Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[NH2:28][NH2:29]>C(O)C>[C:24]([C:22]1[CH:21]=[C:7]([CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[CH:23]=1)[CH2:8][N:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:28][NH2:29])=[O:17])[CH2:13][CH2:14]1)([CH3:26])([CH3:27])[CH3:25]
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC1
Solvent: CCO
Product: CC(C)(C)c1cc(CN2CCN(CC(=O)NN)CC2)cc(C(C)(C)C)c1

Procedure:
Synthesized according to General Procedure C: 6{22} (4.57 g, 12.2 mmol, 1 equiv.), anhydrous hydrazine (1.1 mL, 36.6 mmol, 3 equiv.), ethanol (24.7 mL). Purification by silica gel column chromatography (4:1 EtOAc:MeOH) afforded 1{22} (2.88 g, 66%) as a beige solid. 1H-NMR (500 MHz, CDCl3): δ 8.17 (br s, 1H), 7.31 (t, 1H, J=1.5 Hz), 7.13 (d, 2H, J=1.5 Hz), 3.84 (br s, 2H), 3.51 (s, 2H), 3.08 (s, 2H), 2.55 (br s, 4H), 2.47 (br s, 4H), 1.32 (s, 18H). 13C-NMR (125 MHz, CDCl3): δ 170.5, 150.5, 136.7, 123.2, 120.9, 63.3, 60.6, 53.7, 52.9, 34.7, 31.5.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[N:17]=[CH:16][CH:15]=2)=[C:10]([CH3:27])[N:9]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[C:8]1=[O:38])C.[OH-].[Na+].O>CO.C(OCC)C>[C:25]([C:22]1[CH:21]=[CH:20][C:19]([N:18]2[C:14]([C:11]3[C:12](=[O:13])[N:7]([CH2:6][CH2:5][C:4]([OH:39])=[O:3])[C:8](=[O:38])[N:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=4)[C:10]=3[CH3:27])=[CH:15][CH:16]=[N:17]2)=[CH:24][CH:23]=1)#[N:26]
Reactant: CCOC(=O)CCn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(CCC(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid ethyl ester (prepared in Example 4) (351.0 mg) in methanol (1.0 ml) was cooled under ice-cooling and thereto was added 2N aqueous sodium hydroxide solution (340 μl) and the resulting mixture was stirred at room temperature for twelve hours. The reaction mixture was diluted with diethylether (30 ml) and thereto was added water (30 ml). The organic layer and the aqueous layer were separated and the aqueous layer was then acidified with sodium hydrogen sulfate (500 mg) and extracted with ethyl acetate (50 ml×3). The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained amorphous was washed with hexane (30 ml) to afford 3-[5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl]propanoic acid (239.5 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]2OCC[O:10]2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].Cl>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH:9]=[O:10])#[CH:2]
Reactant: C#Cc1cccc(C2OCCO2)c1
Agent: Cl
Solvent: O
Product: C#Cc1cccc(C=O)c1
Temperature: 60 °C
Yield: 87.8 %

Procedure:
A multinecked, round bottom flask fitted with a mechanical stirrer, reflux condenser and thermometer, was charged 50.4 g (0.289 mol) of the product of Example XI, 400 ml of distilled water and 1 of concentrated hydrochloric acid. The mixture was heated to 60° C. and maintained at that temperature for about 4 hours and then cooled to room temperature which yielded the product as a yellow precipitate. The product was filtered, washed with distilled water and allowed to dry on the funnel overnight to yield 33 g (0.254 mol, 87.8% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:21])[CH2:13][CH2:14][NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17].[H-].[Na+]>>[CH3:11][N:12]([CH3:21])[CH2:13][CH2:14][N:15]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCS(=O)(=O)NCCN(C)C
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitro-benzene, N-(2-dimethylamino-ethyl)-ethanesulphonamide and sodium hydride as base
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15]([C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:28])([CH3:27])[C@H:21]23)=[O:16])=[CH:8][C:7]=1[CH3:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(OC([NH:69][CH2:70][C:71](O)=[O:72])=O)(C)(C)C>C(Cl)Cl.CC(=O)OCC>[NH2:69][CH2:70][C:71]([NH:1][CH2:2][CH:3]([OH:30])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][CH2:14][C:15](=[O:16])[C:17]2[S:24][C:23]([CH3:25])=[C:22]3[C:18]=2[CH2:19][C@H:20]2[C:26]([CH3:27])([CH3:28])[C@H:21]23)=[CH:8][C:7]=1[CH3:29])=[O:72]
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC(O)CN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCC(O)CNC(=O)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.8 %

