Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C=O)C>[C:8]1([CH2:7][O:6][C:5]([NH:4][CH2:3][CH2:2][N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:19][CH2:20]2)=[O:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(CCNC(=O)OCc2ccccc2)CC1
Yield: 93.3 %

Procedure:
A mixture of phenylmethyl (2-bromoethyl)carbamate (12.9 g, 50 mmol) (prepared from phenylmethyl (2-bromoethyl)carbamate and phenylmethyl chloridocarbonate according to the method of A. J. Brouwer and R. M. J. Liskamp, European Journal of Organic Chemistry (2005), (3), 487-495), 1,1-dimethylethyl 4-piperidinylcarbamate (10 g, 50 mmol), potassium carbonate (6.9 g, 50 mmol), acetonitrile (100 ml) and DMF (30 ml) was heated at 40° C. for 2.5 days. The solvents were decanted from inorganic residues and evaporated. The residue was partitioned between ethyl acetate and dilute brine. The organic extract was dried (MgSO4) and evaporated affording a white solid (17.6 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][C:16]=1[F:24].[F-].[Cs+]>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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[C:16]([F:24])[CH:17]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Product: COC(=O)c1cc(N)c(F)c(-c2ccc(Cl)c(F)c2)n1
Temperature: 85 °C
Yield: 71 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (3.0 g, 14.66 mmol), (4-chloro-3-fluorophenyl)boronic acid (3.07 g, 17.60 mmol), bis(triphenylphosphine)palladium(II) dichloride (1.029 g, 1.466 mmol), and cesium fluoride (4.45 g, 29.3 mmol) were comined in a flask that was sealed and purged with nitrogen. Dioxane (50 ml) and Water (10.00 ml) were added and the reaction mixture was heated at 85° C. for 18 hrs. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with saturated sodium chlride, dried over magnesium sulfate, filtered, and concentrated onto silica. The product was purified by flash chromatography (SiO2, 0-40% EtOAc:Hex gradient) to provide the title compound (3.11 g, 10.41 mmol, 71.0% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) d 3.85 (s, 3H), 6.72 (s, 2H), 7.49 (d, J=6.3 Hz, 1H), 7.68-7.80 (m, 2H), 7.84 (dd, J=10.8, 1.3 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) d −144.47, −116.07; ESIMS m/z 299 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]([NH2:9])=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[CH:5]=[CH:6][C:7]#[N:9]
Reactant: NC(=O)C=Cc1cccc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC=Cc1cccc(Cl)c1
Yield: 59.4 %

Procedure:
m-Chlorocinnamamide (1.39 g.) was mixed with sodium metabisulphite (0.72 g.) and phosphoryl chloride (3 ml.). The mixture was heated on the steam-bath for 2.5 hr. and the phosphoryl chloride removed under reduced pressure. The residue was washed well with water, leaving slightly impure m-chlorocinnamonitrile (0.744 g., 59.5%). Recrystallisation from aqueous acetone gave m-chlorocinnamonitrile, m.p. 56°-57°, λmax. (EtOH) 226, 270 nm. ε 19000, 22500.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C1COCC1>[Br:1][C:2]1[S:6][C:5]([S:7]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (3.0 g, 11.5 mmol) in THF (22 ml) was added at room temperature triethylamine (1.76 ml, 12.6 mmol), the mixture was cooled (ice-water), and a solution of commercially available 1-methylpiperazine (3.82 ml, 34.4 mmol) in THF (22 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (dichloromethane/methanol) and subsequent crystallization from dichloromethane/hexane to yield the title compound (3.12 g, 84%) as a white solid. MS (ISP) 324.8 [(M+H)+], mp 122° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[CH:8]1([CH2:12][N:13]([CH2:27][CH3:28])[C:14]2[N:19]=[C:18]3[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:17]3=[CH:16][C:15]=2[CH:25]=O)[CH2:11][CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH:8]1([CH2:12][N:13]([C:14]2[N:19]=[C:18]3[N:20]([CH3:24])[N:21]=[C:22]([CH3:23])[C:17]3=[CH:16][C:15]=2[CH2:25][NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[CH2:27][CH3:28])[CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(N)no1
Reactant: CCN(CC1CCC1)c1nc2c(cc1C=O)c(C)nn2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CC1CCC1)c1nc2c(cc1CNc1cc(C)on1)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-Methyl-isoxazol-3-ylamine (0.37 g, 3.8 mmol) was added to a solution of 6-(cyclobutylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.54 g, 1.9 mmol) in anhydrous chloroform (20 mL) and acetic acid (0.2 mL) under nitrogen. After stirring for 15 min at RT, sodium triacetoxyborohydride (1.20 g, 5.7 mmol) was added slowly and this mixture was stirred at RT overnight. After evaporation of chloroform in vacuo, water (30 mL) and ethyl acetate (30 mL) were added to the residue. The organic layer was separated, washed with brine, dried over sodium sulfate, and concentrated to give title compound, which was taken on without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:16])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.[NH:17](C1C=CC(C2C(C)CC(=O)NN=2)=CC=1)N>>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:16])=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1)[NH2:17]
Reactant: Cc1cc(=O)n(C)nc1-c1ccc(N)cc1
Reactant: CC1CC(=O)NN=C1c1ccc(NN)cc1
Product: Cc1cc(=O)n(C)nc1-c1ccc(NN)cc1

