Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:10](C(OCC2C=CC=CC=2)=O)[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CO>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[NH:10][C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1CN(Cc2ccccc2)C(=O)N1
Yield: 94.3 %

Procedure:
7.4 g of tert.-butyl (4S)-1-benzyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 0.1 g of palladium black and 200 ml of methanol are treated in the same manner as described in Preparation 1-(3). 4.7 g of tert.-butyl (4S)-1-benzyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals. Yield: 94.3%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[O:15][CH2:16][O:17][CH3:18].CN(C)CCN(C)C.C([Li])CCC.[CH2:32]1[O:34][CH2:33]1.B(F)(F)F.CCOCC>O1CCCC1>[OH:34][CH2:33][CH2:32][C:5]1[C:4]([O:15][CH2:16][O:17][CH3:18])=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]=1[O:13][CH3:14]
Reactant: C1CO1
Reactant: COCOc1cc(OC)c(OCOC)cc1OC
Agent: CN(C)CCN(C)C
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCOc1cc(OC)c(OCOC)c(CCO)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
10 Grams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)benzene was dissolved in 500 ml of tetrahydrofuran, then to this solution was added 7.01 ml (46.44 mM) of N,N,N',N'-tetramethylethylenediamine and the whole mixture was cooled to -78° C. in a dry ice-acetone bath. To this cooled mixture was added dropwise 29.1 ml of n-butyllithium (1.6M-hexane solution), then stirred for 30 minutes. Next, 26.4 ml (2.091M solution) of tetrahydrofuran solution of ethylene oxide and 0.5 ml of boron trifluoride-diethyl ether (BF3 ·Et2O were added to the reaction mixture. 10 Minutes after, the dry ice-acetone bath was removed from the reaction equipment, then 2 hours later, the reaction mixture was concentrated to obtain the residue and 500 ml of diethyl ether was added thereto, and washed 4 times with 200 ml of water, further washed 4 times with 200 ml of a saturated sodium chloride aqueous solution, next dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was treated by a silica gel column chromatography [diameter 6 cm×length 30 cm, eluent: ethyl acetate:n-hexane=(2:3), "Wakogel C-200"] to yield 8.5 g of 1-(2-hydroxyethyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene. Colorless needless crystals. Melting point: 121°-123° C.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>C(O)C>[N:25]1([C:23]([N:9]2[CH2:10][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:12][CH:7]([C:5]3[O:4][N:3]=[C:2]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[N:6]=3)[CH2:8]2)=[O:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Reactant: C1CCNCC1
Solvent: CCO
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(N3CCCCC3)no2)C1
Reaction time: 2 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 195 mg (2.25 mmol) of piperidine, and then the reaction mixture was stirred in the microwave at 80 for 2 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 90.0 mg (80% of theory)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][Mg]Br.[CH3:11][C:12]([S@:15](/[N:17]=[CH:18]/[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:16])([CH3:14])[CH3:13].[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH:18]([NH:17][S@@:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: CC(C)(C)[S@@](=O)/N=C/C1(c2ccc3ccccc3c2)CCCCC1
Reactant: Br[Mg]CCC1OCCCO1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)[S@@](=O)NC(CCC1OCCCO1)C1(c2ccc3ccccc3c2)CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A flame dried flask under N2 was charged with anhydrous Et2O (3 mL) and (1,3-Dioxan-2-ylethyl)-magnesium bromide (0.5M in THF, 6.78 mL, 3.39 mmol) and cooled to −78° C. (R,E)-2-methyl-N-((1-(naphthalen-2-yl)cyclohexyl)methylene)propane-2-sulfinamide (524 mg, 1.54 mmol) in anhydrous Et2O (3 mL) was added dropwise and the solution was stirred at −78° C. for 1 h, then allowed to warm to RT overnight. After 20 h sat'd aqueous Na2SO4 solution (4 mL) was added and the suspension was filtered, dried (Na2SO4), filtered and concentrated. Purification on the Biotage with a 25M column and an ethyl acetate/hexane (0.1% DEA) gradient (0→100% EtOAc over 3 CV, hold at 100% EtOAc for 5 CV) gave the title compound (581 mg, 83%) as a clear oil. HPLC (JPK method) Rt=2.61 min; 1H NMR (400 MHz, CDCl3) 7.85-7.80 (m, 4H), 7.53 (d, J=8.8 Hz, 1H), 7.48-7.45 (m, 2H), 4.38 (t, J=5.13 Hz, 1H), 4.10-3.99 (m, 2H), 3.77-3.62 (m, 2H), 3.25 (d, J=8.8 Hz, 1H), 3.15-3.10 (m, 1H), 2.88 (d, J=12.1 Hz, 1H), 2.51 (d, J=11.7 Hz, 1H), 2.03-1.90 (m, 2H), 1.64-1.59 (m, 4H), 1.49-1.42 (m, 2H), 1.31-1.23 (m, 4H), 1.12 (s, 9H), 0.87-0.83 (m, 1H); 13C NMR (100 MHz, CDCl3) 138.5, 133.6, 132.0, 128.2, 128.1, 127.5, 126.9, 126.2, 126.0, 102.1, 67.0, 66.7, 57.0, 46.4, 35.0, 34.8, 32.8, 26.2 (d), 25.9, 23.3, 22.6, 22.2; LC-MS 10.4 min, (M+1)+458 @10.6 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6](I)=[CH:7][CH:8]=2)[N:3]=1.[SH:14][C:15]1[CH:16]=[C:17]([C:21]2([C:27]#[N:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.CCN(C(C)C)C(C)C.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>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([S:14][C:15]3[CH:16]=[C:17]([C:21]4([C:27]#[N:28])[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[CH:18]=[CH:19][CH:20]=3)=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1cc(Cl)c2ccc(I)cc2n1
Reactant: N#CC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(c2cccc(Sc3ccc4c(Cl)cc(Cl)nc4c3)c2)CCOCC1
Temperature: 60 °C

