Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[N:8][C:7]=1[NH:13][NH2:14])[C:2](=[CH2:4])[CH3:3].[OH-].[Na+].[H][H]>CO.[Pd]>[CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[N:8][C:7]=1[NH:13][NH2:14])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: C=C(C)CNc1cc(Cl)nnc1NN
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CNc1ccnnc1NN
Reaction time: 4 h

Procedure:
A solution of 4.0 of 4-methallylamino-6-chloro-3-hydrazinopyridazine in 150 ml. of methanol and 50 ml. of 0.5 N sodium hydroxide in methanol are charged into a Paar shaker. To this solution 2.0 g. of 10% palladium on carbon is added. The Paar shaker is charged with hydrogen at room temperature to an initial pressure of 50 psi and shaken. After about 4 hours, the reaction mixture is filtered, the solvent evaporated and the residue extracted with chloroform. The chloroform is evaporated off and the 4-isobutylamino-3-hydrazinopyridazine obtained is dissolved in methanol. Hydrogen chloride gas is bubbled in, and the product, 4-isobutylamino-3-hydrazinopyridazine hydrochloride (m.p. 211°-212°C.) which precipitates, is collected by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].C([Sn](CCCC)(CCCC)[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)CCC.O.Cl>CN(C=O)C.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.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:9]=2)=[O:4]
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Reactant: COC(=O)c1ncc2cc(Br)ccc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2cc(C#Cc3ccccc3)ccc2c1O
Temperature: 120 °C
Yield: 104.3 %

Procedure:
A mixture of 7-bromo-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (500 mg, 1.77 mmol), tributyl(phenylethynyl)tin (0.8 mL, 2.13 mmol), and PdCl2(PPh3)2 (249 mg, 0.35 mmol) in DMF (18 mL) was heated at 120° C. for 2 h under N2 atmosphere. After cooling the mixture to r.t., water and EtOAc were added. 1 M HCl was added with stirring until pH was ˜2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by column chromatography (0-40% EtOAc/hexanes) to give 560 mg of the title compound as a yellow solid. MS: (+) m/z 304.10 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1.[NH3:20].C>>[ClH:1].[NH2:20][CH2:2][C@@H:3]([OH:19])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C:13]2=[O:18])=[CH:8][CH:7]=1
Reactant: N
Reactant: O=C1COCCN1c1ccc(NC[C@@H](O)CCl)cc1
Product: Cl
Product: NC[C@@H](O)CNc1ccc(N2CCOCC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.3 %

