Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=2)[CH2:26][CH2:25]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:35]([C:34]3[CH:33]=[CH:32][C:31]([CH2:30][N:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)=[CH:38][CH:37]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3ccc(CN4CCOCC4)cc3)nc2c1N1CCN(Cc2nccs2)CC1
Temperature: 85 °C
Yield: 40.2 %

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-(thiazol-2-ylmethyl)piperazin-1-yl)pyridin-2-amine (0.088 g, 0.22 mmol) and EtOH (2.5 mL), 4-(morpholinomethyl)-benzaldehyde (0.045 g, 0.24 mmol) in EtOH (2.5 mL) was added, followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.66 mL, 0.66 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 96:4) to give the title compound as a solid (0.049 g, 40%); 1H-NMR (500 Mz, DMSO-d6): δ 2.33-2.43 (m, 4H), 2.72-2.79 (m, 4H), 3.54 (s, 2H, NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.70 (t, J=4.5 Hz, 4H), 3.95 (s, 2H, NCH2), 7.48 (d, J=8.5 Hz, 2H, ArH), 7.69 (d, J=3.5 Hz, 1H, thiazole 5-H), 7.75 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.15 (d, J=8.0 Hz, 2H, ArH), 8.24 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.49 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z) 2.37 min—554/556 [(M+H)+, Br isotopic pattern]. ESI-HRMS: Found: 554.1341, calculated for C25H29BrN7OS (M+H)+: 554.1338.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]([N:20]1[C:24]([CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:23][C:22]([CH:29]=O)=[N:21]1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([N:20]1[C:24]([CH2:25][CH:26]([CH3:27])[CH3:28])=[CH:23][C:22]([CH2:29][NH:15][CH2:14][CH2:13][N:10]2[CH2:9][CH2:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][CH2:11]2)=[N:21]1)([CH3:19])([CH3:18])[CH3:17]
Reactant: NCCN1CCN(c2ccccc2)CC1
Reactant: CC(C)Cc1cc(C=O)nn1C(C)(C)C
Product: CC(C)Cc1cc(CNCCN2CCN(c3ccccc3)CC2)nn1C(C)(C)C
Yield: 25.8 %

Procedure:
Compound 5 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 1-t-butyl-5-iso-butylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[C:27](=[O:36])/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (250 mg, 0.72 mmol) in CH2Cl2 (10 mL) was added cinnamoyl chloride (160 mg, 0.93 mmol) and triethylamine (TEA, 0.30 mL, 2.2 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, the residue was purified by preparative TLC (PTLC, 20% EtOAc/CH2Cl2) to provide 290 mg (85%) of the desired product. 1H NMR (500 MHz, CDCl3): 8.05 (s, 1H), 7.62 (d, J=15.5 Hz, 1H), 7.32-7.20 (m, 10H), 7.17 (d, J=7.9 Hz, 1H), 6.74 (dd, J=6.8, 1.5 Hz, 1H), 6.15 (d, J=15.5 Hz, 1H), 4.80-4.69 (m, 1H), 4.20-4.09 (m, 3H), 3.51-3.45 (m, 1H), 3.31-3.20 (m, 2H), 2.95-2.82 (m, 2H), 2.23 (s, 3H), 2.19-2.08 (m, 2H), 1.91-1.71 (m, 2H). MS: exact mass calculated for C31H33N3O2, 479.26; m/z found, 480.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[NH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>O>[C:9]1([C:7]2[CH:8]=[C:3]([OH:2])[N:4]=[N:5][C:6]=2[C:15]2[CH:16]=[CH:17][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:32]=[C:31]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=5)[NH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4cc(-c5ccccn5)[nH]n4)CC3)cc2)nn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Oc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(c4cc(-c5ccccn5)[nH]n4)CC3)cc2)nn1
Temperature: 150 °C

