Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].O([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([NH:33][C:34](=[O:41])[CH2:35][CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH:31]=2)[CH:26]=[CH:25][CH:24]=1)S(C(F)(F)F)(=O)=O.C(OCC)(=O)C>O1CCCC1.[Zn].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]>[CH:36]1([CH2:35][C:34]([NH:33][C:30]2[CH:31]=[C:32]3[C:27]([CH:26]=[CH:25][CH:24]=[C:23]3[CH2:2][C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=3[O:13][CH3:14])=[CH:28][CH:29]=2)=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Reactant: O=C(CC1CCCC1)Nc1ccc2cccc(OS(=O)(=O)C(F)(F)F)c2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cccc3ccc(NC(=O)CC4CCCC4)cc23)c(OC)c1
Reaction time: 18 h
Yield: 79 %

Procedure:
A mixture of activated zinc dust (806 mg), methyl 4-bromomethyl-3-methoxybenzoate (2.14 g) and tetrahydrofuran (15 ml) was stirred for 18 h. To the reaction was added dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (76 mg). After stirring for 15 min, 7-(cyclopentylacetamido)naphth-1-yl triflate (830 mg) in tetrahydrofuran (10 ml) was added and the mixture was stirred for 72 h. The mixture was added to 100 ml of ethyl acetate and the ethyl acetate solution was washed (1N HCl, brine), dried (MgSO4) and evaporated. The residue was flash chromatographed, eluting with ether:petroleum ether (2:8,4:6, and 1:4, successively), to give a white solid. Recrystallization from methylene chloride and petroleum ether gave the title compound as a colorless solid (705 mg, 79%); mp 172.5°-174.5° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14](C(OCC)=O)[C:15]3[C:20]([C:21]=2[NH:22][C:23](=[O:26])[CH2:24][CH3:25])=[CH:19][CH:18]=[C:17]([Cl:27])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=O)C.[OH-].[Na+].[Cl-].[NH4+]>C(O)C>[Cl:27][C:17]1[CH:16]=[C:15]2[C:20]([C:21]([NH:22][C:23](=[O:26])[CH2:24][CH3:25])=[C:13]([C:11]([C:8]3[O:9][CH:10]=[C:6]([CH2:5][OH:4])[CH:7]=3)=[O:12])[NH:14]2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)CC)c2ccc(Cl)cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: CCC(=O)Nc1c(C(=O)c2cc(CO)co2)[nH]c2cc(Cl)ccc12
Reaction time: 3 h
Yield: 42.4 %

Procedure:
To a solution of 2-(4-acetoxymethyl-2-furoyl)-6-chloro-1-ethoxycarbonyl-3-(propionylamino)indole (step 1, 114 mg, 0.313 mmol) in ethanol (2 ml) was added 2N aqueous sodium hydroxide (2 ml). After stirring for 3 h, the mixture was poured into saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (80 ml). The organic layer was washed with brine (20 ml), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1/1) and recrystalization from 2-propanol/isopropyl ether to give 46 mg (40%) of the titled compound as yellow solids. m.p.: 171-172° C. 1H-NMR (CDCl3) δ: 10.74 (1H, br s), 9.37 (1H, br s), 8.45 (1H, d, J=9.06 Hz), 7.08 (1H, s), 7.42 (1H, s), 7.36 (1H, d, J=1.81 Hz), 7.06 (1H, dd, J=9.06 Hz, 1.81 Hz), 4.67 (2H, s), 2.58 (2H, q, J=7.58 Hz), 1.33 (3H, t, J=7.58 Hz).
Reaction SMILES: C(OC([NH:6][CH:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8](=[O:10])[CH3:9])=O)C.[BrH:15]>>[BrH:15].[NH2:6][CH:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8](=[O:10])[CH3:9]
Reactant: CCOC(=O)NC(C(C)=O)C(C)(C)C
Agent: Br
Product: CC(=O)C(N)C(C)(C)C

