Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][C:20]=3[F:21])[N:17]([CH3:22])[N:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[CH2:23]([Sn](CCCC)(CCCC)C=C)[CH2:24]CC>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>[F:21][C:20]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH3:22])=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([CH:23]=[CH2:24])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Cn1ncc2cc(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=Cc1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Temperature: 120 °C
Yield: 43.1 %

Procedure:
To a degassed solution of 6-chloro-3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (400 mg, 1.267 mmol), was added Pd(Ph3P)4 (220 mg, 0.190 mmol) and tributyl(vinyl)stannane (422 mg, 1.330 mmol). The reaction mixture was heated to 120° C. for overnight. Then the reaction was quenched with NH4Cl(aq), extracted with DCM, dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)-6-vinylimidazo[1,2-b]pyridazine (168 mg, 43%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, 1H), 7.97 (s, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.54 (d, 1H), 7.50 (s, 1H), 6.84 (dd, 1H), 6.31 (d, 1H), 5.72 (d, 1H), 4.37 (s, 2H), 3.98 (s, 3H). LCMS (method B): [MH]+=308, tR=2.49 min.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[C:24](Cl)(=[O:26])[CH3:25]>C(Cl)Cl.C1COCC1>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH:14]3[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C:24](=[O:26])[CH3:25])[CH2:18][CH2:19]3)[NH:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)NCC1CCC(c2nc(-c3cccc(C(F)(F)F)c3)c[nH]2)CC1
Reaction time: 2 h

Procedure:
C-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazole-2-yl]-cyclohexyl}-methylamine (326 mg, 1.0 mmol, from Example 1C) and TEA (102 mg, 1.0 mmol) were dissolved in CH2Cl2/THF (1:1) and brought to 0° C. with an ice bath. Acetyl chloride (79 mg, 1.0 mmol) was added to the reaction mixture slowly and the ice bath was removed. After 2 hours, the solution was diluted with CH2Cl2, added to a separatory funnel and washed with 10% NaOH (3×). The solution was dried (Na2SO4), concentrated under reduced pressure, and the residue purified using flash chromatography (5%→10% MeOH/CH2Cl2) to give (N-{4-[4-(3-Trifluoromethyl-phenyl)-1H-imidazol-2-yl]-cyclohexylmethyl}-acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]=2[C:6]2[C:14]1=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2[nH]c3c(Cl)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccccc1
Reaction time: 0.5 h
Yield: 68.1 %

Procedure:
8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.2019 g, 0.92 mmol) is added to a slurry of pentane-washed NaH (0.0275 g, 0.68 mmol) in DMF (1 mL) and after stirring 22 min benzyl bromide (0.13 mL, 0.0011 mol) is added. Starting material remained after 30 min, so additional NaH (0.0140 g, 0.35 mmol) and DMF (1 mL) are added and the mixture is allowed to stir overnight. The mixture is then partitioned between aq. sodium bicarbonate and ethyl acetate and the organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from 30% ethyl acetate/hexane and dichloromethane to give 0.1942 g (68%) of the title compound; mp 161-162° C.; MS (ESI+) for C19H16ClNO m/z 310.1 (M+H)+; IR (drift) 1644, 1605, 1538, 1484, 1462, 1447, 1425, 1357, 1188, 1106, 793, 784, 737, 725, 699 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.85, 5.82, 6.95, 7.18, 7.28, 8.28. Anal. Calcd for C19H16ClNO: C, 73.66; H, 5.20; N, 4.52. Found: C, 73.41; H, 5.17; N, 4.57.
Reaction SMILES: F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:13][N:14]([CH3:24])[C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.[Cl-:25].[NH2:26][N+:27]1[CH:31]=[CH:30][N:29]([NH2:32])[C:28]=1[CH2:33][CH3:34].CO>C(Cl)Cl>[Cl-:25].[NH2:26][N:27]1[CH:31]=[CH:30][N+:29]([N:32]=[C:21]([CH3:22])[C:18]2[CH:19]=[CH:20][C:15]([N:14]([CH3:24])[CH3:13])=[CH:16][CH:17]=2)=[C:28]1[CH2:33][CH3:34]
Reactant: CCc1n(N)cc[n+]1N
Reactant: CC(=O)c1ccc(N(C)C)cc1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CO
Product: CCc1n(N)cc[n+]1N=C(C)c1ccc(N(C)C)cc1