Procedure:
A mixture of 3-methoxy-5-phenyl-6-(4-([4-(5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl)phenyl)pyridazine (2-3) TFA (36.8 mg, 0.059 mmol) and pyridine hydrochloride (591 mg, 5.1 mmol) was heated at 150° C. for 5 min. This solid was dissolved in water, the solution made basic with NaHCO3, and the product extracted into methylene chloride/methanol (5%). This solution was dried, filtered and the solvents evaporated. This residue was digested in acetonitrile to give 5-phenyl-6-(4-{[4-(5-pyridin-2-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)pyridazin-3-ol (2-4) as a tan solid freebase. NMR (CDCl3/CD3OD): δ8.66 (1H, br d, J=4.5 Hz), 8.40 (1H, br d, J=7 Hz), 8.29 (1H, br m), 7.67 (2H, br m), 7.55 (2H, d, J=7.5 Hz), 7.42 (1H, s), 7.35 (1H, t, J=7.5 Hz), 7.11-7.30 (4H, m), 7.08 (2H, d, J=9 Hz), 6.98 (1H, s), 4.21 (2H, s), 3.47 (2H, d, J=10 Hz), 3.26 (1H, m), 3.00 (2H, m), 2.43 (2H, br d, J=11 Hz), 2.13 (2H, m); m/e (m+1): 489.2.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH:17]([CH2:20][S:21]([OH:24])(=O)=[O:22])[CH2:16]1)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[Cl:3][S:21]([CH2:20][CH:17]1[CH2:18][CH2:19][N:15]([C:13]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:14])[CH2:16]1)(=[O:24])=[O:22]
Reactant: O=C(OCc1ccccc1)N1CCC(CS(=O)(=O)O)C1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCC(CS(=O)(=O)Cl)C1

Procedure:
Thionyl chloride (5 ml) was added to a solution of 1-[(benzyloxy)carbonyl]-3-pyrrolidinylmethanesulfonic acid (600 mg) [Preparation 57] in dimethylformamide (50 ml). The reaction mixture was heated to reflux for 20 mins after which time the cooled mixture was evaporated to dryness. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure to afford benzyl 3-(chlorosulfonylmethyl)-1-pyrrolidinecarboxylate (560 mg) as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:19][O:20][CH:21]([O:25][CH3:26])[CH:22]([NH2:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>CS(C)=O>[CH3:19][O:20][CH:21]([O:25][CH3:26])[CH:22]([NH:24][C:2]1[CH:3]=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH3:23]
Reactant: COC(OC)C(C)N
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: COC(OC)C(C)Nc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of benzyl 3-chloro-4-nitrophenyl ether (48.2 g, 0.183 mole), 2-aminopropionaldehyde dimethyl acetal (65.3 g, 0.55mole), potassium carbonate (101 g, 0.73 mole) and toluene in dry dimethyl sulfoxide, under nitrogen, is stirred at 99°-105° C. for 20 hours, cooled to room temperature and filtered. The filter cake is washed with ether. The combined filtrates are mixed with ice water. The phases are separated and the aqueous phase is extracted with ether. The ether extracts are combined with the organic phase. The combined organic phase is washed with six portions of water, dried (Na2SO4) and concentrated in vacuo to give an oil residue which is crystallized in methanol to afford the title product as a yellow solid, 39.6 g (64.5%). A sample is recrystallized from methanol to afford a yellow solid, mp 57°-62° C., identified by elemental and NMR analyses.
Reaction SMILES: P([O-])([O-])([O-])=O.I([O-])(=O)(=O)=O.[Na+].[CH3:12][S:13]([C@H:16]1[N:19](C(C(OC)=O)=C(C)C)[C:18](=[O:28])[C@H:17]1[C@H:29]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH3:30])(=[O:15])=[O:14].[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O.[Mn]([O-])(=O)(=O)=O.[K+].C(OCC)(=O)C.O>[Si:32]([O:31][C@@H:29]([C@H:17]1[C@@H:16]([S:13]([CH3:12])(=[O:15])=[O:14])[NH:19][C:18]1=[O:28])[CH3:30])([C:35]([CH3:36])([CH3:37])[CH3:38])([CH3:34])[CH3:33]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1S(C)(=O)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
Phosphate buffer (pH 7, 680 ml), potassium permanganate (0.98 g, 0.006 mole), sodium periodate (87.3 g, 0.41 mole) and acetone (320 ml) were combined at ambient temperature and then cooled to 0° C. Over 8 minutes unsaturated ester of Example 1 (33.6 g, 0.08 mole) in acetone (320 ml) was added. The reaction was stirred 30 minutes at 0°-5° C. and then allowed to warm to ambient temperature. Over 1 hour reaction time the purple solution had changed to a pink color, and 30 ml of aqueous potassium permanganate (15 g, 0.095 mole in 500 ml water) was added. At 1 hour intervals, two more portions (50 ml and 75 ml) of aqueous potassium permanganate were added. The reaction was complete after 6 hours. Water (500 ml) and ethyl acetate were added, and the phases separated. The aqueous phase was extracted with ethyl acetate (3×250 ml). The combined organic layers were washed with water (2×500 ml), dried with sodium sulfate, and solvent removed under vacuum yielding 22.7 g (92%) of a thick colorless oil. Crystals formed on standing at 0° C.; m.p. 101°-102° C. IR(CHCl3) 3404, 2950, 2930, 2886, 2856, 1793, 1463, 1321, 1145, 1128 cm-1. NMR(250 MHz) 6.53 (bs, 1H), 4.74 (d, J=2.1 Hz, 1H), 4.32 (m, 1H), 3.56 (t, J=2.5 Hz, 1H), 2.96 (s, 3H), 1.26 (d, J=6 Hz, 3H), 0.86 (s, 9H), 0.07 (s, 3H), 0.05 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].Cl>C(O)C.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]([F:13])([F:14])[F:15]
Reactant: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(N)cc1C(F)(F)F