Procedure:
N-ethoxycarbonyl-3-amino-4,4-dimethyl-pentan-2-one (203 mg) is dissolved in 48% aqueous hydrobromic acid (4 ml) and the solution is stirred under reflux for 6 hours. The reaction mixture is then evaporated under reduced pressure to give a solid residue, that is further purified by recrystallisation (from ethanol/diethylether) to afford 149 mg of pure (3RS)-3-amino-4,4-dimethyl-pentan-2-one hydrobromide (m.p. 218°-220° C.)
Reaction SMILES: Cl.C([N:9]1[CH2:21][C@@H:20]2[C@H:11]([C:12](=[O:25])[N:13]3[CH2:24][CH2:23][CH2:22][C:15]4[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]3=4)[CH2:10]1)C1C=CC=CC=1.[Cl:26]C(OC(Cl)C)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl.CCOCC>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[ClH:26].[CH:18]1[CH:17]=[CH:16][C:15]2[CH2:22][CH2:23][CH2:24][N:13]3[C:14]=2[C:19]=1[C@@H:20]1[CH2:21][NH:9][CH2:10][C@H:11]1[C:12]3=[O:25]
Reactant: O=C1[C@@H]2CN(Cc3ccccc3)C[C@H]2c2cccc3c2N1CCC3
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C1[C@@H]2CNC[C@H]2c2cccc3c2N1CCC3
Temperature: 110 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of (±)-trans-10-benzyl-5,6,9,10,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinolin-8(8aH)-one from EXAMPLE 1, Part E (1.2 g, 3.8 mmol) in 20 mL of toluene was added 1-chloroethyl chloroformate (0.81 mL, 7.53 mmol) and the resulting solution was stirred at 110° C. for 3 h. The reaction mixture was cooled and the toluene was removed under reduced pressure. The residue was taken up in 20 mL of methanol and was stirred at 65° C. for 1 h. The reaction was cooled and the methanol was removed under reduced pressure. A portion of the residue (50 mg, 0.19 mol) was partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo. The residue was dissolved in ether and there was added 2M HCl in ether (0.095 mL, 0.19 mmol). The solvent was decanted and the remaining solid was triturated twice with ether and was dried in vacuo to afford 25 mg (50%) of the title compound of EXAMPLE 3 as an off white powder. LRMS (ES)+: 270.3 (M+H+CH3CN)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:6][CH:7]=2)=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCc1ccccc1)c1ccc(OCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCOc1ccc(C(=O)CCc2ccccc2)cc1
Reaction time: 0.75 h

Procedure:
A solution of 1-[4-(2-hydroxy-ethoxy)-phenyl]-3-phenyl-propan-1-one (prepared in Example N; 6.0 g, 22.2 mmol) and triethylamine (NEt3) (4.60 mL, 33.3 mmol) in CH2Cl2 (50 mL) was cooled to 0° C. under a nitrogen atmosphere and treated with mesyl chloride (2.1 mL, 26.6 mmol). The mixture allowed to stir for 45 minutes, and then diluted with additional CH2Cl2 and washed with H2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to provide the title compound which was used without further purification. 1H NMR (DMSO-d6) δ 2.90 (t, 2 H), 3.20 (s, 3 H), 3.29 (t, 2 H), 4.32-4.34 (m, 2 H), 4.52-4.55 (m, 2 H), 7.05 (d, 2 H), 7.22-7.32 (m, 5 H), 7.95 (d, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][NH:9][C:10](=[O:26])[C@H:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=2[CH3:25])[C@@H:12]([OH:14])[CH3:13])=[O:7])=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:34][C:35]([Si:38](Cl)([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10](=[O:26])[C@H:11]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=2[CH3:25])[C@@H:12]([O:14][Si:38]([C:35]([CH3:37])([CH3:36])[CH3:34])([CH3:40])[CH3:39])[CH3:13])=[O:7])=[CH:27][CH:28]=1
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(Br)cc2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 4-bromo-N′-((2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoyl)benzohydrazide (4.0 g, 8.6 mmol) in DMF (60 mL) were added imidazole (2.3 g, 33.8 mmol) and TBSCl (2.6 g, 17.2 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature gradually and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by SiO2 column to give the title compound (4.68 g, 94%), which was used directly in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:32])[C:10](=[O:31])[C@@H:11]([NH:23]C(=O)OC(C)(C)C)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=1>C(Cl)Cl>[NH2:23][C@@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=1)[C:10]([N:9]([CH3:8])[CH3:32])=[O:31]
Reactant: CC(C)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(C[C@H](N)C(=O)N(C)C)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (1 mL, 10 mmol) was added to (S)-tert-butyl 1-(dimethylamino)-3-(4-isopropoxyphenyl)-1-oxopropan-2-ylcarbamate in methylene chloride (2 mL). After stirring for 1 h., the reaction was concentrated under reduced pressure to give the crude product, (2S)-2-amino-3-(4- isopropoxyphenyl)-N,N-dimethylpropanamide (40 mg, 100%). Analytical LCMS (M+H)+: m/z=251.0.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14](Cl)=[C:15]([F:20])[CH:16]=2)[N:11]([CH:22]2[CH2:24][CH2:23]2)[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O:30][C:31](=[O:38])[NH:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].C(N(CC)CC)C>CN(C=O)C.O>[C:26]([O:30][C:31](=[O:38])[NH:32][CH:33]1[CH2:37][CH2:36][N:35]([C:14]2[CH:13]=[C:12]3[C:17]([C:18](=[O:19])[N:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:10](=[O:25])[N:11]3[CH:22]3[CH2:24][CH2:23]3)=[CH:16][C:15]=2[F:20])[CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=c1c2cc(F)c(Cl)cc2n(C2CC2)c(=O)n1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3C2CC2)C1
Temperature: 70 °C
Yield: 46.6 %

