Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])OC[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][C:5]=1[Br:17].C[O-].[Na+].Cl.CO.[N+](C1C=CC=C(O)C=1)([O-])=[O:27]>CCCCCCC.C(Cl)Cl>[Br:17][C:5]1[CH:6]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[OH:27]
Reactant: CC(C)(C)c1cc(Br)c(COC(=O)[O-])cc1[N+](=O)[O-]
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1cc(Br)c(O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(2-Bromo-4-tert-butyl-5-nitro-phenyl)methyl carbonate (72.9 g, 219.5 mmol) was charged to a reactor and DCM (291.6 mL) was added. The yellow reaction solution was cooled using an ice bath. Sodium methoxide (67.04 g, 69.11 mL of 5.4 M, 373.2 mmol) was added portion-wise at 2.2-6.9° C. After complete addition, the reaction was slowly warmed to ambient temperature. When complete, the reaction was cooled to 0° C. and quenched with 1M HCl (373.2 mL, 373.2 mmol). The biphasic mixture was stirred for 20 min and transferred to a separatory funnel. The organic layer was separated and washed with water (300 mL) followed by brine (300 ml). The organic layer was concentrated and the crude product dried under high vacuum. The product was further purified using Supercritical Fluid Chromatography (SFC) separation on a Berger MultiGram III (Mettler Toledo AutoChem, Newark Del.). The method conditions were 20% methanol at 250 mL/min on a PPU column (30*150) from Princeton Chromatography, 100 bar, 35 C, 220 nm. An injection of 3.5 mL of a 55-70 mg/mL solution was injected. The data was collected using SFC ProNTo software. The purified product received from SFC purification was a methanol solvate. To remove the methanol, an azeotropic distillation was performed. The dark yellow solid, 2-bromo, 4-tertbuyl, 5-nitro phenol methanol solvate, (111.3 g, 59.9 mmol) was charged to a 1 L round bottom flask, followed by heptane (500 mL). The slurry is heated to 64° C. to obtain a clear solution. The solvent was distilled under reduced pressure (649 mbar) for 30 minutes and then stripped to dryness. This procedure was repeated three times until no MeOH was detected by 1H-NMR. The product was dried under high vacuum for 16 hours to give the product as a dark yellow semi solid. 1H-NMR (400 MHZ, DMSO-d6) δ 11.2 (bs, OH), 7.69 (s, 1H); 7.03 (s, 1H); 1.30 (s, 9H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]2O[C:24]([CH2:27][O:28][CH:29]([CH3:31])[CH3:30])=[N:25][N:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][NH2:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:22]2[N:33]([CH3:32])[C:24]([CH2:27][O:28][CH:29]([CH3:30])[CH3:31])=[N:25][N:26]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN
Reactant: CC(C)OCc1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)o1
Product: CC(C)OCc1nnc(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 25 °C

Procedure:
In a pressure vessel, 4-tert-butyl-N-[4-chloro-2-(5-isopropoxymethyl-[1,3,4]oxadiazol-2-yl)-phenyl]-benzenesulfonamide (71 mg, 0.15 mmol) and methyl amine (40% in H2O, 1.5 mL, 0.6 mmol) were heated at 135° C. for 18 h. The reaction was cooled to room temperature, concentrated in vacuo, and the residue purified by flash column chromatography (0-50% ethyl acetate in hexane) to yield the title compound as a white solid: MS (ES) M+H expected 477.2, found 477.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:10]=2[C:11]([OH:13])=O)=[CH:5][N:4]=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([NH:28][CH2:29][C@@H:30]3[C@H:35]([CH3:36])[CH2:34][CH2:33][CH2:32][NH:31]3)=[N:25][C:24]=2[CH:37]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([NH:28][CH2:29][C@@H:30]3[C@H:35]([CH3:36])[CH2:34][CH2:33][CH2:32][N:31]3[C:11]([C:10]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[N:4][CH:5]=3)=[O:13])=[N:25][C:24]=2[CH:37]=1
Reactant: COc1ncc(-c2ccc(C)cc2C(=O)O)cn1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: COc1ncc(-c2ccc(C)cc2C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)cn1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 2-(2-methoxypyrimidin-5-yl)-5-methylbenzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 506 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH2:21]>>[Cl:18][C:19]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: Nc1cc(O)ccc1Cl
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: Oc1ccc(Cl)c(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (40 mg, 0.154 mmol) and 2-chloro-5-hydroxyaniline (30 mg, 0.231 mmol) similar to Example 185 and was isolated as an off white solid (15 mg, 28%). 1H NMR (DMSO-d6): 9.89 (s, 1H), 9.85 (brs, NH), 8.74 (d, J=5.7, 1H), 8.22 (d, J=7.8 Hz, 1H), 7.97 (ddd, J=1.8, 5.7, 7.8 Hz, 1H), 7.54 (ddd, J=4.5, 6.0, 7.8 Hz, 1H), 7.35 (m, 2H), 7.19 (s, 1H), 6.70 (dd, J=2.7, 5.7 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CCCCBr
Reactant: Sc1nc2ccccc2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCCCSc1nc2ccccc2[nH]1