Procedure:
A suspension of 4-methoxy-3-trifluoromethyl-nitrobenzene (2.2 g) and iron powder (1.68 g) in ethanol (35 mL) and water (15 mL) is treated with a solution of concentrated hydrochloric acid (0.42 mL) in ethanol (6 mL) and water (3 mL) and the mixture is heated to reflux for approximately 1 hour. The mixture is then cooled, filtered, and concentrated under reduced pressure. The resulting oil is dissolved in ethyl acetate and extracted three times with 5% aqueous hydrochloric acid. The pooled acidic extracts are then cooled in an ice bath and basified with solid potassium carbonate, then extracted with ethyl acetate. These organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, then passed through a short column of silica gel (ethyl acetate is used as the eluant) to provide the desired compound as an amber oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O:14][CH:15]1[C:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:17](=O)[NH:16]1)(=O)C.C(OCC)(=O)C>[OH-].[Na+].CC(C)=O>[CH2:19]([C:18]1([CH2:21][CH3:22])[C:15](=[O:14])[NH:16][CH:17]1[O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCC1(CC)C(=O)NC1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCC1(CC)C(=O)NC1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.7 %

Procedure:
A solution of 4-nitrophenol (2.37 gm, 17.0 mmol) in 2.5N sodium hydroxide (6.82 mL) was added to a solution of 2-acetoxy-3,3-diethyl-4-oxoazetidine (1.05 gm, 5.7 mmol) in acetone (5 mL). After stirring at room temperature for 2.5 hours, ethyl acetate (100 mL) was added and the solution successively washed with water (3×20 mL) and saturated salt solution (20 mL). The solution was dried over anhydrous sodium sulfate and the solvent removed by rotoevaporated. The product was purified by flash column chromatography on silica gel eluted with 25% ethyl acetate in hexanes and isolated as a beige solid (1.20 gm, 80% yield): 1H-NMR δ (CDCl3) 0.94 (6H, t, J=7 Hz), 1.62-1.92 (4H, m), 5.38 (1H, s), 6.90 (2H, d, J=9 Hz), 7.66 (1H, s), 8.10 (2H, d, J= 9 Hz).
Reaction SMILES: [OH:1][C@H:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].[CH3:15]I>C1COCC1>[CH3:15][O:1][C@H:2]([CH3:12])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9]
Reactant: CI
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](C)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxypropyl]carbamate (0.4 g, 2.28 mmol) in THF (5 mL), sodium hydride (0.06 g, 2.51 mmol) was added at 0° C. The resulting solution was stirred for 30 minutes at that temperature and then methyl iodide (0.14 mL, 2.28 mmol) was added. The reaction was warmed to room temperature slowly and allowed to stir for an additional two hours. The reaction was quenched by adding water and extracted with ethyl acetate. The extract was washed with sodium bicarbonate solution, water and brine. It was dried over magnesium sulfate and concentrated. The desired product was obtained as clear oil (0.31 g) and it did not need any further purification.
Reaction SMILES: [CH:1]1([N:5]2[C:9]3[N:10]=[C:11]([CH:17]4[CH2:19][CH2:18]4)[CH:12]=[C:13]([C:14](O)=[O:15])[C:8]=3[C:7]([CH3:20])=[N:6]2)[CH2:4][CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[CH:1]1([N:5]2[C:9]3[N:10]=[C:11]([CH:17]4[CH2:18][CH2:19]4)[CH:12]=[C:13]([C:14]([NH:21][CH2:22][C:23]4[C:24](=[O:31])[NH:25][C:26]([CH3:30])=[CH:27][C:28]=4[CH3:29])=[O:15])[C:8]=3[C:7]([CH3:20])=[N:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nn(C2CCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2c(C)nn3C2CCC2)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 1-cyclobutyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (164 mg, 0.604 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (129 mg, 0.846 mmol), 1-hydroxy-7-azabenzotriazole (165 mg, 1.209 mmol), EDC (232 mg, 1.209 mmol), N-methylmorpholine (0.266 mL, 2.418 mmol), and DMSO (10 mL). The final product was collected as 0.240 g (98%). LCMS E-S (M+H)=406.