Procedure:
380 mg (2 mmol) of triethyloxonium tetrafluoroborate are dissolved in 15 ml of methylene chloride. 326 mg (2 mmol) of p-dimethylaminoacetophenone are added thereto at -15°. After 5 minutes there are added thereto at the same temperature 162 mg (1 mmol) of 1,3-diamino-2-ethyl-imidazolium chloride and the mixture is stirred at -10° for 1 hour and at 0° for 2 hours. After the addition of a small amount of methanol the mixture is evaporated and the residue is placed on a column loaded with 10 g of silica gel. The product is eluted with chloroform/methanol (87:13 parts by weight) and crystallized using ether. The crystallizate is dissolved in 80 ml of water, placed on a column loaded with ion exchanger Amberlite IRA 400 (chloride) and elution is carried out with water. The eluate is evaporated and the residue is crystallized from ethanol/water. There is obtained 3-amino-1-[[p-(dimethylamino)-α-methylbenzylidene]amino]-2 -ethylimidazolium chloride of melting point 223°-225°.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:22]#[C:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)NC(=O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1ccc(C#Cc2ccccc2)cn1
Temperature: 70 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (31 mg, 44.7 μmol, 0.05 equiv.) was dissolved in 2 ml DMF. (230 mg, 894 μmol) 5-Bromo-pyridine-2-carboxylic acid tert-butylamide (Example 1, step 1) and phenylacetylene (183 mg, 196 μl, 1.79 mmol, 2 equiv.) were added at room temperature. Triethylamine (272 mg, 374 μl, 2.68 mmol, 3 equiv.), triphenylphosphine (7 mg, 26.8 μmol, 0.03 equiv.) and copper(I)iodide (5 mg, 26.8 μmol, 0.03 equiv.) were added and the mixture was stirred for 2 hours at 70° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 5-phenylethynyl-pyridine-2-carboxylic acid tert-butylamide (174 mg, 70% yield) was obtained as a light yellow solid, MS: m/e=279.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:19])[CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:24]3[S:20][C:21](=[O:26])[NH:22][C:23]3=[O:25])=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCC(O)c2cccc(Cl)c2)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccc(OCC(O)c3cccc(Cl)c3)cc2)S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
To a stirring solution of 4-[2-(3-chlorophenyl)-2-hydroxyethoxy]benzaldehyde (1.08 g, 3.90 mmol) in absolute EtOH (50 mL) was added 2,4-thiazolidinedione (0.50 g, 4.29 mmol) and piperidine (0.42 mL, 4.3 mmol), and the resulting solution was heated to reflux and then stirred overnight at room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in EtOAc. This solution was washed with aqueous HOAc (pH 5-6), brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and chromatographed eluting with 10-20% EtOAc/DCM. Fractions containing product were combined and evaporated in vacuo to give 1.31 g (89%) of the product as a light yellow solid. MS (ESI+) for C18H14ClNO4S m/z 375.0 (M+H)+. MS (ESI−) for C18H14ClNO4S m/z 374.1 (M−H)−.
Reaction SMILES: Cl[Si:2]([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].C[Si]([C:18]1([Li])[CH:22]=[CH:21][CH:20]=[CH:19]1)(C)C.O>O1CCCC1>[CH3:3][Si:2]([CH2:3][Si:2]([CH:21]1[CH:20]=[CH:19][CH:18]=[CH:22]1)([C:5]1[CH2:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:4])([CH3:5])[CH3:4]
Reactant: C[Si](C)(Cl)C1=Cc2ccccc2C1
Reactant: [Li]C1([Si](C)(C)C)C=CC=C1
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)C[Si](C)(C1=Cc2ccccc2C1)C1C=CC=C1
Temperature: 0 °C
Reaction time: 15 h
Yield: 54.6 %

