Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:41][O:42][C:43]1[CH:44]=[N:45][CH:46]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:48]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][CH:28]([C:33]2[CH:38]=[CH:37][C:36]([C:47]3[CH:46]=[N:45][CH:44]=[C:43]([O:42][CH3:41])[CH:48]=3)=[CH:35][C:34]=2[F:40])[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(OC(c3ccc(Br)cc3F)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cncc(-c2ccc(C(Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)c(F)c2)c1
Temperature: 150 °C
Yield: 38.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[1-(4-bromo-2-fluoro-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (130 mg, 0.2 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (70 mg, 0.3 mmol) 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg (5 mol %) of dichlorobis(triphenylphosphine)palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified with Prep HPLC to give 51 mg of (S)-3-[4-(2-amino-6-{2,2,2-trifluoro-1-[2-fluoro-4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert-butoxycarbonylamino-propionic acid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][C@H]1N[C@H](C)CC1>>[CH3:6][C@H:5]1[CH2:4][CH2:3][C@H:2]([CH3:25])[N:1]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]3=[CH:14][C:13]=2[CH:12]=1
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: O=C1NCCn2c1cc1cc(OCCCN3CCCCC3)ccc12
Product: C[C@H]1CC[C@H](C)N1CCCOc1ccc2c(c1)cc1n2CCNC1=O
Yield: 7 %

Procedure:
The title compound was synthesized in analogy to example 2, from 8-(3-chloro-propoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 2, intermediate) and (2R,5R)-(−)-trans-2,5-dimethylpyrrolidine (commercially available), to give the desired product as a white solid (7%).
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:33][CH2:34][CH2:35][O:36][CH3:37])[C@@H:21]1[OH:38])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1>[CH3:37][O:36][CH2:35][CH2:34][O:33][C@@H:22]1[C@H:21]([OH:38])[C@@H:20]([CH2:19][OH:18])[S:24][C@H:23]1[N:25]1[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S[C@H]1n1ccc(=O)[nH]c1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)S[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of Compound 114 (0.49 g, 0.88 mmol) in anhydrous THF (37 mL) 1M tetrabutylammonium fluoride in THF (1.8 mL) was added. Acetic acid (0.12 mL, 2.03 mmol) was added to this mixture and the resulting reaction mixture stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue obtained was purified by flash silica gel column chromatography and eluted with acetone to yield Compound 51 (0.23 g, 83%). 1H NMR (300 MHz, DMSO-d6): 11.2 (s, 1H), 8.04 (d, 1H,), 5.94 (d, 1H), 5.69 (d, 1H), 5.20 (d, 1H), 4.15 (t, 1H), 4.04 (m, 1H), 3.67-3.53 (m, 6H), 3.47-3.36 (m, 2H), 3.31 (s, 3H); MS (API-ES) m/z 341.0 [M+Na]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:24])[C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[C@H:17]([NH:16][C:9]1[C:4]2[N:5]([CH:14]=[C:2]([Br:1])[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:11]([NH2:13])=[O:12])[CH3:24]
Reactant: C[C@@H](N)C(C)(C)C(N)=O
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(C)(C)C(N)=O
Temperature: 100 °C
Reaction time: 12 h
Yield: 70.8 %

Procedure:
To a solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (400 mg, 1.457 mmol) in DMF (30 mL) was added (R)-3-amino-2,2 dimethylbutanamide hydrochloride (486 mg, 2.91 mmol) and DIPEA (1.273 ml, 7.29 mmol) at RT and the reaction mixture was allowed to stir at 100° C. for 12 h. It was then quenched with water (300 ml) and extracted with EtOAc (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. Crude product was purified by combi-flash (12 g silica column, 85% EtOAc: Pet-Ether) to afford an off white solid (380 mg, 70.8% yield). 1HNMR (400 MHz, DMSO) δ ppm: 1.13-1.18 (m, 9H), 4.51-4.55 (d, J=16 Hz, 1H), 6.98 (s, 3H), 7.05-7.05 (d, J=1.6 Hz, 1H), 7.272 (s, 1H), 7.88-7.89 (d, J=4.0 Hz, 1H), 8.236 (s, 1H), 10.88-10.90 (d, J=8.0 Hz 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]=[CH:4]1)[CH3:2].Cl.Cl.[NH2:25][OH:26]>O>[CH2:1]([C:3]([CH2:21][CH3:22])([CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:5])[CH:4]=[N:25][OH:26])[CH3:2]
Reactant: NO
Reactant: CCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1
Agent: Cl
Solvent: O
Product: CCC(C=NO)(CC)CC=CCCC=CCC(N)c1ccccc1
Yield: 97.5 %

