Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:18]([O:20]C(C)(C)C)=[O:19])[N:7]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2>C(O)(C(F)(F)F)=O.C(Cl)Cl.O>[CH2:11]([O:10][C:8]([N:7]1[CH:4]2[CH2:3][CH2:2][C:1]1([C:18]([OH:20])=[O:19])[CH2:6][CH2:5]2)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)C12CCC(CC1)N2C(=O)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1C2CCC1(C(=O)O)CC2

Procedure:
7-benzyl 1-tert-butyl 7-azabicyclo[2.2.1]heptane-1,7-dicarboxylate (C-34)(synthesized following the procedure reported in J. O. C, 1996, 61, 6313-6325) was stirred in TFA/DCM/H2O (95/5/5, 0.3 M) for 10 minutes. Evaporation of the solvent afforded the titled compound (C-35).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].I[CH3:24].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([CH3:24])[CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC#Cc1ccc(OC(F)(F)F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
[3-(4-Trifluoromethoxy-phenyl)-prop-2-ynyl]-carbamic acid tert-butyl ester (500 mg, 1.6 mmol) was added to an ice cold solution of iodomethane (100 μl, 1.7 mmol) and sodium hydride (73 mg, 1.7 mmol; 55% suspension in mineral oil) in DMF (5 ml). The reaction mixture was stirred for 5 h at ambient temperature, cooled to 0° C. and carefully quenched with saturated aqueous ammonium chloride solution. Ice water/ethyl acetate 1/1 were added, the layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, heptane/AcOEt) to give 258 mg (0.8 mmol, 49%) of the title compound as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>ClCCl>[C:7]1([C:6]2[NH:5][N:4]=[C:3]([C:13]([F:16])([F:15])[F:14])[C:2]=2[NH:1][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1c(C(F)(F)F)n[nH]c1-c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.0 g of 4-amino-5-phenyl-3-trifluoromethyl-1H-pyrazole in 30 mL of dichloromethane was treated with 1.1 mL of pyridine followed by 0.57 mL of benzoyl chloride. The reaction mixture was stirred at RT for 5 hours and then concentrated. The residue was partitioned between ethyl acetate and water. The organic portion was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by MPLC, eluting with 2/3 ethyl acetate/heptane, to give the title compound as a white solid, melting point 229–230° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[N:26]=[C:25]([N:35]2[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N:37]=[C:36]2[CH:44]([F:46])[F:45])[N:24]=1.C(O)(=O)C>C1COCC1.O>[F:46][CH:44]([F:45])[C:36]1[N:35]([C:25]2[N:26]=[C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:28]=[C:23]([NH:1][C:2]3[CH:3]=[N:4][C:5]4[C:10]([CH:11]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:24]=2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cnc3ccccc3c2)nc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 45.7 %

Procedure:
To a solution of 0.323 g (2.24 mmol) of 3-aminoquinoline in THF (5 mL) at 0° C. was added 1.6 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.280 g (0.77 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (4 mL) was added and the resulting mixture was stirred for 1 hr at RT. The resulting mixture was neutralized with acetic acid, diluted with water, and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried, and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1), and then CH2Cl2-EtOAc (1:3) gave a pink powder. Recrystallization from ethanol gave 0.167 g (46% yield) of N-[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-quinolinamine: mp 270-273° C.; 1H NMR (CDCl3) δ 9.08 (br s, 1H), 8.48-8.43 (m, 2H), 8.12 (d, J=8.4 Hz, 1H), 7.93-7.90 (m, 1H), 7.80 (dd, J=8.0, 1.1 Hz, 1H), 7.69 (dt, J=6.9, 1.4 Hz, 1H), 7.61-7.41 (m, 4 H), 7.30 (d, J=5.3 Hz, 1H), 3.97-3.95 (m, 4H), 3.83 (s, 4H); Anal. Calcd. for C24H20F2N8O: C, 60.75; H, 4.3; N, 23.6. Found: C, 60.7; H, 4.2; N, 23.5%.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:39])([F:38])[C:22]([C:24]1[S:28][C:27]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])=[CH:26][CH:25]=1)=[O:23]>>[C:1]1([C:7]2[N:8]=[C:9]([C:12]3([CH2:18][NH:19][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:27]5[S:28][C:24]([C:22](=[O:23])[C:21]([F:20])([F:38])[F:39])=[CH:25][CH:26]=5)[CH:30]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Reactant: NCC1(c2nc(-c3ccccc3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3ccccc3)cs2)CCOCC1)c1cccc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Yield: 15 %