Procedure:
Part A. A solution of 2-mercapto-1H-benzimidazole (4.75 g, 31.6 mmol), ethyl 5-bromovalerate (5.00 mL, 31.6 mmol), potassium carbonate (5.68 g, 41.1 mmol), and tetra-n-butylammonium iodide (2.33 g, 6.31 mmol) in tetrahydrofuran (200 mL) was heated to reflux for 24 hours. The solution was cooled, and poured into water (200 mL). The layers were separated, and the aqueous layer was extracted with methylene chloride (2×200 mL). All three organic phases were washed over brine, combined, dried over anhydrous magnesium sulfate, filtered and evaporated to afford a pale yellow oil. The oil was purified by elution through a short plug of silica gel (1:1 ethyl acetate-hexane) to afford the product, 2-[4-(carboethoxy)butylthio]-1H-benzimidazole, as a waxy solid, m.p. 88°-90° C. (8.03 g, 28.9 mmol, 91%). 1H NMR (CDCl3): 10.61 (1H, br s); 7.66 (1H, br s); 7.36 (1H, br s); 7.19 (2H, dd, J=5.7, 2.7 Hz); 4.12 (2H, q, J=7.0 Hz); 3.30 (2H, t, J=6.2 Hz); 2.32 (2H, t, J=5.9 Hz); 1.95-1.74 (4H, m); 1.24 (3H, t, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)[S:4][N:3]=1.[CH2:18]([C:20]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C(OCC)(=O)C.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>[Cl:17][C:9]1[CH:8]=[C:7]([C:5]2[S:4][N:3]=[C:2]([C:27]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:24]=[CH:25][CH:26]=3)[CH:22]=[O:23])[N:6]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 120 °C
Yield: 77.6 %

Procedure:
To a solution of 3-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazole (D43) (500 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (390 mg) and tripotassium phosphate (954 mg) in N,N-dimethylformamide (DMF) (3 mL) and water (0.75 mL) stirred under nitrogen was added Pd(Ph3P)4 (173 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was diluted with ethyl acetate (50 mL), the organic phase was washed with water, dried over sodium sulphate and concentrated, the residue was purified by column chromatography to give 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylbenzaldehyde (D53) (450 mg) as an oil. MS (ES): C20H19ClN2O2S requires 386. found 387.1 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]([C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH2:21])=[C:11]([C:15]([O:17]CC)=O)[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:26])[CH3:2].[NH3:27]>C1(C)C=CC=CC=1.CO.C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]3[C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][NH:27][C:15](=[O:17])[C:11]=3[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:26])[CH3:2]
Reactant: N
Reactant: C=C(C(=O)OC)c1c(C(=O)OCC)c(OC)c2n1[C@@H](C)CN(CC)C2=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]cc(C(=O)OC)c32)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl (4S)-2-ethyl-8-(methoxy)-6-[1-(methoxycarbonyl)vinyl]-4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.19 g, 0.54 mmol) in a mixture of toluene (10 mL) and methanol (4 mL) was treated with a saturated solution of ammonia in methanol (10 mL). The mixture was stirred at rt overnight. The product mixture concentrated under vacuum to provide the corresponding cyclization product. Treatment of the above intermediate (0.34 g, 1.01 mmol) and manganese(IV) oxide (0.26 g, 3.04 mmol) in toluene (10 mL) was heated in a sealed tube in an oil bath 80° C. overnight. The reaction mixture was cooled to rt, diluted with chloroform (100 mL) and filtered through a pad of Celite. The filtrate was concentrated under vacuum. The filtrate was subjected to column chromatography on silica gel eluting with ethyl acetate. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]([C@@H:22]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C@H:23]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C@H:24]([OH:34])[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[CH2:11]([O:18][C@H:19]([C@@H:22]([O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C@H:23]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:24](=[O:34])[CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:20]=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)C(=O)COCc1ccccc1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 90 %