Procedure:
The procedure described in Example (1b) is repeated, except that 95.3 g(0.323 mol) of 3,3-diethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene, 20 g of37% hydrochloric acid, 22.4 g (0.322 mol) of hydroxylamine hydrochloride and 250 ml of water are used. Working up yields 103.1 g (0.314 mol) of 2,2-diethyl-11-phenyl-11-amino-undeca-4,8-dienal oxime; yield 97.5% of theory.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[C:7]2[C:19]3[N:18]4[CH:20]=[CH:21][N:22]=[C:17]4[C:16](=[O:23])[NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[N:3]=[CH:2]1.CN(C)C=O>[Pd].C(O)(=O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH:7]2[C:19]3[N:18]4[CH:20]=[CH:21][N:22]=[C:17]4[C:16](=[O:23])[NH:15][C:14]=3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[N:3]=[CH:2]1
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3c[nH]cn3)c2n2ccnc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1c[nH]cn1)c1ccccc1-2
Yield: 14.4 %

Procedure:
The process is performed as in Example 3 but starting with 1.1 g of 10-(4-imidazolylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 250 ml of dimethylformamide, 5 ml of acetic acid and 0.1 g of 10% palladium-on-charcoal. After evaporation of the solvents, the crude product is purified by chromatography on a column of silica (100 g partially deactivated with 3% water), eluting with a mixture of chloroform, methanol and 28% aqueous ammonia (24/6/1 by volume). A pale yellow solid is obtained which is triturated with 20 ml of water, filtered, washed with 20 ml of ethyl ether and dried at 80° C. under vacuum (2 mmHg; 0.26 kPa) to give 0.16 g of 10-(4-imidazolylmethyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one in the form of an off-white solid melting above 260° C. (Analysis, % calculated C: 67.32, H: 4.32, N: 23.09, O: 5.27, % found C: 67.7, H: 4.2, N: 22.6).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: O=C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC(OC(=O)c1ccccc1)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 122 mg (1 mmole) of benzoic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedures as described in Example 1 to obtain 117 mg (Yield: 30%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: C([C:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18](=[O:36])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[CH:14][CH:15]=2)[NH:10][N:9]=1)(OC(C)(C)C)=O.C(Cl)(=O)C1C=CC(OC)=CC=1.NC1C=CC=CC=1C(NC1C=C2C(C=NN2[C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])=CC=1)=O>>[C:63]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:36])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[CH:12]=2)[CH:8]=[N:9]1)([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(NC(=O)c3ccccc3N)cc21
Reactant: COc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc3c(C(=O)OC(C)(C)C)n[nH]c3c2)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc3cnn(C(=O)OC(C)(C)C)c3c2)cc1

Procedure:
By methods substantially equivalent to those described in Example 1-C, N-(-Boc-6-indazolyl)-2-[(4-methoxybenzoyl)amino]benzamide (280 mg, 39%) was prepared from p-anisoyl chloride and 2-amino-N-(1-Boc-6-indazolyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=O)[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:36])[NH2:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.[NH2:39][O:40][CH2:41][C:42]1[NH:43][CH:44]=[C:45]([OH:49])[C:46](=[O:48])[N:47]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][CH2:41][C:42]2[NH:43][CH:44]=[C:45]([OH:49])[C:46](=[O:48])[N:47]=2)/[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[C@@H:12]2[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]2[N:30]4[N:31]=[C:32]([C:34](=[O:36])[NH2:35])[N:33]=[C:29]4[N:28]=[C:27]([CH3:37])[CH:26]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: NOCc1nc(=O)c(O)c[nH]1
Reactant: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=O)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\OCc4nc(=O)c(O)c[nH]4)c4csc(N)n4)[C@H]3SC2)n2nc(C(N)=O)nc2n1
Reaction time: 0.33 h

Procedure:
0.230 g (0.4 mmol) of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido) -3-[[(2-carbamoyl-5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid was dissolved in 3.5 ml of dimethylacetamide. Within 6 hours 0.11 g (0.7 mmol) of 2-(aminooxy)methyl-5-hydroxy-4(1H)-pyrimidinone and 0.133 g (0.7 mmol) of p-toluenesulfonic acid hydrate were added. After further stirring for 18 hours the dimethylacetamide was evaporated off at strongly reduced pressure, and the residue was taken up in water and stirred for 20 minutes in order to completely precipitate the product. The product was filtered off, washed well with water and dried under strongly reduced pressure at room temperature. (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(1,4-dihydro -5-hydroxy-4-oxo-2-pyrimidinyl) methoxy]imino]-acetamido]-3-[[(2-carbamoyl -5-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid was obtained as a beige powder.
Reaction SMILES: Cl.COC1C=C2C(=CC=1)C=C(C([NH2:16])C)C=C2.[CH:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:17](=[NH:16])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc2cc(C(C)N)ccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C=N)cc1
Reaction time: 15 h
Yield: 230.8 %