Procedure:
This compound was synthesized from (4-(4-phenylthiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)benzoic acid as described in example 118 step 3 (0.022 g, yield 15%). 1H NMR (400 MHz, DMSO) δ 8.650-8.681 (t, 1H), δ 8.132 (s, 2H), δ 8.071 (s, 1H), δ 7.973-7.991 (d, 1H), δ 7.897-7.915 (d, 1H), 7.826-7.846 (d, 1H), 7.786-7.797 (d, 1H), 7.532-7.571 (t, 1H), 7.320-7.357 (t, 2H), 7.254-7.272 (d, 1H), 3.814-3.843 (d 2H), 3.553-3.568 (d, 2H), 3.282-3.409 (d, 2H), 2.22-2.26 (d, 2H), 1.936-2.006 (m, 2H); MS (ESI+) m/z 555.1 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=O)[O:21]C3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[O:21])=[CH:8][N:9]2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
4-Methyl-piperazine-1-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate M and 4-methyl-piperazine. MS calcd. for C22H24ClN4O2 [(M+H)+] 411.2, obsd. 411.0.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([C:8]#N)=[O:7])=[CH:4][CH:3]=1.[Br-].[Na+].S(=O)(=O)(O)[OH:15].[CH2:19]([OH:21])[CH3:20]>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[O:7])[C:8]([O:21][CH2:19][CH3:20])=[O:15])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CCO
Reactant: N#CC(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(=O)c1ccc(Cl)cc1
Yield: 54 %

Procedure:
4-Chlorobenzoyl cyanide (13.0 g, 0.079 mol) prepared in Example 1a was added to a stirred mixture of sodium bromide (1.0 g, 0.01 mol) and 80% sulphuric acid (10 ml). An exothermic reaction took place with the formation of a solid yellow mass. Ethanol (50 ml) was added and the mixture was heated under reflux to give a yellow solution. On cooling, a colourless precipitate formed. The mixture was diluted with cold water and extracted with isopropyl ether. The organic extract was washed with water, sodium bicarbonate solution and then again with water and dried over sodium sulphate. Evaporation and distillation of the solution gave the product as a yellow oil (8.2 g, 54%)--b.p. 82°-84° C./0.05 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Cl:25])[C:3]=1[O:4][C:5]1[C:6](C(O)=O)=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2.C[C:27]([OH:29])=[O:28].[CH2:30]1COCC1>CCOCC>[CH3:30][O:29][C:27]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([O:4][C:3]1[C:2]([Cl:1])=[CH:21][C:20]([N+:22]([O-:24])=[O:23])=[CH:19][C:18]=1[Cl:25])=[CH:14]2)=[O:28]
Reactant: O=C(O)c1nc2ccccc2cc1Oc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: CC(=O)O
Reactant: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc2ncc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2,6-Dichloro-4-nitro-phenoxy)-quinoline-6 carboxylic acid (94) (443 mg, 0.93 mmol) in dry THF (20 mL) was added CH2N2 in Et2O solution [Prepared from nitrosomethylurea (1.65 g) and 50% KOH (5 mL)]. This mixture was stirred at room temperature for 1 h. AcOH (1 mL) was added to the reaction mixture, which was then concentrated. Sat NaHCO3 was added to the residue, which was extracted twice with AcOEt. Organic layer was washed by brine, dried over anhydrous MgSO4, and concentrated to afford compound 95 (415 mg). 1H NMR (300 MHz, DMSO-d6) δ 3.89 (3H, s), 5.75 (2H, br s), 6.76 (2H, s), 7.73 (1H, d, J=2.9 Hz), 8.09 (2H, s), 8.67 (1H, s), 8.94 (1H, d, J=2.9 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]23O[CH:10]([C:11]4[C:16]2=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=4)[C:9]([C:22]([O:24][CH3:25])=[O:23])=[C:8]3[C:26]([O:28][CH3:29])=[O:27])=[CH:3][CH:2]=1.FB(F)F.C(OCC)C>C(#N)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:22]([O:24][CH3:25])=[O:23])[C:8]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:3][CH:2]=1
Reactant: COC(=O)C1=C(C(=O)OC)C2(c3ccncc3)OC1c1cc(OC)c(OC)cc12
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Yield: 72.9 %

