Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1.[CH2:14](N(CC)CC)[CH3:15].C(#N)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOCC>[CH:14]([C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])=[N:6][CH:7]=1)=[CH2:15]
Reactant: CC(C)C(=O)Nc1ncc(Br)cn1
Reactant: CCN(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOCC
Product: C=Cc1cnc(NC(=O)C(C)C)nc1
Temperature: 80 °C

Procedure:
A glass-lined pressure vessel was charged with 4.85 g of 5-bromo-2-(isobutyramido)pyrimidine, 5.0 ml of triethylamine, 15 ml of acetonitrile, 245 mg of tris(O-tolyl)phosphine, and 55 mg of palladium acetate. The vessel was placed under an ethylene atmosphere at 200 psi and heated at 80° C. for 18 hours in a rocking autoclave. The vessel was cooled and then vented. The residue was treated with 50 ml of ether and the resulting mixture filtered. The solid was further washed with ether (2×25 ml). The organic filtrate was concentrated and then chromatographed on silica gel. Elution with methylene chloride:methanol (95:5) afforded 2.99 g of product, mp 110°-112° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=O)[CH3:2].[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:23]=1[NH2:24])=[O:18].[Sn](Cl)(Cl)(CCCC)CCCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:22][C:23]=1[NH:24][CH:6]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[O:18]
Reactant: CCOC(=O)CC(=O)C1CCCCC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(Nc1cc(-c2ccccc2)sc1C(=O)OC)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
To a solution of 3-Cyclohexyl-3-oxo-propionic acid ethyl ester (1.0 g, 5.0 mmol, 1.0 equiv) in THF (5.0 mL) was added 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.17 g, 5.0 mmol, 1.0 equiv) and SnBu2Cl2 (0.15 g, 0.50 mmol, 0.1 equiv) at room temperature. After stirred at room temperature for 5 minutes, the solution was added PhSiH3. The resulting reaction mixture was stirred at 65° C. under N2 for 18 hours, after which the solution was concentrated under vacuum and the residue was purified by silica gel column chromatography EtOAc/heptane, 10-60% to give product (0.7 g). MS: 416 [M+H+].
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[CH2:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH:18]1[NH2:26]>>[OH:15][C:12]1[CH:13]=[CH:14][C:5]([C:3](=[O:4])[CH2:2][NH:26][CH:18]2[CH2:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:16])[CH:8]=[CH:7]2
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Product: O=C(CNC1Cc2ccccc2C1)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
5-(Chloroacetyl)-8-hydroxy-2(1H)-quinolinone (25 mg, 0.105 mmol) prepared from literature procedure (Yoshizaki, Shiro; Tanimura, Kaoru; Tamada, Shigeharu; Yabuuchi, Youichi; Nakagawa, Kazuyuki. J. Med. Chem. (1976), 19(9), 1138-42) is reacted neat with indan-2-ylamine (205 mg, 1.21 mmol) at 25° C. for 2 hours. The reaction mixture is purified by flash chromatography (silica, CH2Cl2/methanol 9:1). ES+ MS m/e 335 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:29][CH2:30]1
Reactant: ClCCCCn1cnc2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2nc(N3CCN(CCCCn4cnc5ccccc54)CC3)cnc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-quinoxalinyl) piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.9 g compound (I-17) with a yield of 59.6%. ESI-MS [M+H]+: m/z 387.2.
Reaction SMILES: [Cl-].C[Al+]C.[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.C[O:13][C:14]([C:16]1[CH:17]=[C:18]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)[CH:19]=[C:20]2[O:24][CH:23]([CH3:25])[CH2:22][C:21]=12)=O>>[N:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:14]([C:16]1[CH:17]=[C:18]([O:26][C:27]2[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:34])=[O:35])=[CH:29][CH:28]=2)[CH:19]=[C:20]2[O:24][CH:23]([CH3:25])[CH2:22][C:21]=12)=[O:13]
Reactant: Nc1ccccn1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Agent: C[Al+]C
Agent: [Cl-]
Product: CC1Cc2c(cc(Oc3ccc(S(C)(=O)=O)cc3)cc2C(=O)Nc2ccccn2)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
Dimethylaluminum chloride (1.0 M solution in hexanes, 3 mL, 3.0 mmol) was added to a solution of 2-aminopyridine (282 mg, 3.0 mmol) in 1,2-dichloromethane at 0° C. The mixture was stirred at room temperature for 15 min and then 6-(4-methanesulfonyl-phenoxy)-2-methyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (1f) (108 mg, 0.30 mmol) in 1,2-dichloromethane (3 mL) was added. The mixture was stirred at room temperature overnight, and carefully quenched with 20% aqueous potassium sodium tartrate tetrahydrate (5 mL), diluted with H2O (30 mL), extracted with CH2Cl2 (2×50 mL) and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 50% EtOAc in hexane to give a white solid (67 mg, 53% yield). 1H NMR (400 MHz, CDCl3) δ 8.39 (br. s., 1 H) 8.21-8.34 (m, 2 H) 7.87-7.96 (m, 2 H) 7.70-7.81 (m, 1 H) 7.04-7.17 (m, 3 H) 6.94 (d, J=2.02 Hz, 1 H) 6.67 (d, J=1.77 Hz, 1 H) 4.97-5.18 (m, 1 H) 3.71 (dd, J=16.67, 8.84 Hz, 1 H) 3.19 (dd, J=16.67, 7.58 Hz, 1 H) 3.07 (s, 3 H) 1.53 (d, J=6.32 Hz, 3 H); LCMS for C22H20N2O5S m/z 425.10 (M+H)+; Anal. Calcd. for C22H20N2O5S.0.2H2O: C, 61.73; H, 4.80; N, 6.54. Found: C, 61.71; H, 4.81; N, 6.41.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7](=[O:20])[CH:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[NH:9][C:10](=[O:11])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][O:32][C:33](=[O:35])[CH3:34]>CN(C)C=O.C(OCC)(=O)C>[C:33]([O:32][CH2:31][CH2:30][N:6]1[C:5]2[CH:21]=[CH:22][C:2]([Cl:1])=[CH:3][C:4]=2[C:10](=[O:11])[NH:9][CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]1=[O:20])(=[O:35])[CH3:34]
Reactant: O=C1NC(Cc2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCCN1C(=O)C(Cc2ccccc2Cl)NC(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 7-chloro-3-(2-chlorobenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (0.5 g, 1.5 mmol) in N,N-dimethylformamide (10 mL), was added powdered potassium carbonate (0.31 g, 2.2 mmol) followed by 2-bromoethylacetate (0.17 mL, 1.6 mmol). The mixture was stirred at ambient temperature overnight. After 20 hours, more 2-bromoethylacetate (0.05 mL, 0.5 mmol) was added and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (3×50 mL), washed with brine (50 mL), dried with anhydrous sodium sulfate, decanted, and concentrated to yield crude 2-(7-chloro-3-(2-chlorobenzyl)-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-1-yl)ethyl acetate, which was used directly in the next step without further purification. MS (m/z): 421.1 (M+H)+.
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].Cl[CH2:6][C:7](=O)[CH2:8][C:9]([O:11][CH3:12])=[O:10]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:2][C:1]1[O:3][CH:6]=[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=1
Reactant: CC(N)=O
Reactant: COC(=O)CC(=O)CCl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COC(=O)Cc1coc(C)n1
Temperature: 120 °C