Procedure:
The title compound was prepared from 6-(4-aminophenyl)-2,5-dimethyl-2H-pyridazin-3-one similarly as 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one.
Reaction SMILES: [F-].[K+].[F:3][C:4]([Si](C)(C)C)([F:6])[F:5].[CH2:11]([O:18][C@H:19]([CH3:31])[C@@H:20]([CH3:30])[O:21][C:22]1[C:27](I)=[CH:26][N:25]=[C:24]([Cl:29])[N:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Na+]>CN1C(=O)CCC1.C1COCC1.[Cu]I.CCCCCC.C(OCC)(=O)C>[CH2:11]([O:18][C@H:19]([CH3:31])[C@@H:20]([CH3:30])[O:21][C:22]1[C:27]([C:4]([F:6])([F:5])[F:3])=[CH:26][N:25]=[C:24]([Cl:29])[N:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1I
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [Cl-]
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 54 %

Procedure:
3.82 g (20.0 mmol) of copper(I) iodide, 0.97 g (16.7 mmol) of potassium fluoride and 2.47 ml (16.7 mmol) (trifluoromethyl)-trimethylsilane were added, with stirring, to a solution of 4.66 g (11.1 mmol) of 4-((1R,2R)-2-benzyloxy-1-methyl-propoxy)-2-chloro-5-iodo-pyrimidine in 15.8 ml NMP and 15.8 ml THF at room temperature. The mixture was stirred for 5.5 hours at 80° C. After cooling, the mixture was added to dilute sodium chloride solution and was extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was chromatographically (hexane/ethyl acetate 4:1). 2.17 g (6.0 mmol; yield: 54%) of the product was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:32]5[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[N:30][CH:31]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: COc1ccc(B(O)O)cn1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc(OC)nc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methoxy-5-pyridineboronic acid following a procedure analogous to that described for Intermediate 6. LC (method 2): tR=1.19 min; Mass spectrum (ESI+): m/z=466 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1)(=[O:31])[C:28]([CH3:30])=[CH2:29]
Reactant: C=C(C)C(=O)Cl
Reactant: CC(C)=C1C(=O)N(c2ccc(N)cc2)C(=O)/C1=C(\C)c1cc(C)oc1C
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=C(C)C(=O)Nc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(C)oc3C)C2=O)cc1
Reaction time: 4 h
Yield: 40 %

Procedure:
To a solution obtained by dissolving 105 mg of N-(4-aminophenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 1 in 2 ml of chloroform, 5 ml of pyridine was added, followed by dropwise addition of 0.84 ml of methacryloyl chloride in 10 minutes. The reaction was carried out at room temperature for additional 4 hours with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to the removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give yellow crystals of N-(4-methacryloylaminophenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethyliden]-3-isopropylidenesuccinimide in yield of 40.0%.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16]CC4C5C=NN(S(C6C=CC(C)=CC=6)(=O)=O)C=5C=CN=4)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ncc3c(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)nccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1

