Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[C:31]1([CH3:40])[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 73.2 %

Procedure:
To a stirred solution 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (200 mg, 0.42 mmol) and p-tolyl boronic acid (86 mg, 0.63 mmol) in dioxane (3 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (150 mg, 73%). LCMS: 488.20 (M+1)+; HPLC: 99.33% (@ 254 nm) (Rt; 5.393; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.51 (d, 2H, J=8 Hz), 7.37 (s, 1H), 7.25 (d, 2H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.81-3.83 (m, 2H), 3.22-3.27 (m, 2H), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.33 (s, 3H), 2.23 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.55 (m, 2H), 0.82 (t, 3H, J=6.8 Hz).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[OH-].[Na+]>ClCCCl>[CH2:21]([N:20]([CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
To a solution of ethyl 4-oxocyclohexanecarboxylate (1.9 g, 11 mmol) in 1,2-dichloroethane (113 mL) at 23° C. was added dibenzylamine (3.4 g, 3.3 mL, 17 mmol) in one portion. After 10 min, sodium triacetoxyborohydride (4.81 g, 22.7 mmol) was added, and the resulting cloudy suspension was stirred for 48 hrs. The suspension was poured into 1N aqueous hydrogen chloride (100 mL), the resulting mixture was basified to pH 9.0-10.0 with 12.5 M aqueous sodium hydroxide. The basic layer was extracted with ethyl acetate (3×50 mL), and the combined organic layers were washed with saturated aqueous sodium chloride (70 mL), dried over sodium sulfate, and concentrated in vacuo. The resulting residue was purified by flash chromatography (5-10% ethyl acetate in hexanes) to yield ethyl 4-(N,N-dibenzylamino)cyclohexanecarboxylate (3.4 g, 84%) as a clear oil. MS (ESI) 352 (M+H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(=O)([O-])[O-].[K+].[K+].C(=O)=O.[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26](Cl)=[O:27])[CH:20]=[CH:19]2>O.ClCCl>[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[CH:22]=[C:21]([C:26]([N:3]([O:4][CH3:5])[CH3:2])=[O:27])[CH:20]=[CH:19]2
Reactant: CNOC
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2cc(Br)ccc2c1
Yield: 99.9 %

Procedure:
N,O-Dimethylhydroxylamine Hydrochloride (41.3 g, 423 mmol, 1.5 equiv.) was dissolved in distilled water (200 mL) and potassium carbonate (117 g, 3.0 equiv.) was added portion wise (CO2 evolution). Water (300 mL) and dichloromethane (200 mL) was added and a solution of 6-bromo-2-naphthoyl chloride (76.1 g, 282 mmol, 1.00-equiv.) in dichloromethane (300 mL) was added portion wise to this mixture while stirring. The reaction mixture was stirred 1 hour. The organic layer was separated, dried over sodium sulphate, filtrated, concentrated and dried in vacuum overnight, yielding 6-bromo-N-methoxy-N-methyl-2-naphthamide (82.9 g, 100%) as a brown solid.
Reaction SMILES: C([C@@:10]([CH2:17][C:18](=[O:20])[O-:19])([CH2:12][N+:13]([CH3:16])([CH3:15])[CH3:14])[OH:11])(=O)CCCCCCC.CCCCCCCC(OC(C[N+](C)(C)C)CC(O)=O)=O.[Cl-]>C([O-])(=O)C.P([O-])([O-])([O-])=O.NCC(O)=O.[OH-].[Na+]>[OH:11][C@H:10]([CH2:17][C:18](=[O:19])[O-:20])[CH2:12][N+:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: CCCCCCCC(=O)[C@@](O)(CC(=O)[O-])C[N+](C)(C)C
Agent: CC(=O)[O-]
Agent: CCCCCCCC(=O)OC(CC(=O)O)C[N+](C)(C)C
Agent: NCC(=O)O
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]