Procedure:
A mixture of acetamide (1.312 g, 22.21 mmol) and methyl chloroacetoacetate in 20 mL of 1,4-dioxane and 20 mL of toluene was heated at 120° C. for 4 hours. The solution was concentrated and the residue was purified by silica gel chromatography using a hexanes/EtOAc gradient to give the indicated compound (a pale yellow oil). 1H NMR (CDCl3, 500 MHz) δ 7.58 (1H, s), 3.78 (3H, s), 3.64 (2H, s), 2.51 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=2)=[O:10])=[CH:4][C:3]=1[C:18]1([CH2:25][F:26])[CH2:23][O:22][CH2:21][C:20](=S)[NH:19]1.C(OO)(C)(C)C.[O-]S([O-])(=S)=O.[Na+].[Na+].[NH3:40]>CO>[ClH:1].[NH2:40][C:20]1[CH2:21][O:22][CH2:23][C:18]([C:3]2[CH:4]=[C:5]([NH:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][N:12]=3)=[O:10])[CH:6]=[N:7][C:2]=2[Cl:1])([CH2:25][F:26])[N:19]=1
Reactant: N
Reactant: O=C(Nc1cnc(Cl)c(C2(CF)COCC(=S)N2)c1)c1ccc(Br)cn1
Agent: CC(C)(C)OO
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Product: Cl
Product: NC1=NC(CF)(c2cc(NC(=O)c3ccc(Br)cn3)cnc2Cl)COC1
Reaction time: 20 h