Procedure:
To a mixture of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-pyrazolo[4,3-c]pyridin-4-yl)methyl)pyrimidine-2,4-diamine (400 mg, 0.80 mmol) in MeOH (5 mL) was added aqueous NaOH (2 N, 5 mL). The mixture was heated at reflux overnight. The reaction mixture was extracted with EtOAc (100 mL×3), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford 30 mg (6.3%) of N241H-pyrazolo[4,3-c]pyridin-4-yl)methyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine as yellow solid. 1H NMR (500 MHz, DMSO-d4) δ 9.44 (brs, 1H), 8.32 (brs, 1H), 8.23 (d, J=6 Hz, 1H), 7.80 (d, J=5 Hz, 1H), 7.40 (d, J=6 Hz, 1H), 6.14-5.99 (m, 2H), 4.87 (d, J=5.5 Hz, 2H), 1.80 (s, 1H), 0.88-0.87 (m, 2H), 0.66 (s, 2H); MS (ESI): m/z=348.1 [M+1]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[CH:12]=[CH:11][C@H:10]([OH:13])[CH2:9]1>C1C=CC=CC=1.[O-2].[O-2].[Mn+4]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:9][C:10](=[O:13])[CH:11]=[CH:12]1
Reactant: O[C@H]1C=C[C@H](OC2CCCCO2)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: O=C1C=C[C@H](OC2CCCCO2)C1
Yield: 67.4 %

Procedure:
Six milligrams of (R)-trans-5-tetrahydropyranyloxycyclopent-1-en-3-ol was dissolved in a solvent mixture of 3 milliliters of petroleum ether and 0.5 milliliter of benzene, and the resulting solution was refluxed after the addition of 10 milligrams of active manganese dioxide. Six hours later, the resulting precipitate was separated by filtration and, after distilling off the organic solvent, purified by thin-layer chromatography (cyclohexane-ethyl acetate = 7:3) to obtain 4 milligrams (67%) of (R)-4-tetrahydropyranyloxycyclopent-2-en-1-one.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=2)[NH:3]1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[CH:17]=[N:16]1.N1CCCCC1>CO>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=4)[CH:22]=2)[CH:17]=[N:16]1
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2
Temperature: 85 °C
Yield: 34.6 %

Procedure:
To a solution of N-(2-oxoindolin-5-yl)acetamide (19 mg, 0.1 mmol) was added 1H-indazole-6-carbaldehyde (16 mg, 0.12 mmol), piperidine (2 uL, 0.011 mmol) and MeOH (2 mL). The reaction was then heated to 85° C. for 30 min. The MeOH was removed in vacuo and the solid triturated with ether to give 11 mg, 34% of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 8.06 (s, 1H), 7.92-7.88 (m, 2H), 7.84 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.35 (d, 1H), 6.88 (d, J=8.3 Hz, 1H), 2.04 (s, 3H); MS ESI 319.1 [M+H]+, calcd for [C18H17N5O3S+H]+ 319.11.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][N:5]([S:7]([CH3:10])(=[O:9])=[O:8])[CH2:4][C@H:3]1[NH:11][C:12]1[C:13]2[N:14]([CH:21]=[C:22]([C:24]3[CH:25]=[N:26][NH:27][CH:28]=3)[CH:23]=2)[N:15]=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19].C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]1([CH3:44])[CH2:43][O:42]1>C(#N)C.CO>[OH:42][C:41]([CH3:44])([CH3:43])[CH2:40][N:26]1[CH:25]=[C:24]([C:22]2[CH:23]=[C:13]3[C:12]([NH:11][C@H:3]4[C@@H:2]([CH3:1])[CH2:6][N:5]([S:7]([CH3:10])(=[O:8])=[O:9])[CH2:4]4)=[C:17]([C:18]([NH2:20])=[O:19])[CH:16]=[N:15][N:14]3[CH:21]=2)[CH:28]=[N:27]1
Reactant: C[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cn[nH]c3)cc12
Reactant: CC1(C)CO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: CO
Product: C[C@H]1CN(S(C)(=O)=O)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(C)(C)O)c3)cc12
Temperature: 60 °C
Yield: 31.9 %