Procedure:
30.00 g of 4-[4-((R)-3-chloro-2-hydroxy-propylamino)-phenyl]-morpholin-3-one (MW=284.75; 1 eq.) were added to 634 g of conc. aqueous ammonia (MW=17.03; 88 eq.). The reaction mixture was stirred for 4 h at room temperature. Then 3.0 g of charcoal were added and after 10 min of stirring, the suspension was filtered and the cake was washed with 90 mL of water. Filtrate and wash water were combined and concentrated in vacuo to a mass of 37 g. To the residue were added 107 mL of ethanol. The resulting suspension was stirred for 1 h at ambient temperature and then cooled to 0° C. After stirring for at least 2 h at this temperature, the product was isolated by filtration and the filter cake was washed with 75 mL of ethanol. After drying in vacuo at 30° C., 24.89 g of the crystalline title compound were isolated. Yield=78.3%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33]([OH:35])=O)=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:45]([O:49][C:50](=[O:58])[NH:51][CH:52]1[CH2:56][CH2:55][CH:54]([NH2:57])[CH2:53]1)([CH3:48])([CH3:47])[CH3:46].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=3)[C:16]([C:24]3[N:25]=[C:26]4[C:32]([C:33](=[O:35])[NH:57][CH:54]5[CH2:55][CH2:56][CH:52]([NH:51][C:50]([O:49][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:58])[CH2:53]5)=[CH:31][N:30]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:27]4=[N:28][CH:29]=3)=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3cnc4c(n3)c(C(=O)O)cn4COCC[Si](C)(C)C)c3ccc(F)cc32)CC1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)C1
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: CC(C)(C)OC(=O)NC1CCC(NC(=O)c2cn(COCC[Si](C)(C)C)c3ncc(-c4nn(C5CCN(C(=O)OC(C)(C)C)CC5)c5cc(F)ccc45)nc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
A 10 ml round-bottomed flask was charged with 2-[1-(1-tert-butoxycarbonyl-piperidin-4-yl)-6-fluoro-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (85 mg, 0.14 mmol) and (3-aminocyclopentyl)-carbamic acid tert-butyl ester hydrochloride (50 mg, 0.21 mmol). Then, DMF (1 ml) was added followed by N,N-diisopropylethylamine (0.07 ml, 0.40 mmol) and HATU (59 mg, 0.155 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 12 g silica gel with EtOAc/hexanes (gradient: 0-50% EtOAc) to afford 121 mg (99%) of 4-{3-[7-(3-tert-butoxycarbonylamino-cyclopentylcarbamoyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-6-fluoro-indazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil. The isolated product was determined to be a single diastereomer of unknown relative stereochemistry by NMR analysis.
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH:4]([OH:19])[CH2:5][CH2:6][S:7]2(=[O:18])=[O:17].Cl[C:21]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([Cl:31])=[CH:23][N:22]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:31][C:24]1[C:23]([O:19][CH:4]2[C:3]3[C:8](=[C:9]([CH3:16])[CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:2]=3[CH3:1])[S:7](=[O:17])(=[O:18])[CH2:6][CH2:5]2)=[N:22][CH:21]=[C:26]([C:27]([F:29])([F:28])[F:30])[CH:25]=1
Reactant: COC(=O)c1cc(C)c2c(c1C)C(O)CCS2(=O)=O
Reactant: FC(F)(F)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c2c(c1C)C(Oc1ncc(C(F)(F)F)cc1Cl)CCS2(=O)=O
Reaction time: 3 h

Procedure:
0.48 g (1.7 mmol) of methyl 5,8-dimethyl-4-hydroxy-1,1-dioxo-1,2,3,4-tetrahydro-1λ6-thiochromene-6-carboxylate and 0.4 g (1.9 mmol) of 2,5-dichloro-3-(trifluoromethyl)pyridine were dissolved in 20 ml of tetrahydrofuran and subsequently admixed with 0.21 g (1.9 mmol) of potassium tert-butoxide. The mixture was stirred for 3 h and subsequently concentrated using a rotary evaporator. The residue was taken up in 100 ml of ethyl acetate, washed with sat. NaCl solution (2×20 ml), dried over MgSO4 and concentrated using a rotary evaporator. The residue was purified by chromatography (silica gel, ethyl acetate: heptane=1:3).
Reaction SMILES: ClCCl.[CH:4]1([NH:9][C:10]([C:12]2[CH:53]=[CH:52][C:15]3[N:16]([CH:38]4[CH2:43][CH2:42][CH:41]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:40][CH2:39]4)[C:17]([NH:19][C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26](Br)[CH:27]=5)[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[N:21]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[Si:45]([O:44][CH:41]1[CH2:40][CH2:39][CH:38]([N:16]2[C:15]3[CH:52]=[CH:53][C:12]([C:10]([NH:9][CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8]4)=[O:11])=[CH:13][C:14]=3[N:18]=[C:17]2[NH:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=4[O:55][CH3:54])[CH:27]=3)[N:22]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:36])([CH3:37])[CH3:35])[N:21]=2)[CH2:43][CH2:42]1)([C:48]([CH3:49])([CH3:50])[CH3:51])([CH3:47])[CH3:46]
Reactant: COc1ccccc1B(O)O
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2c(Nc3nn(COCC[Si](C)(C)C)c4ccc(Br)cc34)nc3cc(C(=O)NC4CCCC4)ccc32)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc2c(c1)c(Nc1nc3cc(C(=O)NC4CCCC4)ccc3n1C1CCC(O[Si](C)(C)C(C)(C)C)CC1)nn2COCC[Si](C)(C)C

