Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH2:8][O:9][C:10]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:11]=2[CH:12]=1.CC(C)([O-])C.[K+].Br[C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(O)(C)(C)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]1[CH2:8][O:9][C:10]2[CH:16]=[CH:15][C:14]([O:17][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:13][C:11]=2[CH:12]=1
Reactant: Cn1ccnc1C1=Cc2cc(O)ccc2OC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1)C=C(c1nccn1C)CO2
Yield: 68.6 %

Procedure:
A mixture of 4.56 g (0.02 mol) of 3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-ol [m.p. 210°-215° C., prepared following the procedure described in J. Heterocyclic Chem. 23, 1693 (1986)] and 2.3 g (0.02 mol) of potassium tert.butoxide in 100 ml of tert.butanol is heated, under vigorous stirring, at 50° C. for 30'. A solution of 3.9 g (0.02 mol) of ethyl bromoisobutyrate in 10 ml of tert.butanol is rapidly added dropwise and the resulting mixture refluxed for 4 hours. The solvent is evaporated under vacuum and the residue is taken up with H2O (100 ml) and ethyl acetate. The aqueous solution is separated and extracted again with ethyl acetate (2×100 ml). The combined organic layers are washed with brine and dried over Na2SO4. After removal of the solvent under vacuum, the residue is chromatographed over silica gel (eluant chloroform/methanol 95/5) giving 4.7 g of ethyl 2-[3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-yl]oxy-2-methylpropanoate, colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11]C.Br.C(O)(=O)C>O>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])ccc1O

Procedure:
2-Methyl-4-nitroanisole (4.0 g) in 50 ml 1:1 hydrobromic acid:acetic acid is heated 12 hours at 120°. Solvent is stripped, the residue taken up in water and ethyl acetate, the mixture is filtered to remove insolubles, and the layers are separated. The organic phase is dried, filtered, and stripped to afford 2-methyl-4-nitrophenol. NMR (CDCl3): δ 2.3 (3H, s), 6.8 (1H,d), 7.9 (1H,d of d), 8.0 (1H,d).
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)=O.[BH4-].[Na+].[OH-].[Na+]>CO>[NH:7]([CH2:8][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C=O)cc1
Reactant: Nc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.2 %