Procedure:
To a suspension of 5-bromo-pyridine-2-carboxylic acid [6-chloro-5-(3-fluoromethyl-5-thioxo-morpholin-3-yl)-pyridin-3-yl]-amide (26 mg, 0.057 mmol) in 7M NH3 in MeOH (0.23 ml) was added at −20° C., tert.-butylhydroperoxide (0.055 ml, 0.566 mmol) and aq. 25% NH3 (0.15 ml, 0.99 mmol), the reaction mixture was stirred at room temperature for 80 min, 7M NH3 in MeOH (0.69 ml) were added and stirring continued for 20 h. At 0° C. halfsaturated aq. Na2S2O3 was added and the mixture extracted with EtOAc. The combined organic layers were washed with halfsaturated aq. NaCl, dried with Na2SO4 and evaporated. The residue was purified by preparative TLC DCM/MeOH 9:1 to yield the desired compound as colorless foam. The product was dissolved in DCM/MeOH, 5 equivalents of 5M HCl in Et2O were added and the solvents evaporated to provide the title compound as beige solid.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.Cl[CH2:12][CH2:13][CH2:14][C:15]#[N:16]>C(OCC)C>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:15]2[CH2:14][CH2:13][CH2:12][N:16]=2)=[CH:5][CH:4]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: N#CCCCCl
Agent: [Mg]
Solvent: CCOCC
Product: Fc1ccc(CC2=NCCC2)cc1
Reaction time: 2 h
Yield: 37.6 %

Procedure:
Magnesium turnings (for Grignard, 6.4 g, 0.266 mol) are covered with a layer of 20 ml of a solution of 4-fluorobenzyl bromide (50 g, 0.265 mol) in abs. (absolute) diethyl ether (250 ml) in a 500 ml three-necked flask and the mixture is briefly heated until the reaction starts. The remaining volume of 4-fluorobenzyl bromide is added dropwise in the course of 30 min and at the same time the mixture is kept at a temperature of 40° C. for a further 2 h in an oil bath. A solution of 4-chlorobutyronitrile (13.6 g, 0.132 mol) in diethyl ether (50 ml) is added dropwise in the course of 30 min to the still warm, freshly prepared Gringnard solution. The largest part of the ether (200 ml) is distilled off over a bridge and replaced by abs. toluene (250 ml). Diethyl ether is driven off until a boiling temperature of 95° C. is achieved in the bottom. The mixture is stirred at this temperature for a further 2 h and then allowed to stand at RT overnight. The organic phase is transferred to a separating funnel and hydrolysed and extracted with 10% strength HCl (3×100 ml each). The toluene phase is discarded, and the HCl-acidic aqueous phase is again washed with toluene (100 ml) and then maintained at pH 10 using conc. NaOH (32% strength). The pyrroline base depositing is taken up with diethyl ether (100 ml) in the separating funnel. After separating the ether phase, the mixture is again extracted with ether (2×50 ml), and the combined ether phases are dried over K2CO3 sicc. and concentrated. 8.8 g of 2-(4-fluorobenzyl)-1-pyrroline (37.8% based on chloronitrile) are obtained.
Reaction SMILES: [CH3:1][Zn]C.[CH3:4][O:5][C:6]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[C:23]([CH3:31])[C:7]=1[C:8]([C:10]1[C:11]([O:21][CH3:22])=[N:12][CH:13]=[C:14](Br)[C:15]=1[C:16]([F:19])([F:18])[F:17])=[O:9].O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:4][O:5][C:6]1[C:26]([O:27][CH3:28])=[C:25]([O:29][CH3:30])[CH:24]=[C:23]([CH3:31])[C:7]=1[C:8]([C:10]1[C:11]([O:21][CH3:22])=[N:12][CH:13]=[C:14]([CH3:1])[C:15]=1[C:16]([F:19])([F:18])[F:17])=[O:9]
Reactant: COc1cc(C)c(C(=O)c2c(OC)ncc(Br)c2C(F)(F)F)c(OC)c1OC
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)c(C(=O)c2c(OC)ncc(C)c2C(F)(F)F)c(OC)c1OC
Temperature: 25 °C
Reaction time: 192 h
Yield: 97.1 %