Procedure:
2,4-Dichloro-7-iodo-quinoline (3.4 g, 10.5 mmol), 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (3a, 2.3 g, 10.5 mmol), iPr2NEt (3.67 mL, 21.0 mmol), Pd2dba3 (240 mg, 0.26 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (303 mg, 0.52 mmol) were dissolved in 1,4-dioxane (50 mL) and degassed for 10 minutes with N2. The reaction was then sealed and heated to 60° C. for 1 hour. After cooling to room temperature, the reaction was diluted with EtOAc and saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentration. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 3b.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:8]1[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(O)c1ccc(NS(C)(=O)=O)c(Nc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 59 %

Procedure:
Sodium borohydride (0.2 g) was added portionwise to a solution of 4'-acetyl-2'-(2,4-difluorophenylamino)methanesulfonanilide (1.5 g) in methanol (15 ml) at 5° to 10° C. The mixture was stirred for 10 hours at room temperature, treated with acetic acid, and concentrated. The residue was triturated with water and filtered. The solid (1.6 g) was recrystallized from a mixture of ethanol and ethyl acetate to give colorless needles of 2'-(2,4-difluorophenylamino)-4'-(1-hydroxyethyl)methanesulfonanilide (0.89 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[CH2:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][CH2:26][CH2:27][CH2:28]Br>CC(C)=O>[Cl:25][CH2:26][CH2:27][CH2:28][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[CH2:11]
Reactant: C=C(c1ccccc1O)c1cccc2[nH]ccc12
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=C(c1ccccc1OCCCCl)c1cccc2[nH]ccc12