Procedure:
Phenylamine (56 mg) was added to the compound (120 mg) prepared in Example 4 in methanol solution (3 mL) and stirred for 4 hours at room temperature. The reaction mixture was added to sodium borohydride (37 mg) and stirred for 1.5 hours. To alkalinize, 5 mol/L sodium hydroxide solution was added to the concentrated reaction mixture and then extracted with ethyl acetate. The organic layer was washed with saturated sodium and dried by anhydrous sodium sulfate, and then concentrated to obtain the titled compound (124 mg) having the following physical data by purifying the obtained residue by silica gel column chromatography (diethyl ether:hexane=1:2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[N:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4([NH:44]C(=O)OC(C)(C)C)[CH2:43][CH2:42][CH2:41]4)=[CH:36][CH:35]=3)[C:11]3=[N:12][C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([N:22]5[CH2:27][CH2:26][O:25][CH:24]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[CH2:23]5)[CH:17]=4)=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:52].O1CCOCC1>C(Cl)Cl.CO>[ClH:52].[ClH:52].[ClH:52].[NH2:44][C:40]1([C:37]2[CH:36]=[CH:35][C:34]([N:33]3[C:11]4=[N:12][C:13]([C:16]5[CH:17]=[C:18]([N:22]6[CH2:27][CH2:26][O:25][CH:24]([C:28]([N:29]([CH3:31])[CH3:30])=[O:32])[CH2:23]6)[CH:19]=[CH:20][CH:21]=5)=[CH:14][CH:15]=[C:10]4[N:9]=[C:8]3[C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)=[CH:39][CH:38]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CN(C)C(=O)C1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(NC(=O)OC(C)(C)C)CCC6)cc5)c4n3)c2)CCO1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CN(C)C(=O)C1CN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)CCO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
tert-Butyl (1-{4-[2-(2-aminopyridin-3-yl)-5-{3-[2-(dimethylcarbamoyl)morpholin-4-yl]phenyl}-3H-imidazo[4,5-b]pyridin-3-yl]phenyl}cyclobutyl)carbamate (25.6 mg, 0.0372 mmol) was dissolved in DCM (1 mL)-MeOH (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 1.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (25.6 mg, 98.6%) as yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.COC1N=C([Sn](CCCC)(CCCC)CCCC)C([N+]([O-])=O)=CC=1.FC(F)(F)S(O[C:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[C:48]([O:53][CH3:54])[CH:49]=2)[CH:44]=1)(=O)=O>>[CH3:12][O:11][C:4]1[N:3]=[C:2]([C:43]2[CH2:52][CH2:51][C:50]3[C:45](=[CH:46][CH:47]=[C:48]([O:53][CH3:54])[CH:49]=3)[CH:44]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)CCC(OS(=O)(=O)C(F)(F)F)=C2
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Agent: CCCC[Sn](CCCC)(CCCC)c1nc(OC)ccc1[N+](=O)[O-]
Product: COc1ccc2c(c1)CCC(c1nc(OC)ccc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 2-chloro-6-methoxy-3-nitropyridine according to an analogous synthetic method to Preparation Example 76, 6-methoxy-3-nitro-2-tributylstannylpyridine (5.5 and 6-methoxy-3,4-dihydronaphthalen-2-yl trifluoromethanesulfonate (1.5 g) were used according to an analogous synthetic method to Preparation Example 77 to provide 6-methoxy-2-(6-methoxy-3,4-dihydronaphthalen-2-yl)-3-nitropyridine (933 mg). This compound (930 mg) was used according to an analogous synthetic method to Example 30 to provide the title compound (340 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][C:12]([OH:14])=O)[N:3]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O.O.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CO>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH2:21]([N:28]1[CH2:33][CH2:32][N:31]([C:12]([CH2:11][CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[N:3]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:14])[CH2:30][CH2:29]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)CC1c2ccccc2C(=O)N1c1ccccc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: O=C(CC1c2ccccc2C(=O)N1c1ccccc1)N1CCN(Cc2ccccc2)CC1
Yield: 83.5 %

Procedure:
An oily product (4.3 g), which was prepared from 2.67 g of 3-oxo-2-phenylisoindoline-1-acetic acid and 1.94 g of 1-benzylpiperazine in the same manner as Example 3, was dissolved in 4 ml of methanol, and to this solution a solution of 1.5 g of oxalic acid dihydrate in 6 ml of methanol was added, and the crystals precipitated were collected by filtration. Yield, 4.90 g; m.p., 207°-210° C. (recrystallization from methanol).
Reaction SMILES: [F:1][C:2]1([F:19])[C:6]2[N:7]([CH2:14][C:15]([OH:17])=O)[N:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:5]=2[C@H:4]2[CH2:18][C@@H:3]12.Cl.[NH2:21][C@H:22]([C:32]1[C:37]([C:38]2[CH:39]=[CH:40][C:41]([F:47])=[C:42]([CH:46]=2)[C:43]([NH2:45])=[O:44])=[CH:36][C:35]([N:48]2[C:56](=[O:57])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]2=[O:58])=[CH:34][N:33]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:19][C:2]1([F:1])[C:6]2[N:7]([CH2:14][C:15]([NH:21][C@H:22]([C:32]3[C:37]([C:38]4[CH:39]=[CH:40][C:41]([F:47])=[C:42]([CH:46]=4)[C:43]([NH2:45])=[O:44])=[CH:36][C:35]([N:48]4[C:49](=[O:58])[C:50]5[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=5)[C:56]4=[O:57])=[CH:34][N:33]=3)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)=[O:17])[N:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[C:5]=2[C@H:4]2[CH2:18][C@@H:3]12
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@@H](N)Cc2cc(F)cc(F)c2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)ccc1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (13 mg, 0.045 mmol), (S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(1,3-dioxoisoindolin-2-yl)pyridin-3-yl)-2-fluorobenzamide hydrochloride (30I, 25 mg, 0.045 mmol) and HATU (21 mg, 0.054 mmol) were dissolved in 10 mL DMF, cooled to 0° C., then N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 min, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with NaHCO3 (sat'd aq.) and brine. After dried over MgSO4, it was filtered and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 8.87 (s, 1H), 7.98 (m, 2H), 7.88 (m, 2H), 7.76 (d, 1H), 7.54-7.30 (m, 2H), 7.24 (dd, 1H), 6.67 (t, 1H), 6.39 (m, 2H), 5.51-5.26 (m, 1H), 4.88 (s, 2H), 3.18-2.98 (m, 2H), 2.63-2.41 (m, 2H), 1.40 (m, 1H), 1.11 (m, 1H). MS (m/z) 781.03 [M+H]+.
Reaction SMILES: CN(C)C=O.[C:6]([Cl:11])(=O)C(Cl)=O.[NH:12]1[C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[S:14]C1=S.C([O-])(O)=O.[Na+]>ClCCCl.O>[Cl:11][C:6]1[S:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[N:12]=1
Reactant: S=c1[nH]c2ccncc2s1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nc2ccncc2s1
Temperature: 25 °C
Yield: 87 %

