate anhydride was stirred under nitrogen at 140° C. for 2 hours. The mixture was cooled to room temperature and, the crude product was purified by column chromatography on silica gel (40% ethyl acetate in hexane) to provide 3.134 g of succinic acid mono-(1-octyl) ester (45.36%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[BH4-].[Na+]>ClCCCl>[CH2:32]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:7][CH:8]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN([C@H]2CC[C@@H](n3cc(-c4ccc(CNCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of cis-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (100 mg, 0.238 mmol), benzaldehyde (28 mg, 0.262 mmol) and acetic acid (43 mg, 0.714 mmol) in 1,2 dichloroethane (4 mL) was stirred at ambient temperature for 1 hour. Sodium triacetoxyborohydride (100 mg, 2.6 mmol) was added and the mixture was stirring continued for 2 hours. Sodium borohydride (100 mg, 2.60 mmol) was added and stirring was continued for an additional 30 minutes, the solvents were removed under reduced pressure and the residue purified by preparative reverse phase chromatography to yield cis-5-{4-[(benzylamino)methyl]phenyl}-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine: 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.2-7.50(m, 1OH), 6.03(bs, 2H), 4.67 (m, 1H), 3.71(d, 2H), 1.52-2.50(m, 20H); R-P-HPLC (Hypersil HS C18, 5 μm, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 14.42 min.; MS:MH+ 510.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.[N+](C=CC1C=CC=CC=1)([O-])=O>C(N)C1C=CC=CC=1>[CH2:23]([N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccccc3)cn2Cc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=[N+]([O-])C=Cc1ccccc1
Solvent: NCc1ccccc1
Product: c1ccc(Cn2cc(-c3ccccc3)c3c2CCNC3)cc1

Procedure:
1-Benzyl-3-phenyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. The desired compound (380.7 mg) was prepared from 0.51 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 280 μL of benzylamine, and 0.39 g of (2-nitro-vinyl)-benzene as in Example 1, Step A. MS (ESI): exact mass calculated for C25H28N2O2, 388.22; found, m/z 389.2 [M+H]+.