Procedure:
To a stirred solution of oxalyl chloride (12.8 mL, 147.7 mmol) in DCM (150 mL) was added drop wise a solution of DMSO (13.1 mL) in DCM (90 mL) over 10 min at −78° C. and then the reaction mixture was stirred at same temperature for 40 min. Then a solution of (2S,3R,4R,5R)-2,3,4,6-tetrakis(benzyloxy)hexane-1,5-diol 2 in DCM (75 mL) was added drop wise to the reaction mixture over a period of 15 min keeping the reaction mixture below −70° C. After stifling the reaction mixture for 2 h at below −70° C., Et3N (62.15 mL, 443 mmol) was added drop wise over a period of 10 min and then the reaction mixture was allowed to warm to −5° C. over a period of 2 h. The reaction mixture was concentrated under reduced keeping the temperature below 25° C. to afford crude (2R,3R,4S)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexanal 3 (18 g, 90%) as sticky yellowish oil which was used for the next step without any purification.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[CH3:10][S:11][C:12]1[CH:25]=[CH:24][C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:26])[CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=1>O1CCCC1>[CH3:10][S:11][C:12]1[CH:25]=[CH:24][C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:26])[CH:20]=3)[C:15]([CH:2]3[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)([OH:27])[C:14]=2[CH:13]=1
Reactant: CN1CCC(Cl)CC1
Reactant: CSc1ccc2sc3cc(F)ccc3c(=O)c2c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(O)(C1CCN(C)CC1)c1ccc(F)cc1S2
Yield: 60.1 %

Procedure:
To a Grignard-solution prepared from 130 grams of 4-chloro-1-methylpiperidine and 24 grams of magnesium turnings in 500 milliliters of dry tetrahydrofuran was added 174 grams of 2-methylthio-6-fluoro-thioxanthene-9-one in portions while stirring and cooling in an ice-salt mixture. The reaction temperature was kept below 10 degrees Centigrade. The cooling bath was then removed and the reaction mixture was stirred at 35-40 degrees Centigrade for 1.5 hours. The reaction mixture was then poured into a mixture of ice, water and ammonium chloride. The crystalline precipitate which was obtained upon cooling was sucked off, washed with water and dissolved in 10% aqueous acetic acid. The solution was treated with charcoal, extracted three times with 100 milliliters of ether and then made alkaline with 10 N sodium hydroxide solution. After cooling the precipitated base was sucked off, washed with water, suspended in 100 milliliters of acetone, filtered, again suspended in 100 milliliters of acetone, and then filtered and dried to yield 142 grams of 2-methylthio-6-fluoro-9-(1-methyl-4-piperidyl)-thioxanthen-9-ol which melted at 180-189 degrees Centigrade. The analytically pure compound melts at 192-195 degrees Centigrade after recrystallization from diethylether.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17](I)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)O1.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>[Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=3)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(I)cn2[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
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: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(cis-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (100 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (70.6 mg), tetrakis(triphenylphosphine)palladium(0) (23.8 mg) and potassium carbonate (56.8 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (22.7 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([I:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([I:12])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(I)c2nc(-c3ccccc3)sc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
A mixture of 7-hydroxy-4-iodo-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (405 mg, 0.95 mmole), benzyl bromide (170 μl, 1.43 mmole), potassium carbonate (329 mg, 2.38 mmole) in dimethylformamide (5 ml) was stirred at room temperature for four hours before it was partitioned between ethyl acetate and water, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (451 mg). MS: (+) m/z 517.04 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=O)[CH2:15][CH2:16][CH3:17])[CH2:9]2)=[CH:5][CH:4]=1.[OH-].[K+].O.NN.[NH4+].[Cl-]>C(O)COCCO>[CH2:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]2[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:9]1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCC(=O)C1CCCN(Cc2ccc(OC)cc2)C1
Agent: NN
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: OCCOCCO
Product: CCCCC1CCCN(Cc2ccc(OC)cc2)C1
Temperature: 120 °C
Reaction time: 24 h
Yield: 88.9 %