Procedure:
To an ice-cold mixture of dimethylformamide (DMF, 1.1 mL) and DCE (8 mL) was added dropwise a solution of oxalyl chloride (1.73 mL) in DCE (4 mL). A white precipitate formed, and the reaction mixture was stirred at rt for 5 min. [1,3]Thiazolo[5,4-c]pyridine-2(1H)-thione (1 g, 6 mmol) was added in portions, and the reaction mixture was stirred at reflux for 3 h. After cooling to rt, the reaction mixture was treated with water (20 mL) and saturated (satd.) aqueous (aq.) NaHCO3 (100 mL) and then extracted with ethyl acetate (EtOAc) (2×100 mL). The combined organic layers were dried, filtered and concentrated to provide the desired product as a brown solid (1 g, 87%). 1H NMR (400 MHz, CDCl3): 9.11 (d, J=0.8, 1H), 8.68 (d, J=5.6, 1H), 7.85 (dd, J=5.6, 0.8, 1H). MS (ESI): mass calcd. for C6H3ClN2S, 169.97; m/z found, 171.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].CC#N.CCN(CC)CC.[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>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].C(Cl)Cl>[CH2:24]([O:23][C:19](=[O:22])/[CH:20]=[CH:21]/[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8])[CH3:25]
Reactant: C=CC(=O)OCC
Reactant: Cc1ccncc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cnccc1C
Yield: 43.6 %

Procedure:
A mixture of 2.0 g (12 mmol) of 3-bromo-4-methylpyridine, 2.5 mL of CH3CN, 3.2 mL (23 mmol) of Et3N, 5.8 g (58 mmol) of ethyl acrylate, and 0.095 g (0.12 mmol) of PdCl2(dppf).CH2Cl2 is stirred in an evacuated and sealed pressure tube at 125° C. for 1 h. The mixture is concentrated and purified by flash chromatography (5-60% EtOAc in hexanes) to provide 1.0 g (47%) of (E)-3-(4-methyl-pyridin-3-yl)-acrylic acid ethyl ester as a dark oil. This material is stirred in 2 mL of toluene with 0.70 mL (6.0 mmol) of benzyl bromide at 60° C. overnight. The resulting precipitate is filtered and washed with toluene to provide 1.4 g (4.0 mmol) of the benzyl pyridinium bromide as a white powder. To this material in 20 mL of EtOH at 0° C. is added 0.30 g (8.0 mmol) of NaBH4 in portions over 30 minutes. The mixture is stirred for 90 min, concentrated by half, dissolved in CH2Cl2, washed twice with water and once with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (5-50% EtOAc in hexanes) provides 0.42 g (1.5 mmol) of (E)-3-(1-benzyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-acrylic acid ethyl ester as a yellow oil. This material is stirred in 3 mL of EtOH with 42 mg of Pd/C under an H2 atmosphere overnight. The vessel is evacuated with N2, filtered through diatomaceous earth, and concentrated to provide 208 mg of I-031 as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](Cl)=[O:19].Cl[CH2:29][CH2:30][Mg].[NH4+].[Cl-].O>C1COCC1>[Cl:16][C:4]1[CH:5]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:7]=[C:2]([Cl:1])[C:3]=1[CH:17]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:18](=[O:19])[CH2:29][CH3:30]
Reactant: [Mg]CCCl
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: -75 °C
Yield: 17.3 %