Procedure:
Chloro-2-indenyldimethylsilane (5.15 g, 0.025 mol.) according to Example 1 was dissolved in 10 ml of tetrahydrofuran. The solution was cooled to 0° C. and a solution of trimethylsilylcyclopentadienyllithium (3.60 g, 0.025 mol.) in 20 ml of tetrahydrofuran was added. Stirring was carried out for 15 hours at 25° C. 50 ml of water were then added, and the organic phase was washed with water again and dried over Na2SO4. After removal of the solvents under an oil pump vacuum, the yellowish oil that remained was purified by means of column chromatography. The solvents were removed to yield 2.12 g (34%) of trimethylsilylcyclopentadienyl-2-indenyl-dimethylsilane in the form of a colorless oil.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1)#[CH:23]>CC#N.CCN(CC)CC.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>[CH3:9][O:8][C:7]1[C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[N:3][CH:4]=[C:5]([O:20][CH3:21])[C:6]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(COc2c(OC)cnc(I)c2OC)cc1
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(COc2c(OC)cnc(C#Cc3cnn(C)c3)c2OC)cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a stirred solution of 2-iodo-3,5-dimethoxy-4-(4-methoxy-benzyloxy)-pyridine (95 mg, 0.237 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (30 mg, 0.283 mmol) in dry MeCN (1.5 ml) and NEt3 (0.5 ml) was added Pd(Ph3P)2Cl2 (12 mg, 7 mol %) and the reaction vessel was evacuated and backfilled with nitrogen three times. Copper (I) iodide (5 mg, 11 mol %) was added and the reaction mixture immediately became dark. Stirring was continued for 0.5 hours then the crude mixture was concentrated directly onto silica-gel under reduced pressure and the solid residue was purified by flash chromatography (silica-gel, eluted sequentially with EtOAc:hexanes, 2:1, 3:1, 1:0) to give the product as a white solid (85 mg, 95%). 1H—NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.86 (d, J=2H), 5.13 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [OH-].[Na+].[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.CCOC(C)=O>O>[F:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:16]2[CH2:17][O:18]2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(OCCF)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: FCCOc1ccc(OCC2CO2)cc1
Temperature: 100 °C
Yield: 48 %

Procedure:
A solution of NaOH (0.35 g) in 10 mL of water was added to a mixture of 4-(2-f luoroethoxy) phenol (1.10 g, 7.1 mmol) and epichlorohydrin (0.80 mL, 10.2 mmol). The mixture was heated at 100° C. for 3 h. After cooling, the mixture is taken up with AcOEt (50 mL). The organic phase was separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (Petroleum ether/AcOEt, 4:1, as eluent) to afford pure compound in 48% yield. 1H NMR (CDCl3): δ 2.60-2.70 (m, 2H), 3.16 (m, 1H), 3.89-4.04 (m, 2H), 4.17-4.28 (m, 1H), 4.50-4.65 (m, 1H), 6.54 -6.60 (m, 2H), 6.84-6.87 (m, 2H).
Reaction SMILES: C1C=CC2N([OH:10])N=NC=2C=1.C(N)C1C=CC=CC=1.[CH2:19]1[CH2:24][CH2:23][CH:22]([N:25]=[C:26]=[N:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:21][CH2:20]1>C(#N)C>[C:26]([NH:25][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:24][CH2:23]1)([NH:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:10]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Solvent: CC#N
Solvent: NCc1ccccc1
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 16 h

Procedure:
Fmoc-arginine(PMC)—OH AA3 (3.83 g, 5.0 mmol) and HOBT (0.76 g, 5.0 mmol) were combined in acetonitrile (100 mL) and benzylamine (0.54 g, 5.0 mmol) was added dropwise at about rt, followed by DCC (2.06 g, 10.0 mmol) and stirred for about 16 h. A solid was filtered and the filtrate was evaporated in vacuo to an oil, which was then dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO3 (2×), brine (2×), then dried (Na2SO4) and evaporated in vacuo to a solid, which was triturated with hexane (2×) to give a solid (impure with dicyclohexylurea). A portion of this solid (1.17 g, 1.25 mmol) was dissolved in acetonitrile (30 mL), diethyl amine (1.5 mL) was added and the reaction was stirred at about rt for about 1 h. The solution was then evaporated in vacuo to a solid, which was triturated with hexane (2×). The solution was then evaporated in vacuo to a solid, which was then combined in ACN (25 mL) with Fmoc-3,4-difluorophenylalanine (0.53 g, 1.25 mmol) and HOBT (0.19 g, 1.25 mmol). DIC (0.32 g, 2.5 mmol) was added and the reaction was stirred at about rt for about 16 h. Fmoc-protected dipeptide was filtered (0.77 g) and stirred in ACN (30 mL) with diethyl amine (1.5 mL) for about 2.5 h. The reaction was evaporated in vacuo to an oil, which was triturated with hexane (3×) to the white solid AA4.
Reaction SMILES: Cl.C[N:3](C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][C:26]#[CH:27])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22](=[O:23])[NH2:3])[CH2:25][C:26]#[CH:27])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCN=C=NCCCN(C)C
Reactant: C#CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 22.1 %