Procedure:
Combine 1-[1-(4-Methoxy-benzyl)-piperidin-3-yl]-butan-1-one (356.0 mg, 0.95 mmol), Diethylene glycol (15 mL), KOH (479.0 mg, 8.54 mmol), and Hydrazine-monohydrate (1.8 mL) at room temperature under a Nitrogen atmosphere. Heat the reaction mixture to 120° C. for 2 hours and then 220° C. for 24 hours. Cool reaction to room temperature and then pour the reaction mixture over sat NH4Cl (aq). Extract with Ethyl acetate, wash with brine, and dry over Na2SO4. Concentrate under reduced pressure and flash chromatograph using 3% 1N NH3MeOH in CH2Cl2 to give 220.7 mg (89% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 0.7-0.9 (3H, m), 1.1-1.4 (4H, m), 1.5-1.7 (4H, m), 1.7 (1H, d), 1.9 (1H, t), 2.8 (2H, t), 3.4 (2H, dd), 3.6-3.7 (3H, m), 3.8 (3H, s), 6.8 (2H, d), 7.2 (2H, d); MS m/z 262 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[NH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH:23]([C:26]#[N:27])[CH2:22][CH2:21]1.[F-].[K+]>CS(C)=O>[Cl:17][C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:27][CH2:26][C@H:23]4[CH2:24][CH2:25][C@H:20]([C:19]#[N:18])[CH2:21][CH2:22]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Clc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: N#CC1CCC(CN)CC1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#C[C@H]1CC[C@H](CNc2ccc3ncc(-c4cccc(Cl)c4)n3n2)CC1

Procedure:
A mixture of 6-chloro-3-(3-chlorophenyl)imidazo[1,2-b]pyridazine (50 mg, 0.189 mmol), -4-(aminomethyl)cyclohexanecarbonitrile (111 mg, 0.25 mmol) and KF (47 mg, 0.82 mmol) in DMSO (0.5 mL) was heated at 130° C. overnight. LCMS showed the reaction was almost complete. The mixture was purified by prep. HPLC to give EX. 8-88 (26 mg, 38%) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([CH:14]=O)[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8].C(N)CCC.[N+:21]([CH2:24][CH2:25]C)([O-:23])=[O:22].Cl>C(O)(=O)C.O.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([CH:14]=[C:24]([N+:21]([O-:23])=[O:22])[CH3:25])[CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COc1cc(C=O)ccc1OCC(=O)O
Reactant: CCC[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCN
Product: COc1cc(C=C(C)[N+](=O)[O-])ccc1OCC(=O)O
Reaction time: 0.5 h

Procedure:
(2-Methoxy-4-formylphenoxy)acetic acid (10.5 g, 0.05 mole), butylamine (14.6 g, 0.2 mole) and benzene were united and refluxed in a flask equipped with a Dean-Stark water separator. The mixture was refluxed for 4 hours and then the benzene removed by distillation at reduced pressure. The residue consisted of 2-methoxy-4-(butyliminomethylene)-phenoxy)acetic acid which was treated with nitro-propane (17.8 g, 0.2 mole) and acetic acid (50 ml) and heated to boiling. After standing for 30 minutes the mixture was poured into crushed ice and acidified with hydrochloric acid. The solid that separated was removed by filtration, washed with water, dried and recrystallized first from a mixture of water and isopropyl alcohol (3:1) and then from a mixture of benzene and hexane (4:3) to give product melting at 116°-117° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.CC#N.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>[CH3:15][C:14]1[N:13]=[C:12]([N:16]2[C:20](=[O:21])[NH:19][C:18]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[N:17]2)[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)[CH:7]=1
Reactant: CCC(C)(C)c1nn(-c2ccc(Oc3ccnc(Cl)c3)c(C)n2)c(=O)[nH]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(C)(C)c1nn(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(=O)[nH]1
Temperature: 85 °C
Reaction time: 12 h
Yield: 85.2 %

Procedure:
1-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one (0.15 g, 0.40 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g, 0.52 mmol), and K2CO3 (0.14 g, 1.04 mmol) were suspended in dioxane (1.7 mL) and water (0.33 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.046 g, 0.040 mmol) was added and the reaction mixture was stirred at 85° C. for 12 h. EtOAc (15 mL) was added and the suspension was filtered through a pad of diatomaceous earth. The filter cake was washed with EtOAc (3×5 mL) and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM). Product was isolated as a colorless oil that was dissolved in MeCN/water, frozen to −78° C., and lyophilized to afford 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(tert-pentyl)-1H-1,2,4-triazol-5(4H)-one (0.143 g, 79%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.91 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.86 (d, J=8.7 Hz, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.18 (s, 1H), 6.66 (d, J=5.6 Hz, 1H), 3.84 (s, 3H), 2.33 (s, 3H), 1.61 (q, J=7.6 Hz, 2H), 1.23 (s, 6H), 0.76 (t, J=7.3 Hz, 3H); MS (ESI) m/z: (M+H+).