Procedure:
A mixture of (1,1-Bis(diphenylphosphino)ferrocene)dichloropalladium(II), complexed with dichloromethane (1:1) (1.9 mg, 0.0000023 mol), 50 uL of 0.20 M 2-(5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-3-ylamino)-1-(4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid cyclopentylamide (0.0000116 mol) in dioxane and 92 uL of 0.25 M 2-methoxyphenylboronic acid (3.54 mg, 0.0000233 mol) in dioxane and 29 uL 2.0 M sodium carbonate in water was heated at 120° C. for 4 hours. The reaction mixture was cooled, and 2 mL of H2O was added followed by extraction with 2 mL of methylene chloride 3 times. The combined organic phases were concentrated and purified by flash chromatography with 50% EtOAc/Hexanes to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].N1CCNCC1>C(Cl)Cl.CO>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: O=[N+]([O-])c1ccc2c(Cl)ccnc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: C1CNCCN1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc3cc([N+](=O)[O-])ccc23)CC1

Procedure:
4-Chloro-7-nitroquinoline (Ellis, J.; Gellert, E.; Robson, J. Aust. J. Chem. 1973, 26, 907) (1.8 g, 8.7 mmol) and 1-tert-butoxycarbonylpiperazine (5.0 g, 27 mmol) are reacted according to method A furnishing 0.36 g of the piperazine as brown oil after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH:1]1([N:4]([CH:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][NH:34][C:35]([O:37][CH3:38])=[O:36])[CH:23]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(=O)([O-])O.[Na+]>ClCCl.CO>[CH:1]1([N:4]([C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH:20]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[N:24]([CH2:31][CH2:32][CH2:33][NH:34][C:35](=[O:36])[O:37][CH3:38])[CH:23]=2)[CH3:21])[CH2:3][CH2:2]1
Reactant: COC(=O)NCCCn1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)c2cccnc21
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: COC(=O)NCCCn1cc(C(C)N(C(=O)[C@H]2CNCCO2)C2CC2)c2cccnc21
Reaction time: 1 h
Yield: 53.2 %

Procedure:
To a solution of t-butyl (2R)-2-({cyclopropyl[1-(1-{3-[(methoxycarbonyl)amino]propyl}-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate (116 mg) and 2,6-lutidine (0.077 mL) in dichloromethane (2 mL) was added trimethylsilyltriflate (0.099 mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. Then, thereto were added aqueous sodium hydrogen carbonate solution and methanol (2.0 mL) under ice-cooling, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate→ethyl acetate/methanol=9/1) to give methyl {3-[3-(1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (50 mg) as a colorless oil. Methyl {3-[3-(1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}ethyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (40 mg) was separated by CHIRALPAK IC (eluent: n-hexane/ethanol/diethylamine=50/50/0.1; instrument: Waters 302 (600E system)) into diastereomers to give methyl {3-[3-((1R)-1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}-ethyl-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (18 mg) as a colorless oil and methyl {3-[3-((1S)-1-{cyclopropyl[(2R)-morpholin-2-ylcarbonyl]amino}-ethyl-1H-pyrrolo[2,3-b]pyridin-1-yl]propyl}carbamate (18 mg) as a colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16].C[Si]([N:31]=[C:32]=[S:33])(C)C>C1C=CC=CC=1>[CH2:13]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][CH2:22][CH2:21][CH:20]([C:32](=[S:33])[NH2:31])[C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C[Si](C)(C)N=C=S
Reactant: CCCCc1ccc2c(n1)CCCC2
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CC(C)NC(C)C
Product: CCCCc1ccc2c(n1)C(C(N)=S)CCC2
Yield: 16.1 %