Procedure:
To a solution of the amine 2.1 (2.51 g, 12.5 mmol) in 10 mL methanol were added p-anisaldehyde (1.5 mL, 12.5 mmol) and anhydrous sodium carbonate (1.3 g, 12.5 mmol). The mixture was stirred for 15 hours and was filtered through celite and concentrated to give 3.9 g of the corresponding p-anisaldehyde imine 2.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[CH:5]=[C:4]([Cl:12])[N:3]=1.[N+:13]([O-])([O-:15])=[O:14].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[C:7]2[NH:8][C:9](=[O:11])[NH:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[C:4]([Cl:12])[N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Cl)nc(Cl)c2[nH]1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(Cl)nc(Cl)c([N+](=O)[O-])c2[nH]1
Temperature: 125 °C

Procedure:
To a solution of 4,6-dichloro-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.6 g, 2.94 mmol) from Step C in conc. H2SO4(15 mL) was added KNO3 (2.97 g, 29.4 mmol) and the reaction mixture was heated at 125° C. for 2 h. After cooling, the reaction was mixed with ice and the solid precipitate was isolated by filtration and washed with cold H2O to give the title compound. MS: m/z=290 (M+I+CH3CN).
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=C[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[Cl-].[NH4+:15]>C1COCC1.[Zn]>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[N:15][CH:7]=1)[NH:4][C:3](=[O:12])[CH2:2]2
Reactant: [NH4+]
Reactant: O=C1Nc2ccc(Br)cc2C1(Br)Br
Agent: [Cl-]
Agent: [Zn]
Solvent: C1CCOC1
Product: O=C1Cc2cc(Br)cnc2N1
Reaction time: 0.33 h

Procedure:
A solution of 3,3,5-tribromooxindole (5.0 g, 13.4 mmol) in fresh THF (100 mL) is stirred at room temperature and a saturated aqueous solution of ammonium chloride (100 mL) is added. The flask is placed in a water bath and activated zinc dust (15.0 g, 230 mmol) is added. The mixture is stirred for 20 min and the zinc is removed by filtration through a pad of diatomaceous earth. The organic layer is separated and the aqueous layer is extracted with THF (20 mL). The combined organic layers were washed with saturated brine solution, dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The brown residue is triturated with water (20 mL) and the tan solid is collected by filtration and dried under vacuum to give 5-bromo-7-azaoxindole as a tan solid, 2.02 g (71%). 1H NMR (DMSO-d6) δ 11.13 (s, 1H), 8.15 (s, 1H), 8.76 (s, 1H), 3.57 (s, 2H). MS (AP−ve) 211 (100) (M−H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3scc(C)c23)cc1OC
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3scc(C)c23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-methyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:30]([NH:32][NH2:33])=O)[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>C(O)CCC>[Si:1]([O:8][CH2:9][C@@:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]2[C:30]([C:27]3([C:24]4[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=4)[CH2:29][CH2:28]3)=[N:32][N:33]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CSC1=NCCS[C@](C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC(C)(C)[Si](C)(C)OC[C@]1(C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Temperature: 140 °C
Reaction time: 5 h
Yield: 41.8 %

Procedure:
The compound (2.07 g, 6.54 mmol) obtained in Example 3-1) and the compound (1.38 g, 6.54 mmol) obtained in Example 1-1) were dissolved in 1-butanol (10 mL), and the mixture was stirred at 140° C. for 5 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, then the solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=30% to 80%) to obtain the title compound (1.27 g, 42%) in a white solid form.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH2:15]Br)=O)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C.[CH3:21][NH:22][C:23]([NH2:25])=[S:24].C(=O)(O)[O-].[Na+]>O>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([CH2:12][C:13]2[N:25]=[C:23]([NH:22][CH3:21])[S:24][CH:15]=2)=[O:17])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(N)=S
Reactant: CC(C)(C)c1nnc(NC(=O)CC(=O)CBr)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CNc1nc(CC(=O)Nc2nnc(C(C)(C)C)s2)cs1
Yield: 87.2 %