Procedure:
Octanoyl-L-carnitine solutions, in 100 mM acetate buffer solution (pH 4.5-6.0), in 100 mM phosphate buffer solution (pH 6.5-8.0), in 100 mM tris-HCl buffer solution (pH 8.0-9.0) and in 100 mM glycine/NaOH buffer solution (pH 9.0-10.0) were prepared with a concentration of octanoyl-carnitine of 0.5 mM for each of the solutions. Each of these solutions was subjected to an enzymatic hydrolysis reaction at 37° C. for 10 hours and the amount of L-carnitine formed thereby was determined. The results of the analysis of L-carnitine are shown on the graph of FIG. 1, which shows the optimum pH at about 8.0, wherein high enzymatic activities above 90% were reached within a wide pH range from 6.5 to 9.5.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([CH:14]2[CH2:16][CH2:15]2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[CH3:17]O>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([CH:14]2[CH2:15][CH2:16]2)[CH2:10][C:11]([O:13][CH3:17])=[O:12])=[CH:7][CH:8]=1
Reactant: CO
Reactant: O=C(O)C[C@@H](c1ccc(Cl)cc1)C1CC1
Agent: Cl
Product: COC(=O)C[C@@H](c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
Hydrogen chloride gas is bubbled into a solution of (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanoic acid (5.79 g, 25.85 mmol) in methanol (100 ml) at 0° C. for 30 seconds. The solution is allowed to warm to room temperature and stirred for 18 hours. The solution is concentrated in vacuo, diluted with chloroform (100 ml) and washed with 5% aqueous sodium bicarbonate (100 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel eluting with ether:hexane (10:90) to yield the title compound as a colorless liquid (5.15 g, 84% from (3R)-3-(4-chlorophenyl)-3-cyclopropylpropanenitrile) which is characterized by 1HNMR, IR and mass spectral analyses.
Reaction SMILES: Cl[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)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:26]=[C:23]([CH:24]=[O:25])[C:22]([OH:27])=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:28])[F:29])=[CH:26][C:23]=1[CH:24]=[O:25]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1cc2nccc(Oc3ccc(OC(F)(F)F)cc3C=O)c2cc1OC
Temperature: 130 °C
Reaction time: 8 h

Procedure:
4-Chloro-6,7-dimethoxyquinoline (111 mg), 5-trifluoromethoxysalicylaldehyde (412 mg), and 4-dimethylaminopyridine (244 mg) were suspended in monochlorobenzene (2 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-trifluoromethoxybenzaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:8]([CH3:20])([CH3:19])[CH2:7][CH:6]=[C:5]2[CH3:21].CC([O-])(C)C.[Na+].[NH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1>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].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].C1(C)C=CC=CC=1>[CH2:13]([O:12][C:11]1[C:2]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=2)=[CH:3][C:4]2[C:5]([CH3:21])=[CH:6][CH2:7][C:8]([CH3:20])([CH3:19])[C:9]=2[CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCCCCCOc1cc2c(cc1Br)C(C)=CCC2(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCCCCCOc1cc2c(cc1Nc1ccc(C(=O)OCC)cc1)C(C)=CCC2(C)C
Temperature: 110 °C
Reaction time: 120 h
Yield: 14.8 %

Procedure:
General Procedure P A solution of 6-bromo-7-n-hexyloxy-1,1,4-trimethyl-1,2-dihydronaphthalene (Compound 99, 0.31 g, 0.9 mmol), PdCl2(dppf)(0.070 g, 0.09 mmol), dppf (0.050 g, 0.09 mmol), NaOtBu (0.12 g, 1.3 mmol), ethyl 4-aminobenzoate (0.22 g, 1.35 mmol) and 5 mL of toluene was flushed with argon for 10 min, then stirred at 110° C. in a sealed tube for 5 d. After the reaction mixture was cooled to room temperature, the solvent was removed, and the residue was purified by flash column chromatography (hexane:ethyl acetate=4:1) to give 0.058 g (15%) of the title compound as a yellowish oil.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:24]=[N:25][CH:26]=[N:27][CH:28]=1>>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][N:17]([C:23]2[CH:24]=[N:25][CH:26]=[N:27][CH:28]=2)[CH2:16][CH2:15]3)[CH2:8]1
Reactant: Brc1cncnc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2cncnc2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 5-bromo-pyrimidine.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1.Br[C:18]1[N:34]=[C:21]2[C:22]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)=[CH:23][CH:24]=[CH:25][N:20]2[N:19]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[O-]C1C=CC=CC=1.[Na+]>ClCCl>[Cl:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:18]3[N:34]=[C:21]4[C:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=5)=[CH:23][CH:24]=[CH:25][N:20]4[N:19]=3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][N:5]=1
Reactant: Fc1ccc(-c2cccn3nc(Br)nc23)cc1F
Reactant: NC1CCN(c2ccnc(Cl)c2)CC1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(-c2cccn3nc(NC4CCN(c5ccnc(Cl)c5)CC4)nc23)cc1F