Procedure:
By the method described in Example 11 using di-isopropylamine (4.45 ml 0.03 mol) in benzene (50 ml), n-butyl lithium solution (9% w/v, 13.5 g, 0.03 mol), 2-butyl-5,6,7,8-tetrahydroquinoline (6 g, 0.03 mol) and trimethylsilyl isothiocyanate (4.45 ml 0.033 mol) was obtained 2-butyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (1.2g, 15%) m.p. 54-6° C. (Found: C, 68.0; H, 8.4; N, 11.2. C14H20N2S requires C, 67.8; H, 8.1; N, 11.3%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.BrC1C2N(C(C(NC3C=CN=C(F)C=3)=O)=CN=2)N=C(Cl)C=1.CCN(C(C)C)C(C)C.[CH:52]1([NH2:55])[CH2:54][CH2:53]1.[NH2:56][C@H:57]1[CH2:62][CH2:61][C@H:60]([OH:63])[CH2:59][CH2:58]1>C1COCC1>[CH:52]1([NH:55][C:4]2[C:5]3[N:6]([C:8]([C:11]([NH:13][C:14]4[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=4)=[O:12])=[CH:9][N:10]=3)[N:7]=[C:2]([NH:56][C@H:57]3[CH2:62][CH2:61][C@H:60]([OH:63])[CH2:59][CH2:58]3)[CH:3]=2)[CH2:54][CH2:53]1
Reactant: O=C(Nc1ccnc(F)c1)c1cnc2c(Cl)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: NC1CC1
Agent: O=C(Nc1ccnc(F)c1)c1cnc2c(Br)cc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccnc(F)c1)c1cnc2c(NC3CC3)cc(N[C@H]3CC[C@H](O)CC3)nn12
Temperature: 80 °C

Procedure:
To a ˜1:1 mixture of 6,8-dichloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide (600 mg, 1.84 mmol) and DIEA (0.482 mL, 2.76 mmol) in THF (10.00 mL) was added cyclopropanamine (158 mg, 2.76 mmol), and the reaction was heated at 80° C. in a sealed tube apparatus for 2 hrs. The reaction mixture was concentrated, dissolved in NMP (5 mL), and trans-4-aminocyclohexanol (4238 mg, 36.8 mmol) was added. The reaction mixture was heated at 100° C. for 24 hrs, and purified using preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) with 40% to 100% MeOH (0.1% TFA) in water (0.1% TFA)) to isolate the title compound, 8-(cyclopropylamino)-N-(2-fluoro-4-pyridinyl)-6-((trans-4-hydroxycyclohexyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (179 mg, 0.421 mmol, 22.87% yield), as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.722 (M+H=426.15). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.51 (1H, s), 8.19 (1H, d, J=5.52 Hz), 7.96 (1H, s), 7.60 (1H, s), 7.41-7.57 (2H, m), 6.94 (1H, d, J=7.28 Hz), 5.99 (1H, s), 4.60 (1H, d, J=4.02 Hz), 3.67 (1H, br. s.), 3.47 (1H, br. s.), 2.08 (2H, br. s.), 1.88 (2H, d, J=2.76 Hz), 1.15-1.45 (4H, m), 0.70-0.89 (2H, m), 0.52-0.71 (2H, m).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N:9]([O-])=[O:10].[Na+].Cl.O>C(OCC)C>[OH:10][N:9]=[C:2]([C:3]([CH3:5])=[O:4])[C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC(=O)C(=NO)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a solution of 46.45 g (0.4 mol) of methyl acetoacetate in 200 ml of diethylether, 30.4 g (0.44 mol) of sodium nitrite was added and the mixture was cooled in an ice bath and treated dropwise with 40 ml (0.48 mol) of a concentrated hydrochloric acid. After stirring for 1 hour at room temperature, 200 ml of water was added and the mixture was extracted three times with 200 ml of diethylether. After washing with water and a saturated aqueous sodium chloride followed by drying over with anhydrous magnesium sulfate, the solvent was distilled off to obtain 50.09 g (yield: 86%) of a crude methyl 2-hydroxyiminoacetoacetate as a pale yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[F:25])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: OB(O)c1ccccc1F
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccccc1F
Yield: 33.8 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-fluorophenylboronic acid (available from Combi-Blocks Inc.; 56 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-fluoro-biphenyl-2-carboxylic acid (30 mg, 34%). 1H NMR (400 MHz, DMSO-d6) δ 13.11 (br s, 1H), 8.48 (s, 2H), 8.34 (s, 1H), 8.28 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.3 Hz, 1H), 7.77 (d, J=6.5 Hz, 1H), 7.56 (d, J=6.5 Hz, 1H), 7.39-7.48 (m, 2H), 7.20-7.35 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.[CH3:21][C:22]([CH3:28])=[C:23](B(O)O)[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[CH3:24][C:23]([C:11]1[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1])=[C:22]([CH3:28])[CH3:21]
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Reactant: CC(C)=C(C)B(O)O
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(C(C)=C(C)C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 51 %