Procedure:
A solution of 3-[4-(3-amino-2-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (70 mg, 0.164 mmol, Example 99) in DCM (3 mL) is treated with DIPEA (85 mg, 0.655 mmol), TBTU (74 mg, 0.23 mmol) and tert. butoxycarbonyl glycine (43 mg, 0.246 mmol) and the reaction mixture is stirred at rt for 1 h. The mixture is diluted with EA and washed with sat. aq. NaHCO3 and brine. The organic extract is dried over MgSO4, filtered and evaporated. The residue is dissolved in DCM (2 mL) and TFA (0.1 mL) is added. The mixture is stirred at rt for 3 h before another portion of TFA (0.02 mL) is added. Stirring is continued for 1 h. The mixture is diluted with EA, washed twice with a sat. aq. NaHCO3 solution, dried over MgSO4, filtered and evaporated. The crude product is purified by chromatography on prep. TLC plates with DCM:methanol 9:1 to give 2-amino-N-(3-{2,6-dimethyl-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-2-hydroxy-propyl)-acetamide (3 mg) as a colourless resin; LC-MS: tR=0.86 min, [M+1]+=485.33.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[OH:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@@H:12]2[C@@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:15][N:14]([C:33]([C@H:30]3[CH2:31][CH2:32][C@@H:27]([OH:26])[CH2:28][CH2:29]3)=[O:34])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)[C@H]2CC[C@@H](O)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound rac-[(3R,4S)-4-(3,4-dichloro-phenyl)-1-(cis-4-hydroxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using cis-4-hydroxycyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as a an off-white foam. MS m/e: 509.2 [M]+.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH:15]([O:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.ON1C2C=CC=CC=2N=N1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([NH:19][O:18][CH:15]2[CH2:14][CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:4]=3)(=[O:11])=[O:10])[CH2:17][CH2:16]2)=[O:38])=[CH:35][CH:34]=1
Reactant: NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NOC1CCN(S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (138 mg, 0.72 mmol) was added to a solution of O-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yl)hydroxylamine (195 mg, 0.60 mmol), 1-hydroxybenzotriazole (97.0 mg, 0.72 mmol), 4-fluorobenzoic acid (84.0 mg, 0.60 mmol) and N,N-diisopropylethylamine (233 mg, 1.80 mmol) in N,N-dimethylformamide (8 ml). The reaction mixture was stirred at room temperature for 17 hours and quenched with H2O (50 ml) and aqueous 1 N HCl solution (pH=3). The aqueous phase was extracted with CH2Cl2 (20 ml×3) and the combined organic phase was washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 50/50) to give 4-fluoro-N-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-4-yloxy)benzamide (217 mg, 81%) as a white solid: LCMS: 447 [M+1]+. 1H NMR (DMSO-d6) δ: 1.71 (m, 2H), 1.88 (m, 2H), 3.07 (m, 4H), 3.97 (t, 1H), 7.27 (t, 2H), 7.74 (m, 2H), 7.98 (m, 2H), 8.10 (m, 2H), 11.4 (s, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:21]2[C:20](=[O:22])[NH:19][C:18]([NH2:23])=[N:17][C:16]=2[N:6]([C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]1=[O:24])[CH:2]=[CH2:3]>[Pd].C(O)C>[CH2:1]([N:4]1[C:21]2[C:20](=[O:22])[NH:19][C:18]([NH2:23])=[N:17][C:16]=2[N:6]([C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[C:5]1=[O:24])[CH2:2][CH3:3]
Reactant: C=CCn1c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c21
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)[nH]c(=O)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 55 %

Procedure:
A mixture of 7-allyl-8-oxoguanosine (Example 8; 1.0 g, 2.9 mM) 10% Pd/C (100 mg) and ethanol (100 ml) was stirred at room temperature under an atmosphere of hydrogen for 3 hours. The catalyst was filtered through a pad of Celite and washed with ethanol (100 ml). The combined filtrate was concentrated in vacuo. The residue was dissolved in methanol (20 ml) and treated with ether (200 ml). The resulting solid was filtered and dried at 60° C. to provide the title compound in 55% yield as a white powder, mp 151°-153° C. NMR(DMSO-d6):δ 10.8(bs,1H); 6.5(bs, 2H); 5.5(d J=5.5 Hz, 1H); 0.8(d, J=7 Hz, 3H). IR (KBr): 1680 and 1640 cm-1.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.Cl.[F:11][C:12]([F:46])([F:45])[C:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:16]=[C:15]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=3)[CH:30]=2)[N:14]=1>C1COCC1>[CH3:3][NH:5][S:41]([C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([C:31]2[CH:30]=[C:29]([C:15]3[N:14]=[C:13]([C:12]([F:46])([F:45])[F:11])[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)[N:16]=3)[CH:34]=[CH:33][N:32]=2)[CH:36]=1)(=[O:43])=[O:42]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 85.4 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of methylamine solution (2M in THF) (1.5 ml, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.46 g, 92%). MS (ISP) 538.8 [(M+H)+]; mp 174° C.
Reaction SMILES: ClC1C=CC([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=C(F)C=1.Cl.C(=O)([O-])O.[Na+]>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[N:10]=[CH:9][NH:8][C:7]2=[O:6]
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCN(C)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCN(C)CC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (2.6 g, 5.6 mmol) was treated with 2.0 N aqueous hydrochloric acid (45 ml) and the mixture stirred at 95° C. for 2 hours. The mixture was cooled, basified by the addition of solid sodium hydrogen carbonate and the water removed by azeotroping with toluene. The residue was purified by silica column chromatography eluting with dichloromethane/methanol/0.880 aqueous ammonia (50/8/1) to give 6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)-3,4-dihydroquinazolin-4-one (1.8 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[C:6]([NH2:12])=[N:7][NH:8][C:9]=1[O:10][CH3:11].O=[C:19]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:20][C:21](OCC)=[O:22]>C(O)(=O)C>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[C:9]([O:10][CH3:11])=[N:8][N:7]2[C:21]([OH:22])=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[N:12][C:6]=12
Reactant: COc1[nH]nc(N)c1Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)c1ccncc1
Solvent: CC(=O)O
Product: COc1nn2c(O)cc(-c3ccncc3)nc2c1Cc1cccc(Cl)c1Cl
Yield: 12.9 %