Procedure:
A reaction mixture containing 11.4 g (0.035 mole) of N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-4-bromoacetoacetamide, 150 ml of ethanol and 3.3 g (0.036 mole) of N-methylthiourea was refluxed for four hours. The reaction solution was poured into 300 ml of water and treated with excess aqueous sodium bicarbonate. The product was isolated and dried. There was obtained 9.5 g (87.2%) of white solid, m.p. 198°-200° (dec.). N.M.R. (CDCl3) ∂ 1.4 [C(CH3)3 ], 3.0 (CH3), 3.8 (CH2), 6.4 (hetero-aromatic).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32](B(O)O)[CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:32]4[CH:31]=[CH:30][N:29]=[C:28]([Cl:27])[CH:33]=4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(I)cc3)nc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(Cl)c4)cc3)nc2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a sealed tube was added N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-iodophenyl)acetamide 177-2 (100 mg, 0.22 mmol), 2-chloropyridin-4-ylboronic acid 177-3 (52 mg, 0.33 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol), saturated Na2CO3 (1 mL), ethanol (1 mL) and toluene (3 mL). The reaction was heated to 110° C. and stirred for 16 hours. The reaction was cooled down to room temperature, then extracted with ethyl acetate. The crude product was purified by silica-gel flash chromatography, eluted with ethyl acetate to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-fluoropyridin-4-yl)phenyl)acetamide 177 as off-white solid. MS m/z 450.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ10.51 (s, 1H), 8.40 (d, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.78 (d, 1H), 7.76 (d, 2H), 7.69 (dd, 1H), 7.43 (d, 2H), 7.37 (dd, 1H), 3.68 (s, 2H), 3.52 (m, 4H), 3.09 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][C:6]2=[CH:7][N:8]=1.[OH-].[K+].Br[CH2:18][CH3:19]>CS(C)=O>[CH2:18]([N:9]1[C:6]2=[CH:7][N:8]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[CH:11]=[C:10]1[C:12]([OH:14])=[O:13])[CH3:19]
Reactant: CCBr
Reactant: COc1cc2cc(C(=O)O)[nH]c2cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1c(C(=O)O)cc2cc(OC)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.8 %

Procedure:
To a solution of 5-methoxy-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (500 mg, 2.60 mmol) (available from, for example, Activate Scientific GmbH) in dimethyl sulfoxide (DMSO) (5 mL) was added potassium hydroxide (438 mg, 7.81 mmol) and bromoethane (0.427 mL, 5.72 mmol). The reaction was stirred at room temperature for 18 h before adding further potassium hydroxide (120 mg) and bromoethane (0.13 ml). After stirring for a further 4 h, the reaction mixture was stood under nitrogen for ca. 66 h. It was then partitioned between water and diethyl ether. The layers were separated and the aqueous was washed with diethyl ether. The aqueous was acidified to pH=3, and was extracted with ethyl acetate (twice). The combined ethyl acetate extracts were washed with water and concentrated in vacuo to yield the title compound as a pale beige solid (148 mg).
Reaction SMILES: I[C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:12]3[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24].[ClH:28].O1CCOCC1>C(OCC)(=O)C>[ClH:28].[N:9]12[CH2:14][CH2:13][CH:12]([CH2:11][CH2:10]1)[CH:7]([O:6][C:5]1[CH:15]=[CH:16][C:2]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([NH2:17])[CH:19]=3)=[CH:3][CH:4]=1)[CH2:8]2
Reactant: Ic1ccc(OC2CN3CCC2CC3)cc1
Reactant: Cc1ccc(B(O)O)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1N

Procedure:
The product of Example 1A (330 mg, 1 mmol) was treated with 3-amino-4-methyl-phenylboronic acid (Lancaster, 302 mg, 2 mmol) according to the procedure of Example 1B. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.10) as oil (230 mg, yield, 75%). The free base of the title compound (230 mg, 0.75 mmol) in ethyl acetate (5 mL) was treated with 4M HCl in 1,4-dioxane (0.5 mL, 2 mmol). The title compound was obtained as solid (180 mg, yield, 74%): 1H NMR (MeOH-d4, 300 MHz) δ 1.85-2.19 (m, 3H), 2.28-2.38 (m, 1H), 2.43 (s, 3H), 2.51-2.57 (m, 1H), 3.31-3.45 (m, 5H), 3.82-3.89 (m, 1H), 4.93-4.99 (m, 1H), 7.13 (dt, J=8.8, 3.0 Hz, 2H), 7.44 (d, J=8.8 Hz, 1H), 7.56-7.66 (m, 4H) ppm. MS (DCl/NH3) m/z 309 (M+H)+. Anal. Calculated for C19H22N2O.2.0HCl.0.1H2O: C, 62.70; H, 6.89; N, 7.31. Found: C, 62.52; H, 6.59; N, 7.35.