Procedure:
A solution of 3-benzyloxy-7-chloro-1-cyclopropyl-6-fluoro-1H-quinazoline-2,4-dione (Example E-3, 0.15 g, 0.42 mmol) in DMF (3.0 mL) was reacted with pyrrolidin-3-yl-carbamic acid tert-butyl ester (0.700 g, 3.5 mmol) and triethylamine (0.70 mL, 5.0 mmol) then heated to 70° C. overnight. The mixture was then cooled, diluted with H2O, and extracted with ethyl acetate. The organic layers were combined, dried with sodium sulfate, and concentrated. The residue was then purified by column chromatography (silica gel, 1:1 bexanes/ethyl acetate) to provide 0.10 g of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:11][C@H:10]1[C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[C:54]([CH2:59][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH2:67][CH3:68])=[CH:62][CH:61]=2)[CH:53]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.C(OCC)C.O.C([O-])(O)=O.[Na+]>[CH2:24]([O:23][C@H:13]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:10]([C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[C:54]([CH2:59][C:60]3[CH:61]=[CH:62][C:63]([O:66][CH2:67][CH3:68])=[CH:64][CH:65]=3)[CH:53]=2)[O:11][C@@H:12]1[CH2:31][OH:32])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
To a solution of (2S,3S,4R,5R,6R)-3,4,5-Tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran (12.2 g, 17.9 mmole) in dry DCM (50 mL), AlCl3 (2.8 gm, 21.5 mmole) in diethyl ether was added at 0° C. and stirred at room temperature for 2 hours. The reaction mixture was diluted with water (500 mL) and saturated aqueous NaHCO3 (50 mL), extracted with DCM (2×250 mL). The crude product obtained after the removal of solvent was purified using silica gel column chromatography (10% ethyl acetate in hexane) to furnish 6.1 g of {(2R,3R,4R,5S,6S)-3,4,5-Tris-benzyloxy-6-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-tetrahydro-pyran-2-yl}-methanol.
Reaction SMILES: [C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[C:18]1[N:19]([CH3:38])[C:20](=[O:37])[C:21]([O:28]C(=O)C2C=CC=CC=2)=[C:22]([C:24]([O:26]C)=O)[N:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1.CC#N.O>CO>[C:1]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[C:18]1[N:19]([CH3:38])[C:20](=[O:37])[C:21]([OH:28])=[C:22]([C:24]([NH:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=2)=[O:26])[N:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2Cc3ccccc3N2C(=O)c2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: O
Solvent: CC#N
Solvent: CO
Product: Cn1c(C2Cc3ccccc3N2C(=O)c2ccccc2)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Temperature: 60 °C