Procedure:
1-(4-Pyridyl)- 2,3-bis(methoxycarbonyl)-6,7-dimethoxy-1,4-epoxy-1,4-dihydronaphthalene (3.0 g) and trifluoroborane.diethyl ether (1.95 g) are added to acetonitrile (100 ml), and the mixture is refluxed for 2 hours. The reaction solution is separated with a mixture of chloroform (300 ml) and aqueous sodium hydrogen carbonate solution (50 ml), and the organic layer is further washed with aqueous sodium hydrogen carbonate solution, dried, and concentrated. The resulting residue is washed with a small amount of diethyl ether to give 1-(4-pyridyl)-2,3-bis(methoxy-carbonyl)-6,7-dimethoxynaphthalene (2.1 g) as crystal.
Reaction SMILES: [N:1]1([C:10]2[S:11][C:12](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.O1CCCC1.[H][H]>[C].[Pd].C(O)C>[N:1]1([C:10]2[S:11][C:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)/C=C/c1sc(-n2cnc3ccccc32)nc1C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CCc1sc(-n2cnc3ccccc32)nc1C(C)C
Yield: 99.4 %

Procedure:
A mixture of ethyl (2E)-3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propenoate (1.50 g), 5% palladium-carbon (1.0 g), tetrahydrofuran (20 mL) and ethanol (20 mL) was stirred at room temperature under an atmospheric pressure of hydrogen for 14 hrs. The catalyst was removed by filtration, and the organic layer was concentrated to give ethyl 3-[2-(1H-benzimidazol-1-yl)-4-isopropyl-5-thiazolyl]propionate (1.50 g, 99%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:19][CH2:18][C@@H:17]([O:20][Si](C(C)C)(C(C)C)C(C)C)[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH:10]1[OH:31].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(OCC)(=O)C.CCCCCC>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[OH:31]
Reactant: CC(C)[Si](O[C@@H]1CCC(c2cccc(F)c2F)C(O)c2cccnc21)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 100 mL round-bottom flask was dissolved (9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (mixture of intermediates 2 and 3, 224.3 mg, 0.501 mmol) in tetrahydrofuran (4 mL) to give a colorless solution. TBAF (0.752 mL, 0.752 mmol) was added, and the mixture was stirred at room temperature for 2 h. LCMS indicated complete conversion of major component while the minor one did not change. Tetrahydrofuran was removed in vacuo and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with Sodium sulfate, and concentrated to give a tan oil. FCC up to 50% ethyl acetate/hexane afforded intermediate 3 unchanged (38 mg, 17%) as a white crystalline solid, and intermediate 4 (95 mg, 65%) as a colorless oil (solidified upon standing). Intermediate 4 was further crystallized and single crystals were obtained. Its relative stereochemistry was proven by x-ray studies.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](Cl)=[O:11].[NH2:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10]([NH:18][C:19]1[CH:31]=[C:30]([CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:11]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
0.061 mL of pyridine and 0.086 mL of 2,6-dichlorobenzoyl chloride were added to 3.0 mL of toluene solution containing 0.15 g of tert-butyl 2-amino-4-phenethylbenzoate at room temperature sequentially, and the resulting mixture was heated to reflux for 8 hours. The reaction mixture was cooled to room temperature and a saturated sodium hydrogen carbonate aqueous solution was added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid, aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-(2,6-dichlorobenzamido)-4-phenethylbenzoate.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.CN(C)C=O.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O>[N+:8]([C:7]1[C:2]([NH:29][CH:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncccc2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 79.3 %