Procedure:
At 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (563 mg, 2.94 mmol) was added to a solution of commercially available (S)-2-(tert-butyoxycarbonylaminopent-4-ynoic acid (e.g. Acros, 626 mg, 2.94 mmol) and 1-hydroxybenzotriazole (397 mg, 2.94 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred at 0° C. for 20 min. A 25% aqueous solution of ammonia (2.38 ml) was added. The reaction mixture was stirred for 16 h, while warming up to room temperature. It was diluted with ethyl acetate (150 ml) and washed with a 10% aqueous solution of sodium hydrogensulphate (150 ml). The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with brine (250 ml) and dried over magnesium sulphate. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with a mixture of brine (75 ml) and water (75 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (50 g), using dichloromethane/methanol (10:1) as eluent, to give 138 mg of ((S)-1-carbamoylbut-3-ynyl)carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2([OH:15])[CH:13]3[CH2:14][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:16]([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>Cl>[CH2:16]([O:22][C:2]1[C:3]([C:8]2([OH:15])[CH:13]3[CH2:14][N:10]([CH2:11][CH2:12]3)[CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCO
Reactant: OC1(c2nccnc2Cl)CN2CCC1C2
Agent: Cl
Product: CCCCCCOc1nccnc1C1(O)CN2CCC1C2
Temperature: 80 °C

Procedure:
A mixture of 4.8 g of (26) (0.021 mol) and 125 ml of hexanol that had reacted with 1.5 g of Na (0.065 mol) was heated to 80° C. for 45 min. The reaction was cooled to ambient, 100 ml of 1N HCl was added, and the hexanol was azeotroped off with water. The residue was made basic with 1N NaOH and extracted 3× with 50 ml of CH2Cl2. The extracts were washed with brine, dried, and the solvent evaporated to give a dark solid. Recrystallization of the solid from ether gave 3.83 g of 3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptan-3-ol (26a) as a floculent yellow solid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.65 (7H, m), 1.85 (2H, m), 2.25-3.07 (6H, m), 3.1 (1H, d), 3.75 (2H, d), 4.45 (2H, t), 8.01 (1H, d), 8.07 (1H, d). A solution of 1.5 g of (26a) (0.0052 mol) in 75 ml of CH2Cl2 was cooled to 0° C. as 1.1 ml of thionyl chloride in 10 ml of CH2Cl2 was added dropwise. The cooling was removed and after 1.5 h the reaction was heated to reflux for 45 min. The reaction was cooled to ambient, water was added, and the reaction made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2 the washed with brine, dried, and the solvent evaporated to give a yellow oil. Radial chromatography eluting with 2.5% ethanol-0.25% NH4OH-CHCl3 gave 1.2 g 3-chloro-3-(3-hexyloxypyrazinyl)-1-azabicyclo[2.2.1]heptane (26b) as a pinkish liquid. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.95 (10H, m), 2.25-3.9 (7H, m), 4.4 (2H, t), 8.0-8.1 (2H, m). A mixture of 1.2 g of (26b) (0.0039 mol) and 0.5 g of 10% Pd on carbon in 50 ml of ethanol was hydrogenated for 1 h at 60 psi H2. The catalyst was removed, the solvent evaporated, the residue suspended in water, and the mixture made basic with saturated aqueous K2CO3. The mixture was extracted 3× with 25 ml of CH2Cl2, the extracts dried, and the solvent evaporated. Tlc shows two major spots, 10% ethanol-1% NH4OH-CHCl3. The less polar of the two component was not well separated. The more polar component was treated with HCl in isopropanol and thoroughly evaporated. The residue was recrystallized from ether to give 0.15 g of (27) as slightly hygroscopic colorless crystals, mp 117°-118° C. NMR ppm (CDCl3) 0.9 (3H, t), 1.25-1.55 (8H, m), 1.85 (3H, m), 3.2-3.75 (6H, m), 4.05 (2H, m), 4.38 (2H, m), 8.05 (1H, d), 8.08 (1H, d). Anal. C16H25N3O-HCl-0.5H2O requires C: 59.89; H: 8.48; N: 13.10%. Found C: 59.83; H: 8.31; N: 12.95%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=C)[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.C[N+]1([O-])CC[O:28]CC1.I([O-])(=O)(=O)=O.[Na+]>CC(C)=O.O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([CH:22]=[O:28])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2ncc(Cc3cc4cnn(C)c4cc3F)n2n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: Cn1ncc2cc(Cc3cnc4ccc(C=O)nn34)c(F)cc21
Temperature: 46 °C
Reaction time: 4 h
Yield: 39.7 %