Procedure:
A mixture of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4,-triazin-2(3H)-yl)-benzeneacetyl chloride (0.05 mol) in THF (200 ml) was stirred at −75° C. A solution of chloroethyl magnesium (0.1 mol; 2 M/THF) in THF (50 ml) was added dropwise at −75° C. The reaction mixture was stirred for 90 minutes, then the temperature was raised to −20° C. A saturated aqueous NH4Cl solution was added dropwise. Water was added and the product was extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was filtered over silica gel (eluent: CH2Cl2/CH3OH 98/2). Two fractions were collected and the solvent was evaporated, yielding 3.8 g (±)-2-[3,5-dichloro-4-[1-(4-chlorophenyl)-2-oxobutyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (interm. 69).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(Cl)ccc1CBr
Yield: 67.4 %

Procedure:
303 g of 4-chloro-2-methoxytoluene are dissolved in 1665 ml of carbon tetrachloride and, together with 355 g of N-bromosuccinimide, heated at reflux for 2 h while 4.0 g of AIBN are added. The solid is filtered off and washed with a small amount of carbon tetrachloride, the filtrate is concentrated, and the residue which remains is fractionated. 307 g of colorless oil are obtained (b.p. 103° C./1.5 mbar, m.p. 42-45° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:17][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:8].[H-].[Na+].[CH3:30]C(C)(Br)C(N)=O.O.[CH3:38][N:39]([CH:41]=[O:42])[CH3:40]>>[S:18]([N:17]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:16][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[O:8])[CH2:30][C:41](=[O:42])[N:39]([CH3:40])[CH3:38])([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20]
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1
Reactant: CN(C)C=O
Reactant: CC(C)(Br)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)N(C)C)c2ccc(Cl)cc2C(=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8.4 g of 5,2'-dichloro-2-tosylaminobenzophenone are dissolved in 40 ml of DMF and treated with 0.7 g of 80% sodium hydride; after 15 minutes, 10 g of dimethylbromoacetamide, prepared in Example 1, are added and the mixture is stirred overnight at RT. The reaction medium is poured into water, the precipitate formed is filtered off and taken up with DCM and the solution is dried and concentrated. 9.2 g of the expected product are obtained after crystallization from isopropyl ether.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:31]#[N:32])[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:20][CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=[C:25]([C:31]#[N:32])[C:26]([N:28]([CH3:29])[CH3:30])=[O:27])=[CH:20][CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
In a 25 ml one necked round bottom flask, N-tert-butyl-2-(4-(2-cyano-3-(dimethylamino)-3-oxoprop-1-enyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.1 g, 0.00019 mol) was taken in CH2Cl2 (10 ml) followed by dropwise addition of TFA (2.0 ml) at 0°-5° C. and the reaction was allowed to stir at room temperature for 24 hr. After completion of the reaction, the pH of the solution was adjusted to neutral by the addition of saturated sodium bicarbonate solution and extracted with CH2Cl2 and the combined organic layer was dried over anhy. sodium sulphate and concentrated to obtain crude mixture which was dissolved in ethanol (10 ml). NaOAc.3H2O (0.242 g, 0.00178) was added and the reaction mixture was stirred at room temperature for 20 hr. Ethanol was distilled out and the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate, concentrated to afford crude product which was purified using column purification by eluting the compound with 50% ethyl acetate in hexanes to yield 14.0 mg of N-tert-butyl-2-(4-(2-cyano-3-(dimethylamino)-3-oxoprop-1-enyl)phenylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[C:28]=4[NH:27][CH:26]=[CH:25]5)=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[CH3:29][NH:30][CH3:31].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:21]=[CH:22][CH:23]=[C:24]5[C:28]=4[NH:27][CH:26]=[CH:25]5)=[CH:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([N:30]([CH3:31])[CH3:29])=[O:5]
Reactant: CNC
Reactant: Nc1ccc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(-c2cnc3[nH]cc(-c4cccc5cc[nH]c45)c3c2)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.9 %