Procedure:
3.80 ml (3.80 mmol) of dimethylzinc (1.0 mol/l hexane solution) was dropwise added at 0° C. to a solution having 0.60 g (1.29 mmol) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-5-bromo-4-trifluoromethyl-2-methoxypyridine obtained in Step (d) and 0.10 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium dissolved in 10 ml of tetrahydrofuran, and the temperature was increased naturally, followed by stirring at room temperature for 8 days. Water was added to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. After extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 0.50 g (yield: 96%) of 3-(2,3,4-trimethoxy-6-methylbenzoyl)-4-trifluoromethyl-2-methoxy-5-methylpyridine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:21][C:22]1([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O.C(Cl)[Cl:52]>CCCCO>[ClH:52].[NH2:27][C:22]1([CH3:21])[CH2:26][CH2:25][N:24]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:23]1
Reactant: ClCCl
Reactant: CC1(NC(=O)OC(C)(C)C)CCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CC1(N)CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.085 g, 0.254 mmol, Example 1, Step I), tert-butyl 3-methylpyrrolidin-3-ylcarbamate (0.152 g, 0.76 mmol) and DIEA (0.08 mL, 0.5 mmol) in n-BuOH (2 mL) were stirred at 156° C. (bath) for 6 hours. The solvent was removed, and the residue dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 10-80% CH3CN/water gradient; 25 CV) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give N-(4-(3-amino-3-methylpyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.072 g, 54% yield) as a solid. 1H NMR (400 MHz, D2O) δ 9.16 (s, 1H), 8.84 (d, 1H), 8.78 (d, 1H), 8.22 (s, 1H), 7.98 (m, 1H), 7.40 (s, 1H), 3.80-3.94 (m, 3H), 3.62 (m, 1H), 2.04 (m, 1H), 1.85 (m, 1H), 1.23 (s, 3H); LCMS (APCI+) m/z 415 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]=[O:15])[CH:9]=2)=[CH:4][CH:3]=1>C([Mg]Br)C(C)C.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH:14]([OH:15])[CH2:4][CH:5]([CH3:8])[CH3:6])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1C=O
Agent: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Cl)cc2)cc1C(O)CC(C)C
Yield: 170.5 %

Procedure:
An operation similar to that in Example 3 (2) was performed using 5-(4-chlorophenyl)-2-methyl-3-furaldehyde (1.3 g) and 1N isobutylmagnesium bromide-tetrahydrofuran solution (10 mL) to give the title compound (1.4 g, 85%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH2:19]Cl)[N:3]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:31][CH2:32][NH:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].C(Cl)(Cl)Cl.CO>ClC1C=CC=CC=1>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5](=[O:16])[N:4]([CH2:17][CH2:18][CH2:19][N:33]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:32][CH2:31][C:25]2[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=2)[N:3]=1
Reactant: COc1cc2c(C)nn(CCCCl)c(=O)c2cc1OC
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Solvent: Clc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CCN(CCCn2nc(C)c3cc(OC)c(OC)cc3c2=O)Cc2ccccc2)cc1OC

Procedure:
1-[4-Methyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-[N-benzyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]propane was prepared analogous to Example 1 (a) by reaction of 1-[4-methyl-6,7-dimethoxy-1(2H)-phthalazinone-2-yl]-3-chloro-propane with N-(3,4-dimethoxy-phenylethyl)-N-benzylamine in chlorobenzene. Rf -value (chloroform/methanol = 9/1) : 0.9.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[CH:15]>[Cu]I.[Pd](Cl)Cl.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.C(N(CC)CC)C>[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[C:15][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#CC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 250 mL sealed reaction vessel was added methyl 5-bromopyridine-2-carboxylate (5 g, 23 mmol), copper(I) iodide (0.43 g, 2.3 mmol), bis(triphenylphosphine) palladium(II) chloride (3.23 g, 4.6 mmol), and triethylamine (80 mL). The mixture was allowed to stir for approximately 10 minutes upon which 3,3-dimethylbut-1-yne (2.83 g, 34.5 mmol) was added. The tube was sealed, stirred at room temperature overnight, and heated at 60° C. for one hour. The mixture was allowed to cool, and then concentrated under vacuum to a residue. The residue was purified by column chromatography on silica gel using EtOAc/hexanes (1:10) as eluent to give the product (4.62 g, 92%) as a tan solid which was used directly in the next step.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:4].[H][H].Cl[C:13]1[CH:18]=[C:17]([S:19][CH3:20])[N:16]=[CH:15][N:14]=1>CS(C)=O>[CH3:9][O:8][C:6](=[O:7])[CH:5]([C:3]#[N:4])[C:13]1[CH:18]=[C:17]([S:19][CH3:20])[N:16]=[CH:15][N:14]=1
Reactant: CSc1cc(Cl)ncn1
Reactant: COC(=O)CC#N
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(C#N)c1cc(SC)ncn1
Temperature: 80 °C