Procedure:
A suspension of 1-(2-chloropyridin-4-yl)piperidin-4-amine dihydrochloride (142 mg, 0.50 mmol) in dichloromethane was washed with 2 N NaOH, the aqueous layer extracted with dichloromethane, the combined organic layers dried over sodium sulfate and evaporated. The “free-base” residue was dissolved in dioxane (4 mL), 2-bromo-8-(3,4-difluorophenyl)-[1,2,4]triazolo[1,5-a]pyridine (prepared in analogy to example 66a-d) (170 mg, 0.55 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg, 8 mol %), tris(dibenzylideneacetone)dipalladium chloroform complex (21 mg, 4 mol %) and sodium phenoxide (87 mg, 0.75 mmol) were added, Ar was bubbled through the reaction mixture for 5 minutes and then irradiated at 130° C. in the microwave for 1 hour. The crude material was purified by flash chromatography (silica-NH2, 20 g, 0 to 100% ethyl acetate in heptane). The title compound was obtained as a yellow solid (103 mg, 47%).
Reaction SMILES: Cl.O1CCOCC1.C(O)(C(F)(F)F)=O.C(OC([N:22]1[C@H:27]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][C:35]([C:37]4[CH:38]=[C:39]5[C:44](=[CH:45][CH:46]=4)[CH:43]=[C:42]([C:47]4[NH:51][C:50]([C@@H:52]6[CH2:57][C@@H:56]7[C@@H:54]([CH2:55]7)[N:53]6C(OC(C)(C)C)=O)=[N:49][CH:48]=4)[CH:41]=[CH:40]5)=[CH:36][C:30]=3[N:29]=2)[CH2:26][C@@H:25]2[C@H:23]1[CH2:24]2)=O)(C)(C)C>C(Cl)Cl>[C@@H:54]12[CH2:55][C@@H:56]1[CH2:57][C@@H:52]([C:50]1[NH:49][CH:48]=[C:47]([C:42]3[CH:43]=[C:44]4[C:39](=[CH:40][CH:41]=3)[CH:38]=[C:37]([C:35]3[CH:34]=[CH:33][C:31]5[N:32]=[C:28]([C@@H:27]6[CH2:26][C@@H:25]7[C@@H:23]([CH2:24]7)[NH:22]6)[NH:29][C:30]=5[CH:36]=3)[CH:46]=[CH:45]4)[N:51]=1)[NH:53]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(-c4ccc5[nH]c([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)nc5c4)ccc3c2)[nH]1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1cc2cc(-c3c[nH]c([C@@H]4C[C@H]5C[C@H]5N4)n3)ccc2cc1-c1ccc2nc([C@@H]3C[C@H]4C[C@H]4N3)[nH]c2c1
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
4M HCl in dioxane (10 mL, 40.0 mmol) was added to a stirred solution of a TFA salt of (1R,3S,5R)-tert-butyl 3-(5-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazol-5-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (151 mg) in DCM (3 mL). Precipitate formed immediately. The suspension was agitated for 30 min. The volatile components were evaporated under vacuum. The crude residue was taken in DCM (3 mL) and TFA (2 mL) was added. The solution was agitated for 1 h. The volatile components were evaporated under reduced pressure. The residue was taken into MeOH and filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol and the compound was release from the cartridge by eluting with a solution of 2M of ammonia/methanol. The ammonia/methanol filtrate was evaporated under reduced pressure to yield 6-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-imidazol-4-yl)naphthalen-2-yl)-2-((1R,3S,5R)-2-azabicyclo[3.1.0]hexan-3-yl)-1H-benzo[d]imidazole (79 mg, 0.17 mmol) as yellow solid. LC-MS retention time 1.130 min; m/z 473.35 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire 5u C18 4.6×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% TFA and Solvent B was 10% H2O/90% MeOH/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.19 (s, 1H), 8.07 (s, 1H), 7.92 (dd, J=8.6, 5.8 Hz, 2H), 7.88 (s, 1H), 7.82 (dd, J=5.8, 1.5 Hz, 2H), 7.61-7.66 (m, 2H), 7.51 (s, 1H), 4.24-4.35 (m, 2H), 3.11 (td, J=6.1, 2.4 Hz, 1H), 3.06 (td, J=6.0, 2.6 Hz, 1H), 2.40-2.53 (m, 2H), 2.18-2.33 (m, 2H), 1.69-1.76 (m, 1H), 1.62-1.69 (m, 1H), 0.88 (ddd, J=6.6, 4.3, 2.6 Hz, 1H), 0.79-0.84 (m, 1H), 0.61-0.68 (m, 1H), 0.55-0.60 (m, 1H).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:32]([O:34]CC)=[O:33])[C:7](=[O:31])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][O:24]C4CCCCO4)=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([C:32]([OH:34])=[O:33])[C:7](=[O:31])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NCCOC4CCCCO4)cc3)ccn2c1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccc(NCCO)cc2)ccn2c(=O)c(C(=O)O)cc(C3CC3)c12
Temperature: 50 °C
Reaction time: 9 h
Yield: 10.8 %