Procedure:
Using the procedure of Step E of Example 1, 6.7 g of 2-[1-(1H-indol-4-yl)-ethenyl]-phenol of Step A of Example 22, 70 ml of acetone, 4 g of potassium carbonate and 11.5 ml of 1-chloro-3-bromo-propane were heated for 20 hours at reflux and after Chromatography and crystallization from petroleum ether (Eb=40-70° C.), 7.05 g of the desired product melting at 70 to 72° C. were obtained.
Reaction SMILES: [NH2:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([NH:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1=[O:13])(=[O:16])[CH3:15]
Reactant: Nn1c(=O)c(=O)[nH]c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nn1c(=O)c(=O)[nH]c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A mixture of 1-amino-1,4-dihydro-2,3-quinoxalinedione (53 mg, 0.30 mMol) and pyridine (1 mL, fresh distilled from KOH before use) and acetic anhydride (1 mL, Aldrich) was stirred under nitrogen at 60° C. for 4 hrs. The reaction mixture became a clear solution. All of solvent and reagent were then evaporated under reduced pressure and washed with benzene:cyclohexane=1:1(2×2 mL); ether (2×2 mL), dried at 60° C. with rotavapor for 2 h, affording 57 mg (86%) of pure 1-acetamido-1,4-dihydro-2,3-quinoxalinedione as a white powder; mp: 211°-213° C. IR (KBr, cm-1): 3430; 3127; 1741; 1717; 1668. NMR (1H, DMSO-d6) δ: 2.326 (s, 3H); 7.121-7.287 (m, 4H); 12.345 (s, 1H). Mass:calcd for C10H9N3O3 (M+) m/z: 219.0641; found: 219.0651.
Reaction SMILES: Br[C:2]1[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[Li]C(C)(C)C.[B:19](OCCCC)([O:25]CCCC)[O:20]CCCC>CCOCC>[CH:11]([C:10]1[CH:9]=[CH:8][C:7]2[NH:6][N:5]=[CH:4][C:3]=2[C:2]=1[B:19]([OH:25])[OH:20])([CH3:13])[CH3:12]
Reactant: CC(C)c1ccc2[nH]ncc2c1Br
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC(C)c1ccc2[nH]ncc2c1B(O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-bromo-5-isopropyl-1H-indazole (1.6 g, 6.9 mmol) in Et2O (4 mL) is added slowly to a suspension of KH (1.0 g of 30% dispersion in mineral oil, 7.7 mmol) in Et2O (20 mL) at 0° C. and the mixture is stirred for 20 minutes. After cooling to −78° C., t-BuLi (8.9 mL of 1.7 M in Hex, 15 mmol) is added and the resulting mixture is stirred for 40 minutes at −78° C. To this is added B(On-Bu)3 (5.6 mL, 21 mmol) and the mixture is stirred for 24 hours at room temperature. The reaction mixture is quenched with 1N H3PO4 and extracted with Et2O. The combined Et2O layers are back-extracted with 1N NaOH (3×10 mL). The combined NaOH extracts are acidified with 1N H3PO4 and extracted with EtOAc. The EtOAc extracts are washed with saturated brine, dried (MgSO4), and concentrated to yield 5-isopropyl-1H-indazole-4-boronic acid. 1H NMR (CDCl3) 7.85 (s, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 3.6 (br s, 2H), 2.88 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[CH:14]=[C:13]([Br:15])[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=1>CO>[Br:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([Cl:16])=[CH:10][CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[CH:14]=1
Reactant: Clc1ccc2c(Br)cc(Br)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)c2ccc(Cl)cc2n1
Temperature: 25 °C

Procedure:
Sodium methoxide (0.5 M in MeOH, 2.0 mL, 1.0 mmol) was added to a solution of 2,4-dibromo-7-chloroquinoline (341 mg, 1.06 mmol) in MeOH (7 mL). The mixture was refluxed for one hour then cooled to room temperature. The resulting precipitate was collected by filtration to afford the title compound as an off-white solid: 1H NMR (500 MHz, CDCl3): δ 8.00 (d, J=8.8 Hz, 1H); 7.85 (d, J=2.1 Hz, 1H); 7.40 (dd, J=8.8, 2.1 Hz, 1H); 7.22 (s, 1H); 4.04 (s, 3H); LC4 2.45 min. (M+H)=274.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2oc(-c3ccccc3)cc2n1
Reactant: C1COCCN1
Solvent: CO
Product: Clc1nc(N2CCOCC2)c2oc(-c3ccccc3)cc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
2,4-Dichloro-6-phenylfuro[3,2-d]pyrimidine 43 (165 mg, 1.0 eq) was suspended in methanol (4.2 ml) and treated with morpholine (0.22 ml, 4.0 eq). Reaction mixture was stirred at room temperature for 4 h. Solid was filtered to yield pure 2-chloro-4-morpholino-6-phenylfuro[3,2-d]pyrimidine 44 (163 mg, 83% yield) as a beige solid: 1H NMR (CDCl3, 400 MHz) δ 7.80 (m, 2H), 7.51 (m, 3H), 6.99 (m, 1H), 4.10 (m, 4H), 3.89 (m, 1H); MS (Q1) 316 (M)+.
Reaction SMILES: [I-].C[N+]1C=CN([C:8](=[O:30])/[N:9]=[C:10]2\[S:11][C:12]([CH3:29])=[CH:13][N:14]\2[C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[O:22][C:17]=3[CH:16]=2)C=1.C(N(CC)C(C)C)(C)C.[NH:40]1[CH2:44][CH2:43][CH2:42][CH:41]1[C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>C(#N)C>[CH3:29][C:12]1[S:11]/[C:10](=[N:9]\[C:8]([N:40]2[CH2:44][CH2:43][CH2:42][CH:41]2[C:45]2[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=2)=[O:30])/[N:14]([C:15]2[CH:28]=[CH:27][C:18]3[O:19][C:20]([F:25])([F:26])[C:21]([F:23])([F:24])[O:22][C:17]=3[CH:16]=2)[CH:13]=1
Reactant: c1cncc(C2CCCN2)c1
Reactant: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)n2cc[n+](C)c2)s1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)N2CCCC2c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (Z)-3-methyl-1-(5-methyl-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazol-2(3H)-ylidenecarbamoyl)-1H-imidazol-3-ium iodide core (Example 81A, 0.88 mL of 0.16 M in acetonitrile, 80 mg, 0.1 mmol) was added to a 20 mL vial, followed by N,N-diisopropylethylamine (0.88 mL of 0.2 M in acetonitrile, 24 mg, 0.13 mmol). 3-(Pyrrolidin-2-yl)pyridine (0.79 mL of 0.2 M in acetonitrile, 0.11 mmol) was added last. The resulting mixture was shaken at room temperature overnight. It was then concentrated in vacuo, and the residue was taken up in 1:1 MeOH/DMSO and purified by reverse phase HPLC (acetonitrile/water 0.1% TFA gradient elution method) to give the titled compound. 1H NMR (300 MHz, DMSO-d6/D2O) δ ppm 1.74-1.93 (3H) 2.12-2.21 (3H) 2.33-2.44 (1H) 3.50-3.68 (2H) 4.95-5.07 (1H) 6.91-7.06 (1H) 7.21-7.59 (3H) 7.70-7.91 (1H) 8.33-8.42 (1H) 8.44-8.52 (1H); MS (ESI+) m/z 495 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])=[CH:13][C:12]([CH3:23])=[C:11]([CH3:24])[CH:10]=2)=[O:5])[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:14]2[C:9](=[CH:10][C:11]([CH3:24])=[C:12]([CH3:23])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C)c(C)cc2c1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=CNc2cc(C)c(C)cc2C1c1ccccc1Cl
Yield: 18.8 %