Procedure:
A solution of 4-(2,3-dichlorobenzyl)-5-methoxy-1H-pyrazol-3-amine (301 mg, 1.1 mmol) and ethyl 3-oxo-3-(pyridin-4-yl)propanoate (223 mg, 1.15 mmol) in acetic acid (15 mL) was stirred at 100° C. for 4 h. Then the reaction mixture was concentrated under vacuo and the residue was purified by silica gel chromatography eluted with EA to EA/MeOH=4/1, and further recrystallized with DMSO/H2O to give the titled compound (57 mg, 13%) as a yellowish solid. LC/MS: MS (ES+) m/e 402 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.89 (s, 3H), 4.00 (s, 2H), 6.07 (s, 1H), 7.03 (d, J=8.4 Hz, 1H), 7.25 (t, J=8.4 Hz, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.79 (d, J=5.1 Hz, 2H), 8.71 (d, J=5.1 Hz, 2H), 12.15 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13]([CH3:15])=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20].[CH:22]1(C(Cl)=O)C[CH2:23]1>>[CH3:1][C:2]1([CH3:21])[C:11]2[C:6](=[C:7]([N+:16]([O-:18])=[O:17])[C:8]([NH:12][C:13]([CH:15]3[CH2:23][CH2:22]3)=[O:14])=[CH:9][CH:10]=2)[C:5](=[O:19])[NH:4][C:3]1=[O:20]
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])C(=O)NC(=O)C2(C)C
Product: CC1(C)C(=O)NC(=O)c2c1ccc(NC(=O)C1CC1)c2[N+](=O)[O-]

Procedure:
Prepared analogous to Example 1b from 5.8 gm of 4,4-dimethyl-7-acetamino-8-nitro-2H,4H-isoquinoline-1,3-dione and 6.3 gm of cyclopropane carboxylic acid chloride (heating time: 30 hours).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2.[OH-].[Na+]>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].CN(C=O)C>[N:12]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[C@@H:14]([NH:20][C:21]([C:23]1[O:24][C:25]3[CH:31]=[C:30]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=4)[CH:29]=[CH:28][C:26]=3[CH:27]=1)=[O:22])[CH2:13]2
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc3c2)c1
Temperature: 82.5 °C

Procedure:
A mixture of 130 mg (0.86 mmol) of 3-methoxyphenylboronic acid, 200 mg (0.57 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide (Example 2A), 1.72 ml (1.72 mmol) of 1N sodium hydroxide solution, 40 mg (0.06 mmol) of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 2 ml of DMF is heated at 80-85° C. for 18 h. The solvent is removed under reduced pressure. The crude product is purified on silica gel 60 (Merck, Darmstadt; eluent: dichloromethane, dichloromethane/methanol 20:1, dichloromethane/methanol/ammonia 80:20:2). The solvent is removed under reduced pressure. Finally, the last residues of solvent are removed under high vacuum. 151 mg (64% of theory) of the title compound are isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:38][CH3:39])=[C:33]([N:35]=[C:36]=[O:37])[CH:34]=1>C1(C)C=CC=CC=1>[O:38]([C:32]1[CH:31]=[CH:30][C:29]([Cl:28])=[CH:34][C:33]=1[NH:35][C:36]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=1)=[O:37])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1cc(Cn2ccc3c(N)cccc32)c2cccnc21
Reactant: COc1ccc(Cl)cc1N=C=O
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1NC(=O)Nc1cccc2c1ccn2Cc1cn(C(=O)OC(C)(C)C)c2ncccc12
Yield: 73 %