Procedure:
12 mg of ethyl 1-cyclopropyl-9-methyl-4-oxo-8-{4-[2-(tetrahydro-pyran-2-yloxy)-ethylamino]phenyl}-4H-quinolizine-3-carboxylate (Example 21) was dissolved in 1 ml of ethanol. 1 ml of water and 10 mg of pyridinium p-toluenesulfonate were added to the obtained solution, and they were stirred at 50° C. for 9 hours. The reaction mixture was poured into an aqueous sodium hydrogencarbonate solution. After extracting with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=19/1). 1 ml of ethanol and 1 ml of 1 N sodium hydroxide were added to the obtained crystals, and they were stirred at 50° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and then dissolved in 5 ml of water. The obtained solution was neutralized with 1 N hydrochloric acid. The crystals thus formed were taken by the filtration to obtain 1 mg of 1-cyclopropyl-8-[4-(2-hydroxyethylamino)phenyl]-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10](Br)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2].C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC>C1(C)C=CC=CC=1.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>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:31](=[O:33])[CH3:32])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C(C)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-bromo-1H-benzimidazole (200 mg, 0.5 mmol), tributyl(1-ethoxyvinyl)tin (0.34 ml, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (29 mg) in toluene (10 mL) is heated at reflux for 1 h under argon. The solvent is removed in vacuo, the residue is then dissolved in 10% HCl (5 mL) and THF (5 mL). The mixture is stirred at room temperature for 0.5 h, then extracted with ethyl acetate. The aqueous layer is adjusted to pH 9, extracted with dichloromethane, and the organic layer dried (Na2SO4), concentrated, and the residue purified by preparative silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-acetyl-1H-benzimidazole. 1H NMR (CDCl3): δ 8.36 (d, 1H); 7.99 (dd, 1H); 7.645 (d, 1H); 7.25-7.49 (m, 4H); 7.14 (m, 1H); 6.21 (d, 1h); 4.36 (s, 2H); 4.02 (g, 2H); 2.68 (s, 3H); 1.24 (t, 3H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([O:7][C:8](=[O:30])[C:9](=[CH:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:20][CH:21]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:6].[Cl-].[NH4+]>C(OCC)C.O1CCCC1.N.[Cu](I)I>[CH2:13]([O:12][C:10](=[O:11])[CH:9]([CH:15]([C:16]1[CH:17]=[N:18][C:19]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[CH:20][CH:21]=1)[CH2:1][CH3:2])[C:8]([O:7][CH2:5][CH3:6])=[O:30])[CH3:14]
Reactant: CCOC(=O)C(=Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Reactant: CC[Mg]Br
Agent: I[Cu]I
Agent: N
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)C(CC)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54.6 %

Procedure:
To a stirred suspension of copper iodide (5.71 g, 30 mmol) in diethyl ether (120 mL) under argon was added ethylmagnesium bromide (3 M solution in diethyl ether, 20 mL, 20 mmol) within 10 min at 0° C. After 5 min stirring the mixture was cooled to −78° C. and a solution of 2-(6tert-butoxycarbonylamino-pyridin-3-ylmethylene)-malonic acid diethyl ester (5.47 g, 15.0 mmol) in tetrahydrofurane (60 mL) was added dropwise with in 0.5 h. During this period tetrahydrofurane (40 mL) was added. The mixture was allowed to stir at −40° C. for 2.5 h. Then a solution of ammonium chloride (5%) in aqueous ammonia solution (5%) was added with vigorous stirring, allowing access of air, and the mixture was warmed up to room temperature. The mixture was extracted twice with ethyl acetate. The combined organic layers were washed successively with aqueous ammonia solution (5%) and brine, and dried over magnesium sulphate. The solvent was removed under reduced pressure and the residue was recrystallised from a mixture of diisopropyl ether and tetrahydrofurane (5:1, vol./vol.) to give 2-[1-(6-tert-butoxycarbonylamino-pyridin-3-yl)-propyl]-malonic acid diethyl ester (3.23 g, 55%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>O.O1CCCC1>[ClH:24].[CH3:30][CH:29]([CH3:31])[CH2:28][O:27][C:25]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)COC(=O)Cl
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cccc(NC(=N)N2CCCC2)c1

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to O° C. A solution of 0.71 ml of isobutyl chloroformate in 10 ml of tetrahydrofuran was added. After 16 hours the mixture was diluted with water to 100 ml and washed with 20 ml of chloroform. This solution was then made basic with 50% aqueous sodium hydroxide and extracted with 20 ml chloroform (twice). The chloroform layer was dried over potassium carbonate, filtered and the solvent was driven off by vacuum evaporation. The remaining oil was dissolved in 20 ml of isopropanol and 1 ml of concentrated aqueous hydrochloric acid was added. The solution was then made up to 250 ml with ether. Crystals developed and were washed with 10 ml of ether (twice) and dried in a vacuum oven overnight to yield N-(3-(((2-methylpropyloxy)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.1 g, m.p. 233-235° C.