Procedure:
To a mixture of 4-(2-chlorophenyl)-6,7-dimethyl-3-quinolinecarboxylic acid ethyl ester (26.5 g), sodium borohydride (6.0 g) and ethanol (150 ml) was heated under reflux for 2 hours. After the solvent was distilled off, water was added to the residue, followed by extraction with ethyl acetate. After the extract was washed with water and dried, the solvent was distilled off. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:1) to yield 4-(2-chlorophenyl)-1,4-dihydro-6,7-dimethyl-3-quinolinecarboxylic acid ethyl ester as colorless crystals (5.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1cn2nc(Cl)ccc2n1
Yield: 61.3 %

Procedure:
After 11.2 g of 3-amino-6-chloropyridazine was suspended in 150 mL of ethanol, 28.6 g of ethyl 4-chloroacetoacetate was added thereto and heated under reflux for 24 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was adjusted to pH 7 by the addition of an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with a brine solution and dried over magnesium sulfate. After concentration under reduced pressure. The residue was subjected to silica gel chromatography to be eluted with hexane:ethyl acetate (2:3). The desired fraction was collected to provide 12.7 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CO[C:9]1[C:10](=[O:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1>CO>[N:1]1([C:11]2[C:10](=[O:16])[CH:9]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([C:9]2[C:10](=[O:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: COc1cccccc1=O
Solvent: CO
Product: O=c1cccccc1N1CCN(c2cccccc2=O)CC1
Temperature: 95 °C
Yield: 32.9 %

Procedure:
To a solution of piperazine (7.74 g) in methanol (10 ml) at 70° C., a solution of 2-methoxy-2,4,6-cycloheptatrien-1-one (8.16 g) in methanol (50 ml) was added drop by drop. The reaction mixture was heated at 95° C. for 5 hr, cooled and evaporated. The residue was dissolved in chloroform and water. The organic extract was separated, dried and evaporated. The residue was chromatographed on silica gel (250 g) using chloroform then 5% methanol in chloroform, increasing gradually the concentration of methanol up to 20%. The product was recrystallized from methanol to yield 2.9 g of the title compound: mp 184°-186° C.; ir(CHCl3) 1565 cm-1 ; uv max(MeOH) 355 (ε=19075), 256 (ε=29080) and 223 nm (ε=22460); nmr(CDCl3) δ3.55 (m, 8H) and 7.0 (m, 10H); and Anal. Calcd for C 18 H18N2O2 : C, 73.45% H, 6.16% N, 9.52% and Found: C, 73.76% H, 6.17% N, 9.45%.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:11][CH:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:1]([NH:4][CH:12]([CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCNC(C)c1ccccc1
Yield: 95 %