Procedure:
To a mixture of 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)-6-vinylimidazo[1,2-b]pyridazine (50 mg, 0.163 mmol) osmium(VIII) oxide (103 mg, 8.13 μmol), was added a solution of NMO (29.5 mg, 0.252 mmol) in acetone (2 ml) and H2O (0.16 ml). The reaction mixture was heated to 46° C. After stirring for 4 h, the solvent was removed and a mixture of THF (6 ml) and H2O (1.5 ml) was added to dissolve the residue, then sodium periodate (69.6 mg, 0.325 mmol) was added and the resulting mixture was stirred at 46° C. for 12 h. The reaction mixture was then quenched with Na2SO3(aq), extracted with DCM, dried over Na2SO4, filtered through Celite and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with gradient Hex:EA to give 3-((6-fluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine-6-carbaldehyde (20 mg), yield 38%. 1H-NMR (400 MHz, CDCl3) δ ppm 10.09 (s, 1H), 8.07 (dd, 1H), 7.89 (d, 1H), 7.74 (s, 1H), 7.63 (m, 2H), 7.10 (d, 1H), 4.54 (s, 2H), 4.03 (s, 3H). LCMS (method A): [MH]+=310, tR=3.95 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:5][CH:4]=1.[O:29]=[C:30]1[CH:34]([C:35](O)=[O:36])[CH2:33][CH2:32][NH:31]1.Cl.C(N=C=NCCCN(C)C)C.N1(O)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:35]([CH:34]5[CH2:33][CH2:32][NH:31][C:30]5=[O:29])=[O:36])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10]([CH3:26])=[N:9]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Reactant: O=C(O)C1CCNC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(NC(=O)C5CCNC5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A 100 mL round-bottomed flask was charged with 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (20.0 mg, 0.053 mmol; obtained from Example 5, Step D), 2-oxopyrrolidine-3-carboxylic acid (34.1 mg, 0.26 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (50.7 mg, 0.26 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (35.7 mg, 0.26 mmol), N-ethyl-N-isopropylpropan-2-amine (34.2 mg, 0.26 mmol), and THF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (2 days). Water (10 mL) was added and extracted with CH2Cl2 (3×50 mL). The organic layers were combined, dried over Na2SO4 and concentrated. The residue purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford the desired product (22.3 mg, 86.2%). LRMS (APCI neg) m/e 488 (M−1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][OH:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=1)(=[O:21])=[O:20]
Reactant: OCc1ncc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ncc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
Intermediate 9 (3,5-difluoro-2-pyridinyl)methanol (114 mg, 0.786 mmol) was dissolved in DCM (anh) (6 mL) at 0° C. N,N-diethylethanamine (ALDRICH, 0.131 mL, 0.943 mmol) and methanesulfonyl chloride (ALDRICH, 0.067 mL, 0.864 mmol) were added. Reaction mixture was stirred at 0° C. for 1 h 30 min. Crude of reaction was partitioned between water and DCM, aqueous layer was extracted with DCM (2×10 mL). Organic layers were dried over MgSO4 (anh) and filtered. Solvent was eliminated to yield title compound (3,5-difluoro-2-pyridinyl)methyl methanesulfonate (137 mg, 0.614 mmol, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.58 (d, 1H), 8.06-8.11 (m, 1H), 5.36 (d, 2H), 3.27 (s, 3H). [ES+MS] m/z 224 (MH+).