Procedure:
To the suspension of NaH (2.19 g, 55 mmol, 60% in oil) in DMSO (20 mL) is added methyl cyanoacetate (4.88 mL, 51 mmol) at 23° C. (cooled by ice-water if necessary). After the evolution of hydrogen has ceased, 4-chloro-6-methylsulfanyl-pyrimidine (3.56 g, 22 mmol) is added. The reaction is heated at 80° C. for 5 hours. The reaction mixture is then cooled to room temperature and quenched with ice-cooled saturated NH4Cl (50 mL). The solid is filtered and washed with water. 100 mL of hexanes is added to the solid and heated at 60° C. for 1 hour and then cooled to room temperature. The solid is filtered and washed with hexanes to afford cyano-(6-methylsulfanyl-pyrimidin-4-yl)-acetic acid methyl ester. 1H NMR 400 MHz (d6-DMSO) δ 8.42 (d, 1H), 6.64 (s, 1H), 3.71 (s, 3H), 2.55 (s, 3H). MS m/z 224.10 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5](N)=[C:4]([CH3:12])[CH:3]=1.N([O-])=O.[Na+].C(Cl)Cl.[BrH:20]>O>[Br:20][C:5]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]([F:1])=[CH:3][C:4]=1[CH3:12]
Reactant: Cc1cc(F)cc([N+](=O)[O-])c1N
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc(F)cc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A suspension of 4-fluoro-2-methyl-6-nitroaniline (5.1 g, 30 mmol) in water (38 mL) and aqueous HBr (15 mL, 40%) was refluxed for 10 minutes and then cooled to 0° C. A solution of NaNO2 (2.07 g, 30 mmol) in H2O (12 mL) was added dropwise at a temperature <10° C. The diazonium solution was stirred for 30 minutes at a temperature of 0° C. to 5° C. and was then added slowly to a stirred mixture of CuBr (4.33 g, 30 mmol) in aqueous HBr (12 mL, 40%) and water (23 mL) at RT. The mixture was stirred at RT for 30 minutes and then on a steam bath for 1 hour. The reaction mixture was cooled to RT, DCM (50 mL) was added, and the mixture was washed with saturated NaHCO3 and brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography, eluting with petroleum ether to give the title compound as an oil (2.0 g, 28%). 1H NMR (400 MHz, CDCl3) δ ppm 7.23 (1H, dd, J1=2.4 Hz, J2=7.2 Hz), 7.14 (1H, dd, J1=2.8 Hz, J2=8.8 Hz), 2.44 (3H, s).
Reaction SMILES: [C:1]([O:4][C@@H:5]([C:7]1[NH:12][C:11](=[O:13])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[C:1]([O:4][C@@H:5]([C:7]1[N:12]=[C:11]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH:10]=[CH:9][N:8]=1)[CH3:6])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)O[C@H](C)c1nccc(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of (R)-2-(1-acetoxy-ethyl)-3H-pyrimidin-4-one (prepared according to the method of Preparation Thirteen, 2.58 g, 14.2 mmol) and triethylamine (1.43 g, 14.2 mmol) in dichloromethane (20 mL) was added methanesulfonyl chloride (1.63 g, 14.2 mmol) dropwise and stirred for 1 h. The mixture was washed successively with saturated aqueous sodium bicarbonate and water, dried over magnesium sulfate and filtered. The filtrate was evaporated to give the title compound as an oil, 3.15 g (85%). 1H NMR (CDCl3, 300 MHz) δ 1.56 (d, 3H), 2.18 (s, 3H), 3.82 (s, 3H), 5.56 (q, 1H), 6.38 (d, 1H), 8.24 (d, 1H); MS (CI) 261 (MH+); [α]D+53.8 (c 1.1, MeOH).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:17]=[C:16]([O:18]CC2C=CC=CC=2)[C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][N:2]([CH3:26])[C:3]([C:5]1[CH:17]=[C:16]([OH:18])[C:8]2[N:9]=[C:10]([CH:13]3[CH2:15][CH2:14]3)[N:11]([CH3:12])[C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)c2nc(C3CC3)n(C)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)C(=O)c1cc(O)c2nc(C3CC3)n(C)c2c1
Yield: 91.8 %

Procedure:
A solution of 15.4 g (42.0 mmol) 7-benzyloxy-2-cyclopropyl-3-methyl-3H-benzimidazole-5-carboxylic acid dimethylamide in 200 ml ethanol and 3.6 ml acetic acid was hydrogenated over 3.4 g 10% Pd/C in autoclave (5 bar H2) at 50° C. for 16 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was crystallized from diisopropyl ether to afford 10 g (92%) of the title compound as a white solid.