Procedure:
To slurry of 4-((3S,4S)-4-methyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)-6-(1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 211, 40 mg, 0.099 mmol) in acetonitrile (0.3 mL) was added DBU (0.060 mL, 0.397 mmol) and 2,2-dimethyloxirane (25.02 mg, 0.347 mmol) and the resulting mixture was heated at 60° C. for ˜16 h. The mixture was cooled, diluted with MeOH, and was purified via preparative reverse-phase HPLC (method B). Fractions which contained the major product were combined and concentrated to give an aqueous solution which was lyophilized to afford a near white solid. This solid was triturated with 1 mL of aq sat. NaHCO3, sonicated, and the resulting solid was collected, rinsed with water and dried on the filter to afford 15 mg (30%) of the title compound as an off-white solid. HPLC (method B) retention time=2.57 min. LCMS (M+1)=476.2. 1HNMR (400 MHz, METHANOL-d4) δ 8.18 (s, 1H), 7.99 (s, 1H), 7.88 (d, J=1.5 Hz, 1H), 7.85 (s, 1H), 7.10 (d, J=1.5 Hz, 1H), 4.98-4.93 (m, 1H), 4.15 (s, 2H), 3.85 (dd, J=10.8, 4.4 Hz, 1H), 3.75 (dd, J=9.8, 7.8 Hz, 1H), 3.58 (dd, J=10.9, 1.7 Hz, 1H), 3.25 (t, J=10.1 Hz, 1H), 2.88 (s, 3H), 2.86-2.77 (m, 1H), 1.27-1.22 (m, 9H).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:4][CH:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[C:13]([CH3:19])=[CH:12][C:11]=2[CH3:20])[N:6]=1.O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(O)C>[F:21][C:2]1([F:1])[CH2:4][CH:3]1[C:5]1[O:9][N:8]=[C:7]([C:10]2[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:15]=2)[NH2:16])[N:6]=1
Reactant: Cc1cc(C)c([N+](=O)[O-])cc1-c1noc(C2CC2(F)F)n1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-c2noc(C3CC3(F)F)n2)cc1N
Temperature: 78 °C

Procedure:
A stirring mixture of 5-(2,2-difluorocyclopropyl)-3-(2,4-dimethyl-5-nitrophenyl)-1,2,4-oxadiazole (149) (190 mg, 0.644 mmol) and tin (II) chloride dihydrate (581 mg, 2.57 mmol) in ethanol (10 mL) was heated at 78° C. for 2 hours. The reaction was cooled to room temperature and the pH was adjusted to basic with a saturated solution of sodium bicarbonate. The resulting solid was filtered through a plug of celite and washed with excess ethanol. The solvent was partially reduced and the crude product was extracted with ethyl acetate. The organic was washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated and the crude product was purified by silica chromatography. 1H NMR (400 MHz, d6-DMSO) δ 7.21 (s, 1H), 6.93 (s, 1H), 4.96 (s, 2H), 3.70-3.62 (m, 1H), 2.47-2.41 (m, 1H), 2.37-2.28 (m, 1H), 2.35 (s, 3H), 2.08 (s, 3H). MS m/z 266.10 (M+1)+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([CH3:12])[O:10][CH2:9][CH2:8][NH:7]1)=[O:5])C.[OH-].[K+].Cl>CO.O>[CH3:12][CH:11]1[O:10][CH2:9][CH2:8][NH:7][CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1NCCOC1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1OCCNC1C(=O)O
Temperature: 75 °C