Procedure:
2-Chloro-3-nitro-pyridine (5 g, 33.3 mmol), anhydrous N,N-dimethylformamide (50 mL), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (6.7 g, 33.3 mmol) and anhydrous sodium carbonate (7.1 g, 66.6 mmol) were combined with stirring under nitrogen. The reaction mixture was heated at 90° C. overnight. Then it was poured into water and the resulting yellow solid was filtered off and found to be tert-butyl 4-((3-nitropyridin-2-yl)amino)piperidine-1-carboxylate (8.5 g, 26.4 mmol, 79.4% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:26][N:27]([CH3:39])[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18]([C:33]5[CH:34]=[CH:35][C:30]([C:28]([N:27]([CH3:39])[CH3:26])=[O:29])=[CH:31][CH:32]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#CCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC#N)cc1
Yield: 19.5 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclopropane-carboxamide (40 mg, 0.10 mmol), 4-(dimethylcarbamoyl)phenylboronic acid (29 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in hexanes) to afford 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide (9.1 mg, 20%). ESI-MS m/z calc. 467.2, found 468.5 (M+1)+; retention time 2.96 minutes.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([OH:25])=O)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=[N:38]C=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.N>ClCCl.O1CCOCC1>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=3)[C:23]([NH2:38])=[O:25])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3cccc(C(N)=O)c3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a stirred solution of (S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (76 mg, 0.195 mmol), HOBT (39 mg, 0.289 mmol), Et3N (39 mg, 0.786 mmol) and EDCI (55 mg, 0.289 mmol) in dichloromethane (20 mL) and dioxane (10 mL) was bubbled NH3 gas until saturation and the mixture stirred for 16 h at room temperature. The reaction mixture was filtered then the filtrate concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, MeOH:dichloromethane=1:50) to afford (S)-3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (38 mg, 47%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.93 (s, 1H), 8.47 (s, 1H), 8.14 (d, 1H, J=8.1 Hz), 8.03-7.97 (m, 2H), 7.63-7.58 (m, 2H), 7.44 (t, 1H, J=8.1 Hz), 6.30 (d, 1H, J=7.8 Hz), 6.09 (d, 1H, J=8.1 Hz), 4.32-4.22 (m, 1H), 3.69-3.61 (m, 1H), 3.48-3.42 (m, 1H), 2.17-2.01 (m, 3H), 1.68 (s, 1H), 1.17 (d, 3H, J=6.3 Hz). LC-MS: [M+H]+, 414, tR=1.594 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=4.417 min.
Reaction SMILES: [C:1]1(=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CN.[CH2:12]([N:14](CC)CC)C>ClCCCl>[CH3:12][NH:14][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCCC1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCCl
Product: CNC1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 1,2-dichloroethane (50 ml) were suspended cycloheptanone (2 g), methylamine hydrochloride (3 g) and triethylamine (6.2 ml), and to the suspension was added sodium triacetoxy boron hydride (5.3 g) under ice-cooling. Under nitrogen atmosphere, the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was neutralized with sodium hydroxide. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated to give N-methylcycloheptylamine (1.8 g) as colorless oil.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO[CH:13](OC)[CH2:14]Br.Cl>C(O)C.ClCCl>[CH:1]1([NH:7][C:8]2[S:9][CH:13]=[CH:14][N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CBr)OC
Reactant: NC(=S)NC1CCCCC1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: c1csc(NC2CCCCC2)n1
Yield: 102.6 %

Procedure:
To a suspension of 5 g (0.032 mol) of N-cyclohexyl thiourea in 50 mL of ethanol at rt was added 5.38 g (0.0318 mol) of 1,1-dimethoxy-2-bromoethane. To the reaction mixture was then added 1.25 mL of 12N HCl and the reaction mixture was heated at reflux for 12 h. The reaction mixture was then concentrated to provide an orange-brown oil which was dissolved in 50 mL of dichloromethane. The organic solution was washed twice with 1N NaOH solution (50 mL) and then with H2O. The organic fraction was dried (Na2SO4), filtered and the filtrate was concentrated to give 5.95 g of off-white solid. The residue was purified by chromatography (silica, 0 to 5% EtOAc in cyclohexane) to give the title compound. 1H NMR (CDCl3) δ 6.45 (1H, d), 5.69 (1H, d), 4.20-4.10 (1H, m), 1.99-1.55 (6H, 3 sets of m).