Procedure:
The crude product of Step 2 was dissolved in MeOH and 4-fluorobenzylamine (3.5 eq.) added. The solution was stirred at 60° C. over night. The title product was obtained by preparative RP-HPLC (C18, gradient of CH3CN/H2O+0.01% TFA).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([C:27](=[O:39])[NH:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:25]=[CH:26][C:20]=3[N:19]=2)=[C:13]([CH3:40])[CH:12]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>CCO.[Pd]>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH3:40])[C:14]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([C:27](=[O:39])[NH:28][C:29]4[CH:38]=[CH:37][C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]=4)[CH:25]=[CH:26][C:20]=3[N:19]=2)=[C:15]([CH3:17])[CH:16]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(/C=C/c1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(CCc1cc(C)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(C)c1)OCC

Procedure:
A solution of ((E)-2-{3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-vinyl)-phosphonic acid diethyl ester (300 mg, 0.54 mmol) in EtOH (20 mL) was hydrogenated at one atm over Pd/C (225 mg) for 3 hours. The catalyst was filtered through Celite and was washed with EtOH. The solvent was removed under reduced pressure to give (2-{3,5-dimethyl-4-[6-(quinolin-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-phenyl}-ethyl)-phosphonic acid diethyl ester as a red solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.CS(C)=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17](O)=[C:16]([N+:21]([O-:23])=[O:22])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:8][C:5]1[CH:4]=[N:3][C:2]([C:17]2[CH:18]=[CH:19][C:14]([NH2:13])=[CH:15][C:16]=2[N+:21]([O-:23])=[O:22])=[N:7][CH:6]=1
Reactant: Nc1ccc(O)c([N+](=O)[O-])c1
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(-c2ncc(Cl)cn2)c([N+](=O)[O-])c1

Procedure:
1.43 g of 2,5-dichloropyrimidine was dissolved in 20 mol of dimethyl sulfoxide. To this solution, a mixture of 1.50 g of 4-amino-2-nitrophenol and 5 ml of water, and 2.69 g of potassium carbonate were added, and the mixture was reacted in the atmosphere of nitrogen gas at a temperature of from 100° to 110° C. for 2 hours. After the completion of the reaction, the reaction product was poured into water, and extracted with methylene chloride. The extract layer was washed with brine and dried over anhydrous sodium sulfate, and purified by silica gel column chromatography, whereby 0.74 g of 4-(5-chloro-2-pyrimidinyl)-3-nitroaniline having a melting point of from 151° to 152° C., was obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH:12]=[CH:13][CH:14]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(OCC)(=O)C>CC(N(C)C)=O.O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH2:36][CH:35]([CH2:39][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH3:7])[CH:10]=2)[CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1cccc(CCCCc2ccccc2O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COc1cccc(CCCCc2ccccc2OCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Reaction time: 0.25 h
Yield: 150.9 %

Procedure:
0.965 g of potassium t-butoxide was added to a solution of 1.70 g of 2-[4-(3-methoxyphenyl)butyl]phenol (prepared as described in Preparation 7) in 30 ml of dimethylacetamide, whilst ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. A solution of 3.18 g of 1-t-butoxycarbonyl-3-(p-toluenesulfonyloxymethyl)piperidine in 30 ml of dimethylacetamide was then added dropwise to the solution at the same temperature, and the mixture was stirred at 55° C. for 1.5 hours. At the end of this time, the reaction mixture was cooled, and 200 ml of ethyl acetate and 100 ml of water were added to the mixture, which was then shaken. The ethyl acetate layer was separated, washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 4.54 g (yield 95%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]([CH2:18][CH2:19][F:20])[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[CH:25](=O)[CH3:26]>C(O)=O>[CH2:25]([N:15]1[CH2:16][CH2:17][N:12]([C:11]2[N:10]=[C:9]3[C:4]([C:5](=[O:24])[C:6]([C:21]([OH:23])=[O:22])=[CH:7][N:8]3[CH2:18][CH2:19][F:20])=[CH:3][C:2]=2[F:1])[CH2:13][CH2:14]1)[CH3:26]
Reactant: O=C(O)c1cn(CCF)c2nc(N3CCNCC3)c(F)cc2c1=O
Reactant: CC=O
Solvent: O=CO
Product: CCN1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)CC1