Procedure:
To a solution of 2-methyl-morpholine-3-carboxylic acid ethyl ester (Comp. No. 27) (0.180 g, 1.039 mmol) in methanol (4 ml) was added water (2 ml) and potassium hydroxide (0.291 g, 5.195 mmol). The resulting mixture was heated to 75° C. until the color turned to red. The mixture was allowed to cool to room temperature, diluted with water and acidified to pH=1 with aqueous hydrochloric acid (2 M). The solution was washed with a mixture of dichloromethane and isopropanol (3:1) and freeze-dried. The resulting white solid was used in the next step without further purification. LC/MS (method 7): Rt=0.11 min; m/z=146.20 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]#[N:13].CCN(CC)CC.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>CCO>[C:12]([CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:23]([N:22]([CH3:26])[CH3:21])=[O:24])[CH:3]=2)[NH:7][CH:6]=1)#[N:13]
Reactant: CN(C)C(=O)Cl
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)Nc1ccc2[nH]cc(CC#N)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
To a solution of 7.0 g (0.041 mole) of 5-aminoindole-3-acetonitrile and 5.7 ml (0.041 mole) of Et3N in 100 ml of abs EtOH, under N2, was added 3.78 ml of dimethylcarbamyl chloride (0.041 mole). The reaction was stirred at room temperature for 24 hours. The solvent was removed in vacuo to yield a black goo (7.5 g). It was purified by dry column chromatography. Eluting it with ethylacetate first and then with 5% MeOH in EtOAc to give 3.5 g of brown solid. It was charcoaled to remove the color (MeOH as solvent). Removal of solvent gave 1.4 g of white product.
Reaction SMILES: Cl.[F:2][C:3]([F:31])([F:30])[C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1.Br[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)([O-])C.[Na+].O>C1(C)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]>[F:31][C:3]([F:30])([F:2])[C:4]1[CH:5]=[C:6]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1
Reactant: Brc1ccccc1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccc(Cl)c(Cl)c2)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc(CO[C@H]2CCN(c3ccccc3)C[C@H]2c2ccc(Cl)c(Cl)c2)cc(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 17 h
Yield: 55 %

Procedure:
To a solution of the compound (200 mg) obtained in Example 509, bromobenzene (0.054 ml), tris(dibenzylideneacetone)dipalladium(0) (11 mg) and sodium tert-butoxide (94 mg) in toluene (5.0 ml), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl((±)-BINAP) (7.3 mg) was added, and the reaction mixture was stirred at 85° C. for 17 hours under argon atmosphere. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate hexane=1:10→1:4) to obtain the title compound as colorless oil (120 mg, 55%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:15][CH2:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:7]2=[O:16].[BH4-].[Na+]>CO.O>[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]21[CH2:15][CH2:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]2[OH:16]
Reactant: O=C1c2ccccc2CCC12CCCCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1c2ccccc2CCC12CCCCN2
Reaction time: 0.5 h
Yield: 31 %

Procedure:
In 20 ml of methanol was dissolved 0.80 g of 3,4-dihydrospiro[naphthalene-2(1H),2'-piperidin]-1-one. Then, 0.15 g of sodium borohydride was added portionwise. The mixture was stirred for 30 minutes, after which it was diluted with water and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and the solvent was then distilled off. The solid residue was recrystallized from methylene chloride-ether to provide 0.25 g of white crystals.
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Li].BrC1C=CC=CN=1>CCOCC>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]c1ccccn1
Reactant: C(=Nc1ccncc1)c1ccccc1
Agent: Brc1ccccn1
Solvent: CCOCC
Product: c1ccc(C(Nc2ccncc2)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.7 %

Procedure:
4.55 Grams (0.025 mole) of 4-benzylideneaminopyridine in 50 milliliters of dry ether was added dropwise to a stirred solution of 2-pyridyl lithium (prepared from 0.03 mole of butyl lithium and 4.74 grams [0.03 mole] of 2-bromopyridine) in 100 ml. of hexane-ether cooled to -30° C. under nitrogen. A purple precipitate was formed which was stirred for 4 hours while allowing the product to warm up to room temperature. The mixture was poured onto ice and the organic layer was separated and extracted with 2 N hydrochloric acid. The acid extracts were combined with the aqueous layer and the combined aqueous medium was basified with 5 N sodium hydroxide and extracted into dichloromethane. After drying over magnesium sulphate, the solvent was removed to leave a solid which was recrystallized from a mixture of toluene and light petroleum (b.p. 100°-120° C.) to afford 2.27 grams of the title compound as free base, m.p. 114°-115° C. The base was converted to its colourless dihydrobromide salt, m.p. 230° (decomposition), by dissolution in the minimum quantity of 2-propanol and adding a solution of hydrogen bromide in dry ether.