Procedure:
To a stirred solution of 66.15D (0.231 g, 0.60 mmol) in DMF (4.00 mL) at 23° C. was added 3-methylbut-2-en-2-ylboronic acid (0.14 g, 1.2 mmol, commercially available from Aldrich), and potassium carbonate (0.25 g, 1.8 mmol). Tetrakis(triphenylphosphine)palladium (0.069 g, 0.060 mmol) was then added to the reaction. The mixture was heated to 90° C. and stirring was continued for 18 hours. The reaction was then cooled to room temperature, diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 69.12A as a colorless oil (0.100 g, 51% yield).
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=2)[CH:16]=1)=[NH:5])C.[NH2:27][NH:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32].C[O-].[Na+]>CO>[CH3:26][O:25][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[CH:16]=[C:15]([C:9]1[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([C:4]4[N:5]=[C:29]([CH2:30][N:31]([CH3:33])[CH3:32])[NH:28][N:27]=4)[CH:7]=3)[NH:11][N:10]=1)[CH:24]=[CH:23]2
Reactant: CN(C)CC(=O)NN
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc4cc(OC)ccc4c3)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(-c3n[nH]c4ccc(-c5n[nH]c(CN(C)C)n5)cc34)ccc2c1
Temperature: 95 °C
Yield: 5.6 %

Procedure:
To a suspension of ethoxy[3-(6-methoxy(2-naphthyl))(1H-indazol-5-yl)]methanimine (0.430 g, 1.13 mmol) in methanol (5 mL) was added N-amino-2-(dimethylamino)acetamide (0.396 g, 3.38 mmol) and 4.3 M sodium methoxide (0.578 mL, 2.49 mmol). The mixture was heated in a sealed tube at 95° C. for 16 h. The solvent was removed using a rotary evaporator and gave a solid residue. Purification of the residue by preparative HPLC (10–80%, acetonitrile/water) gave the title compound (0.025 g, 5% yield): 1H NMR (DMSO-d6) δ 13.95 (br s, 1H), 13.40 (br s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.09 (t, 2H), 8.00 (t, 2H), 7.68 (d, 1H), 7.39 (d, 1H), 7.21 (dd, 1H), 3.90 (s, 3H), 3.60 (s, 2H), 2.22 (s, 6H); ES-MS (m/z) 399 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][C:13]([C:15]([O:17]CC)=O)=[N:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:21][O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25]>CCN(CC)CC>[CH3:27][CH:26]([CH3:28])[CH:24]([NH:25][C:15]([C:13]1[O:14][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:11][N:12]=1)=[O:17])[C:23]([O:22][CH3:21])=[O:29]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: CCOC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)o1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)o1)C(C)C
Temperature: 110 °C
Yield: 15.5 %

Procedure:
An ethanolic solution of Ethyl 5-(4-nitrophenyl)oxazole-2-carboxylate (step D product, 3.4 g) and L-valine methyl ester hydrochloride (5.43 g) previously neutralized with Et3N (4.52 ml), was heated in a sealed tube at 110° C. for 2 days. EtOH was removed under reduced pressure and the crude material was chromatographed on silica gel in 1:9 EtOAc:Pet ether to get cream colored solid which was crystallized in EtOAc/pet ether to yield 700 mg (31%) of the title compound. 1HNMR (DMSO-d6, 300 MHz): δ 9.2 (d, 1H), 8.37 (d, 2H), 8.24 (s, 1H), 8.14 (d, 2H), 4.32 (m, 1H), 3.68 (s, 3H), 2.26 (m, 1H), 0.96 (t, 6H); MS (ES+): m/z 348 (M+1).