Procedure:
Introduce 23 ml of propylamine into 200 ml of dimethylformamide, add 32 g of caesium carbonate and 9.25 g of α-methylbenzyl bromide. Leave for 4 hours at room temperature. Evaporate to dryness and take up with water. Extract with ethyl acetate, dry over anhydrous sodium sulphate and evaporate to dryness to obtain the expected product.
Reaction SMILES: [CH3:1][N:2]([CH2:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=1)[C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:7]=1>C(O)C.O1CCCC1.[C].[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:7]=[C:3]([N:2]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=3)[CH3:1])[S:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CN(C)c2nc(-c3ccc([N+](=O)[O-])cc3)cs2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(CN(C)c2nc(-c3ccc(N)cc3)cs2)cc1
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a suspension of methyl 4-(N-methyl-N-(4-(4-nitrophenyl)-2-thiazolyl)aminomethyl)benzoate (200.0 g, 0.522 mol) obtained in Example 1(3) in a mixture of ethanol (800 ml, 4.0 v/w) and tetrahydrofuran (800 ml, 4.0 v/w) was added 10% palladium carbon (20.0 g) and the mixture was stirred overnight under a hydrogen atmosphere at 3 atm. The reaction mixture was filtered through celite and 10% palladium carbon (20.0 g) was added to the filtrate. The mixture was stirred under a hydrogen atmosphere at 3 atm for 3 hr. After celite filtration and solvent evaporation, toluene (800 ml) was added to the residue and the solvent was evaporated to give the title compound (182.5 g, yield 99.0%) as a yellow solid.
Reaction SMILES: [NH:1]1[C:10]2[CH:9]=[C:8]3[O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C:7]3=[CH:6][C:5]=2[C:4](=[O:21])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].F[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[F:38]>CN(C=O)C.CC#N>[F:38][C:30]1[CH:31]=[C:32]([N+:35]([O-:37])=[O:36])[CH:33]=[CH:34][C:29]=1[O:21][C:4]1[C:5]2[CH:6]=[C:7]3[O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][C:8]3=[CH:9][C:10]=2[N:1]=[CH:2][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=c1cc[nH]c2cc3c(cc12)OCCOCCOCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc4c(cc23)OCCOCCOCCO4)c(F)c1
Yield: 39.7 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 7,8,10,11,13,14-Hexahydro-1H-6,9,12,15-tetraoxa-1-aza-cyclododeca[b]naphthalen-4-one (12.2 g, 43.3 mmol, 1.0 eq.), acetonitrile (150 ml), DMF (150 ml) and cesium carbonate (28.2 g, 86.5 mmol, 2.0 eq). The mixture was stirred at room temperature for 30 minutes at which time 1,2-difluoro-4-nitro-benzene (7.57 g, 47.6 mmoL, 1.1 eq) was added over a 10 minute period. After 2 hours the reaction was complete at which time 75% of the MeCN and DMF were removed and the resulting solution was poured over into ice water. The solid was filtered and dried and further columned with a biotage system. The eluent was 1:3 ethyl acetate/hexane. Removal of the solvent afforded 4-(2-Fluoro-4-nitro-phenoxy)-7,8,10,11,13,14-hexahydro-6,9,12,15-tetraoxa-1-aza-cyclodo-deca[b]naphthalene as a pale green solid (7.4 g, 41% yield). 1HNMR (400 MHz, DMSO): 8.58 (s, 1H), 7.80 (s, 1H), 7.50 (s, 1H), 7.04 (t, 1H), 6.88 (m, 1H), 6.50 (m, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H). LC/MS Calcd for (M+H)+431.4. found 431.5.
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[C:7]2=[N:6][C:5]1=[O:17])([CH3:3])[CH3:2].C([O:22][CH:23]([CH3:25])[CH3:24])(=O)C>C(O)(C)C>[CH:23]([O:22][C:7]12[NH:6][C:5](=[O:17])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:18])[N:8]1[C:9](=[O:16])[C:10]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=1)([CH3:25])[CH3:24]
Reactant: CC(C)C1(C)C(=O)N=C2c3ncccc3C(=O)N21
Reactant: CC(=O)OC(C)C
Solvent: CC(C)O
Product: CC(C)OC12NC(=O)C(C)(C(C)C)N1C(=O)c1cccnc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
100 g of silica gel are added to a solution of 200 g of 3-isopropyl-3-methyl-2H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5(3H)-dione in 900 ml of isopropyl acetate and 100 ml of absolute isopropanol, and the resulting suspension is then stirred at room temperature for about 16 hours. The mixture is subsequently filtered, the filtrate is evaporated to dryness and the residue is crystallized from ethyl acetate/n-hexane. There is obtained 1,9b-dihydro-9b-isopropoxy-3-isopropyl-3-methyl-2H-imidazo[1',2':1,2]pyrrolo[3,4-b]pyridine-2,5(3H)-dione as colorless crystals, m.p. 158°-160° C.