Procedure:
A solution of 3-[(4-amino-1H-indol-1-yl)methyl]-1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridine from previous step and 5-chloro-2-methoxyphenyl isocyanate (Int-14, 275 mg, 1.5 mmol) in toluene was stirred overnight. The reaction mixture was concentrated and purified by flash column chromatography to afford product 1-(2-methoxyl-5-chlorophenyl)-3-{1-[1-(t-butyloxycarbonyl)-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-1H-indol-4-yl}urea (518 mg, 73% for two steps).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][CH:17]1OCC[O:18]1)([O-:3])=[O:2].Cl>C(OCC)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=[CH:16][CH:17]=[O:18])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1-n1cccc1C=CC1OCCO1
Agent: Cl
Solvent: CCOCC
Product: O=CC=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Yield: 90.7 %

Procedure:
A solution of 2.6 g (9.1 mmol) 3a in 50 ml diethyl ether was stirred with 10% aqueous HCl for 1 hour. The reaction mixture was washed with 5% NaHCO3, dried over NaHCO3. After evaporation of the solvent, 2 g (91%) of 4a was obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.C(N(CC)CC)C.CN(C)C=O.[C:35]([O:38][CH2:39][C:40](Cl)=[O:41])(=[O:37])[CH3:36]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:40](=[O:41])[CH2:39][O:38][C:35](=[O:37])[CH3:36])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reaction time: 0.33 h
Yield: 17.4 %

Procedure:
To a mixture of 4-[4-(3-indolyl)piperidinomethyl]-2-aminothiazole (1 g), triethylamine (1.3 g) and N,N-dimethylformamide (10 ml) was added dropwise a solution of 2-acetoxyacetyl chloride (0.87 g) in methylene chloride (1 ml) in a stream of nitrogen gas with ice-cooling and stirring over a period of 20 minutes. After 3 hours, the reaction mixture was filtered and the residue on the filter paper was washed with N,N-dimethylformamide (10 ml). The filtrate and washings were combined and concentrated under reduced pressure to remove the solvent. The residue was subjected to column chromatography on silica gel and elution was carried out with a mixture of chloroform and methanol (20:1 V/V). The fractions containing the desired compound were collected and concentrated under reduced pressure and the residue was recrystallized from a mixture of water and ethanol to give 4-[4-(3-indolyl)piperidinomethyl]-2-(2-acetoxyacetylamino)thiazole (0.23 g).
Reaction SMILES: [CH2:1]([C@H:7]1[CH2:11][CH:10]([CH3:12])[O:9][C:8]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-:14].[Na+:15]>C(O)C>[OH:9][CH:10]([CH3:12])[CH2:11][C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([O-:13])=[O:14].[Na+:15]
Reactant: [OH-]
Reactant: CCCCCC[C@H]1CC(C)OC1=O
Agent: [Na+]
Solvent: CCO
Product: CCCCCC[C@@H](CC(C)O)C(=O)[O-]
Temperature: 75 °C
Reaction time: 3 h

Procedure:
To an ethanol solution of the compound prepared in Example 1(6) was added an equivalent of an aqueous solution of sodium hydroxide, and the mixture was stirred at 75° C. for 3 hours. The reaction mixture was concentrated to give the compound of the present invention having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11](COCC[Si](C)(C)C)[C:10]([O:20][C@H:21]3[CH2:30][O:29][C@H:28]4[C@@H:23]([O:24]C(C5C=CC=CC=5)[O:26][CH2:27]4)[CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[I:8].C(O)=O.S([O-])(O)(=O)=O.[K+].[OH-].[Na+]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([O:20][C@H:21]3[CH2:30][O:29][C@H:28]([CH2:27][OH:26])[C@@H:23]([OH:24])[CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[I:8]
Reactant: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(I)c(Cl)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC(C)=O
Product: OC[C@H]1OC[C@H](Oc2nc3nc(I)c(Cl)cc3[nH]2)C[C@@H]1O
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
6-chloro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-imidazo[4,5-b]pyridine-(185 mg, 0.287 mmol) was dissolved in formic acid (1 ml, 26.1 mmol) and saturated potassium hydrogen sulfate (0.1 ml, 0.287 mmol). The reaction was heated to 50° C. for 4 h, and then diluted with EtOAc, followed by the addition of 3 M NaOH until pH 14 was reached. The reaction was stirred for 15 minutes at rt and the layers were separated. The aqueous layer was extracted with EtOAc (×2) and the combined EtOAc extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The resulting crude product was purified by column chromatography on a Biotage™ 25 g column and eluted with 1% to 10% MeOH in DCM to yield the desired product. LC-MS: calculated for C12H13ClIN3O4 424.96 observed m/e: 426.00 (M+H)+ (Rt 1.05/2 min).