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (d, J=6.06 Hz, 4H), 1.85 (dd, J=9.35, 5.05 Hz, 3H), 2.12 (s, 4H), 2.16-2.28 (m, 6H), 2.30-2.44 (m, 7H), 2.63 (d, J=19.96 Hz, 3H), 4.34 (d, J=4.29 Hz, 2H), 5.31 (t, J=8.34 Hz, 1H), 5.87 (s, 1H), 7.01 (s, 1H), 8.59 (br. s., 1H), 11.52 (br. s., 1H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1CCCCC1>N1C=CC=CC=1>[C:1]1(/[CH:7]=[CH:8]/[CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a stirred solution of 2-phenylacetaldehyde (5.0 g, 32.3 mmol) and malonic acid (4.0 g, 38.8 mmol) in pyridine (25.0 mL) was added a catalytic amount of piperidine (0.64 mL, 6.46 mmol) then heated to reflux. After 3 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was slowly added 2N HCl. The white precipitate was filtered off and dried under vacuum to produce the title compound (3.5 g, 55˜80%)
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[NH:18][N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2.[H-].[Na+].I[CH3:25]>CN(C=O)C>[I:1][C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[N:18]([CH3:25])[N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52.6 %

Procedure:
To a solution of 7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (100 mg, 0.26 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in oil, 30 mg, 0.77 mmol) and the reaction stirred at RT. After 5 min, iodomethane (0.06 mL, 0.90 mmol) was added and the reaction stirred at RT for 6 h. The reaction mixture was quenched by addition of water (3 mL) and extracted with EtOAc (×2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 100% EtOAc in cyclohexane) to afford the title compound (55 mg, 55%), LCMS (Method B): RT=3.87 min, [M+H]+=403. 7-iodo-2-methyl-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was also isolated.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].ClC(OCC(C)C)=O.CN1CCOCC1.[Br:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH2:40])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:26]=[CH:27][CH:28]=1>O1CCCC1.N1C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]([NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([NH:40][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CC#CC(=O)O
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CC#CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A solution of 0.50 g of 2-butynoic acid in 10 ml of tetrahydrofuran was cooled in an ice bath. A 0.79 ml portion of isobutyl chloroformate followed by a 0.66 ml portion of N-methyl morpholine were added. After about 1 minute a solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 10 ml of pyridine was added. The reaction was allowed to come to room temperature and stir overnight. The solvents were removed at reduced pressure and the solid was recrystallized from n-butanol to give 1.07 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide: mass spectrum (m/e): 381,383.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:6]([C:11]2(C)CS[C:13](N)=[N:12]2)=NC=C[CH:10]=1.[CH3:22][C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1.ClC1C=C(OC2C=CC=CC=2Cl)C=CN=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].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>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:21]=[CH:20][CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:10]=[CH:13][N:12]=[C:11]([NH:28][C:25]2[S:26][CH:27]=[C:23]([CH3:22])[N:24]=2)[CH:6]=1
Reactant: CC1(c2ncccc2Oc2ccccc2Cl)CSC(N)=N1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Clc1cc(Oc2ccccc2Cl)ccn1
Product: Cc1csc(Nc2cc(Oc3ccccc3Cl)ccn2)n1
Yield: 44 %