Procedure:
To a solution of 2-amino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-benzoic acid (70 mg, 0.11 mmol), dimethylamine (2 N solution in THF, 0.11 mL, 0.22 mmol), diisopropylethylamine (20 mg, 0.16 mmol) in DMF (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (60 mg, 0.16 mmol). The resulting solution was stirred at room temperature for 1 hour. The mixture was diluted with DMF (1 mL) and directly used in purification by mass-triggered reverse-phase HPLC to afford 2-amino-5-[3-(1H-indol-7-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide as a white solid (3 mg, 7%). MS: m/z 396 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.90 (s, 6H), 5.21 (s, 2H), 6.49 (d, 1H), 6.79 (d, 1H), 7.10 (t, 1H), 7.30 (d, 2H), 7.33 (d, 1H), 7.43 (dd, 1H), 7.49 (d, 1H), 7.81 (d, 1H), 8.03 (d, 1H), 8.44 (m, 2H), 10.89 (s, 1H), 11.99 (s, 1H).
Reaction SMILES: C([Li])CCC.C[Si](C)(C)[CH:8]1[S:13][CH2:12][CH2:11][CH2:10][S:9]1.[N:16]12[CH2:24][CH:20]([C:21](=O)[CH2:22]1)[CH2:19][CH2:18][CH2:17]2.O>CCCCCC.C1COCC1>[S:9]1[CH2:10][CH2:11][CH2:12][S:13][C:8]1=[C:21]1[CH2:22][N:16]2[CH2:24][CH:20]1[CH2:19][CH2:18][CH2:17]2
Reactant: O=C1CN2CCCC1C2
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C1CSC(=C2CN3CCCC2C3)SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
n-Butyl lithium (6.05 ml of a 1.6M solution in hexane, 9.7 mmol) was added dropwise to a solution of 2-trimethylsilyl-1,3-dithiane (1.86 g, 9.7 mmol), in THF (30 ml) at -30° C. and the reaction mixture stirred for 2 hr. A solution of 1-azabicyclo [3.2.1]octan-6-one (1.1 g, 8.8 mmol) in THF (10 ml) was added dropwise and the reaction mixture allowed to warm to room temperature. Water (20 ml) was added and extracted (3×50 ml) with dichloromethane. The combined extracts were dried (MgSO4) and evaporated and the residue chromatographed through alumina eluting with dichloromethane/methanol (97:3) to afford the title compound as a clear liquid, (2 g), m/e 227 (M+); δ(60 MHz; CDCl3) 1.10-2.90 (15H, m, 7×CH2 and CH); 3.38 (2H, AB q, J=17 Hz, CH2 --C=C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:49]([O:51][C:52]1[CH:60]=[CH:59][CH:58]=[CH:57][C:53]=1[CH:54]([OH:56])[CH3:55])[CH3:50]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:56][CH:54]([C:53]2[CH:57]=[CH:58][CH:59]=[CH:60][C:52]=2[O:51][CH2:49][CH3:50])[CH3:55])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCOc1ccccc1C(C)O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(C)OC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (77 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (117 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-ethoxy-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (63 mg, yield 46%).