Procedure:
Using 6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylic acid as a starting material, by reaction with acetoaldehyde in the presence of formic acid in accordance with the method of Example 1 is obtained 7-(4-ethyl-1-piperazinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (compound 2) m.p. 223°-224° C.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[CH:25][C:23]=3[N:24]=2)=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1cn(-c2ccc3nc(-c4ccc(C)c(I)c4)[nH]c3c2)cn1
Product: Cc1cn(-c2ccc3[nH]c(-c4ccc(C)c(C#Cc5cnc6cccnn56)c4)nc3c2)cn1

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 2-(3-iodo-4-methylphenyl)-6-(4-methyl-1H-imidazol-1-yl)-1H-benzo[d]imidazole (as prepared above) in a manner similar to that described for in Example 1. The title compound was obtained a pale yellow solid. Mp: 182-184° C.; 1H NMR (400 MHz, CD3OD) δ: 8.57 (2 H, brs), 8.26 (1 H, s), 7.98-8.05 (3 H, m), 7.74 (1 H, s), 7.68-7.70 (1 H, d, J=8.4 Hz), 7.46-7.48 (2 H, m), 7.42-7.44 (1 H, d, J=8.4 Hz), 7.29-7.33 (1 H, dd, J=4.4 and 9.2 Hz), 2.61 (3 H, s), 2.31 (3 H, s). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C26H20N7: 430.1775. found: 430.1778.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: COc1ccc(C#N)cc1B(O)O
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1ccccc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate E) and 2-methoxyphenylboronic acid were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 7.13 min (HPLC 2); ESI-MS: tR=1.20 min, [M+H]+522/524/526 (LC-MS 1); TLC: Rf=0.35 (95:5 CH2Cl2/MeOH); 1H-NMR (d6-DMSO, 600 MHz): 7.91 (m, 1H), 7.88 (m, 1H), 7.44 (m, 1H), 7.43 (m, 2H), 7.33 (m, 2H), 7.25 (m, 1H), 7.11 (m, 1H), 7.02 (m, 1H), 6.34 (s, 1H), 6.21 (s, 1H), 3.92 (m, 1H), 3.74 (s, 3H), 3.44 (s, 3H), 1.33 (m, 3H), 0.39 (m, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C@@H:6]1[C@@H:11]2[CH2:12][CH2:13][N:8]([C@H:9]([CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:10]2[NH:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[O:24][CH3:25])[CH2:7]1)=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+].CS(O)(=O)=O>C1COCC1.CC(C)=O>[CH2:39]([N:3]([CH2:4][C@H:6]1[CH2:7][N:8]2[CH2:13][CH2:12][C@@H:11]1[C@@H:10]([NH:14][CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])[C@H:9]2[CH:26]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:1][CH3:2])[CH3:40]
Reactant: CCN(CC)C(=O)[C@H]1CN2CC[C@@H]1[C@@H](NCc1cc(OC)ccc1OC)[C@H]2C(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)C[C@H]1CN2CC[C@@H]1[C@@H](NCc1cc(OC)ccc1OC)[C@H]2C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A solution of 19 (300 mg, 0.65 mmole) in dry THF (2 ml) was added to a suspension of LiAlH4 (105 mg, 2.75 mmole) in 5 ml of dry THF at 5° C. and stirred at room temperature for 1 hour. Na2SO4 /10H2O (2 g) was added to the reaction mixture and stirred for 15 hours at room temperature. The suspension was filtrated, and the solids were washed with dry THF. The filtrate was concentrated under reduced pressure. The resulting oil was dissolved in 2 ml of acetone, and CH3SO3H (159 mg, 1.65 mmole) was added to the solution of the crude oil in acetone (2 ml). The resulting precipitate was collected by filtration and dried in vacuo to give 20 (254 mg, 0.31 mmole, 57%).