Procedure:
Preparation of N-(4-(2-chloro-phenoxypyridin-2-yl)-4-methylthiazol-2-amine: Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.238 g, 2.08 mmol), 2-chloro-4-(2-chlorophenoxy)pyridine (0.500 g, 2.08 mmol), potassium phosphate (0.486 g, 2.29 mmol), Pd2(dba)3 (0.095 g, 0.104 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.060 g, 0.104 mmol) were reacted to provide N-(4-(2-chlorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine (0.293 g, 44% yield). 1H NMR (d6-DMSO) δ 11.00 (bs, 1H), 8.18 (d, 1H), 7.68 (d, 1H), 7.49 (t, 1H), 7.36-7.40 (m, 2H), 6.47-6.53 (m, 3H), 2.20 (s, 3H).
Reaction SMILES: CNC(NC1SC(C2C=CN=CC=2)=C(C)N=1)=O.[CH3:18][C:19]1[N:20]=[C:21]([NH:36][C:37]([N:39]2[CH:43]=CN=C2)=[O:38])[S:22][C:23]=1[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:25]=1.[CH2:44]([C:46]1[O:50][C:49]([CH2:51]CN)=[N:48][CH:47]=1)[CH3:45]>>[CH2:44]([C:46]1[O:50][C:49]([CH2:51][CH2:43][NH:39][C:37]([NH:36][C:21]2[S:22][C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[N:25]=3)=[C:19]([CH3:18])[N:20]=2)=[O:38])=[N:48][CH:47]=1)[CH3:45]
Reactant: CCc1cnc(CCN)o1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccnc(N2CCOCC2)n1
Agent: CNC(=O)Nc1nc(C)c(-c2ccncc2)s1
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccnc(N4CCOCC4)n3)s2)o1

Procedure:
The titled compound is prepared by an analogous procedure to 1-methyl-3-(4-methyl-5-pyridin-4-yl-thiazol-2-yl)-urea (example 18b) by replacing imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) with imidazole-1-carboxylic acid [4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-amide (26a) and by replacing methylamine with 2-(5-ethyl-oxazol-2-yl)-ethylamine. The preparation of 2-(5-ethyl-oxazol-2-yl)-ethylamine is described in example 20d steps 1-4.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25](=[CH:26][C:27]3[CH2:28][N:29]([CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)[C:30](=[O:35])[C:31]=3[CH:32]=2)[N:24]=1.CCN(C(C)C)C(C)C.[C:57](#[N:60])[CH:58]=[CH2:59]>CO>[CH3:8][C:9]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:10]=1[O:11][CH2:12][C@H:13]([OH:42])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:23]1[NH:34][C:33]2[C:25]([N:24]=1)=[CH:26][C:27]1[CH2:28][N:29]([CH:36]3[CH2:37][CH2:38][N:39]([CH2:59][CH2:58][C:57]#[N:60])[CH2:40][CH2:41]3)[C:30](=[O:35])[C:31]=1[CH:32]=2
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: C=CC#N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCC#N)CC2)C4)c(C)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of the TFA salt of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (40 mg, 0.061 mmol) in MeOH (2.4 mL) was added DIEA (600 μL, 3.4 mmol) at 0° C. under N2 resulting a mixture which was stirred under N2 at 0° C. for 20 min and followed by addition of acrylonitrile (197 μL, 3.0 mmol) via a syringe. The reaction mixture was stirred under N2 at 0° C. for 1 h and at the room temperature for 1 h and then evaporated. The residue was subjected to HPLC purification to afford the title compound in TFA salt form. 1H NMR (DMSO-d6) δ 1.99-2.13 (4H), 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.12 (m, 2H), 3.22 (m, 2H), 3.47 (m, 2H), 3.51-3.75 (4H), 4.01 (m, 2H), 4.13 (m, 1H), 4.34 (m, 1H), 4.47 (s, 2H), 6.22 (d, J=7 Hz, 1H), 6.84 (d, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 6.96 (s, 1H), 7.36 (d, J=7 Hz, 1H), 7.59 (br s, 1H), 7.86 (br s, 1H), 11.13 (br s, 1H, NH), 11.23 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 596.5 (MH+).