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                            The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
 
                
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| CAS No. : | 54044-79-0 | 
| Formula : | C3H3BrN2S | 
| M.W : | 179.04 | 
| SMILES Code : | BrC1=NN=C(S1)C | 
| MDL No. : | MFCD00518965 | 
| InChI Key : | NSMKWTGDPQHTDH-UHFFFAOYSA-N | 
| Pubchem ID : | 7171904 | 
| GHS Pictogram: |   | 
| Signal Word: | Warning | 
| Hazard Statements: | H302-H315-H319-H335 | 
| Precautionary Statements: | P261-P305+P351+P338 | 
| Num. heavy atoms | 7 | 
| Num. arom. heavy atoms | 5 | 
| Fraction Csp3 | 0.33 | 
| Num. rotatable bonds | 0 | 
| Num. H-bond acceptors | 2.0 | 
| Num. H-bond donors | 0.0 | 
| Molar Refractivity | 32.58 | 
| TPSA ? Topological Polar Surface Area: Calculated from  | 54.02 Ų | 
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from  | 1.68 | 
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by  | 1.75 | 
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from  | 1.61 | 
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from  | 0.41 | 
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by  | 3.02 | 
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.69 | 
| Log S (ESOL):? ESOL: Topological method implemented from  | -2.58 | 
| Solubility | 0.47 mg/ml ; 0.00262 mol/l | 
| Class? Solubility class: Log S scale  | Soluble | 
| Log S (Ali)? Ali: Topological method implemented from  | -2.5 | 
| Solubility | 0.564 mg/ml ; 0.00315 mol/l | 
| Class? Solubility class: Log S scale  | Soluble | 
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by  | -2.16 | 
| Solubility | 1.24 mg/ml ; 0.00693 mol/l | 
| Class? Solubility class: Log S scale  | Soluble | 
| GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High | 
| BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes | 
| P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set)  | No | 
| CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | No | 
| CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No | 
| CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No | 
| CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No | 
| CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No | 
| Log Kp (skin permeation)? Skin permeation: QSPR model implemented from  | -6.15 cm/s | 
| Lipinski? Lipinski (Pfizer) filter: implemented from  | 0.0 | 
| Ghose? Ghose filter: implemented from  | None | 
| Veber? Veber (GSK) filter: implemented from  | 0.0 | 
| Egan? Egan (Pharmacia) filter: implemented from  | 0.0 | 
| Muegge? Muegge (Bayer) filter: implemented from  | 2.0 | 
| Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat  | 0.55 | 
| PAINS? Pan Assay Interference Structures: implemented from  | 0.0 alert | 
| Brenk? Structural Alert: implemented from  | 0.0 alert: heavy_metal | 
| Leadlikeness? Leadlikeness: implemented from  | No; 1 violation:MW<1.0 | 
| Synthetic accessibility? Synthetic accessibility score:  from 1 (very easy) to 10 (very difficult) | 2.84 | 
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With hydrogen bromide; bromine; sodium nitrite; In water; at 0 - 10℃; for 1h; | Into a 250-mL 3-necked round-bottom flask wereplaced 5-methyl-1,3,4-thiadiazol-2-amine (20.0 g, 173.68 mmol, 1.0 equiv) and HBr/H20 (50mL). This was followed by the addition of Br2 (50 mL) dropwise with stirring at 0C. To this was added a solution of NaNO2 (30.4 g, 440.58 mmol, 2.5 equiv) in water (50 mL) dropwise with stirring at 0-10C. The resulting solution was stirred for 1 h at 0C in a water/ice bath. The reaction was then quenched by the addition of Na25203 (sat., 100 mL). The pH value of thesolution was adjusted to 8-9 with sodium hydroxide (4 N). The resulting solution was extracted with DCM (3 x 500 mL) and the organic layers were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title product. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With 2-Picolinic acid; copper(l) iodide; caesium carbonate; In 1,4-dioxane; at 100℃; for 16h; | Into a 1-L 3-necked round-bottom flask were placed the intermediate from Step A (23 g, 128.46 mmol, 1.0 equiv),1,3-diethyl propanedioate (62.0 g, 387.1 mmol, 3.0 equiv), C52CO3 (168 g, 515.34 mmol, 4.0 equiv), Cul (4.9 g, 25.73 mmol, 0.2 equiv), pyridine-2-carboxylic acid (6.36 g, 51.66 mmol, 0.4 equiv) and dioxane (400 mL). The resulting mixture was stirred for 16 h at 100C in an oil bath. The solid was filtered out. The resulting mixture was diluted with EtOAc (1 L), washed with brine (3 x 500 mL), dried over anhydrous sodium sulfate and filtered. The filtrate wasconcentrated in vacuo to dryness. The residue was purified by silica chromatography using EtOAc/petroleum ether (1/20) to give the title product. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]
 [ 1000798-21-9 ]
                                                    
                                                    [ 1000798-21-9 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 44% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 140℃; for 0.25h;Microwave irradiation; | EXAMPLE 301 (METHOD AR); 6.6-Dimethyl-2-r6-(5-methyl-l,3,4-thiadiazol-2-yl)-2.3-dihvdro-4H-l,4-benzoxazin-4- yl]-6J-dihydro[l,31thiazolo[5,4-clpyridin-4(5H)-oneTo a stirred solution of 2-bromo-5-methyl-[l,3,4]thiadiazole (0.0062 g, 0.037 mmol) and Example 292 (0.050 g, 0.11 mmol) in DME (2 mL) and water (0.5 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.013 g, 0.011 mmol) and potassium phosphate (0.023 g, 0.11 mmol). The reaction mixture was heated at 1400C under microwave irradiation for 15 minutes, then concentrated in vacuo. It was purified by preparative etaPLC (Method 6) to give the title compound (0.0068 g, 44%) as an off-white solid. deltaeta (CDCl3) 8.68 (IH, d, J2.1 Hz) 7.65 (IH, dd, J8.5 and 2.1 Hz), 7.04 (IH, d, J 8.5 Hz), 5.51 (IH, s), 4.43-4.38 (2H, m), 4.17-4.12 (2H, m), 2.91 (2H, s), 2.81 (3H, s), 1.41 (6H, s). LCMS (ES+) 414 (M+H)+, RT 2.91 minutes (Method 1). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 12% | With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 10h; | EXAMPLE 90; 5,5-Dimethyl-2- {6-lY5-methyl-l .3.4-thiadiazol-2-vnoxy]-2,3-dihvdro-4H-l A- benzoxazm-4-yl}-5,6-dihydro-L3-benzothiazol-7(4/tau0-one; A mixture of Example 6 (75 mg, 0.23 mmol), 2-bromo-5-methyl-l,3,4-thiadiazole (42 mg, 0.23 mmol) and potassium carbonate (64 mg, 0.46 mmol) in DMF (7 mL) was heated to 15O0C for 1Oh. The solvent was removed in vacuo and the residue was purified by prep HPLC to give the title compound (12 mg, 12%) as an off-white solid. 5H (CDCl3) 1.14 (6H, s), 2.43 (2H, s), 2.67 (3H, s), 2.77 (2H, s), 4.09-4.15 (2H5 m), 4.33-4.40 (2H, m), 6.96-7.06 (2H, m), 8.22-8.24 (IH, m). LCMS (ES+) 429 (M+H)+. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 32% | With potassium carbonate; at 120℃; | A suspension containing <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (Modarai, B., et al. J. Heterocyclic Chem. (1974) 11, 343-5) (100 mg, 0.56 mmol), 4-piperidine ethanol (87 mg, 0.67 mmol) and potassium carbonate (77 mg, 0.56 mmol) was heated overnight at 120 C. The reaction was cooled and the mixture partitioned between water (10 ml) and ethyl acetate (30 ml), then the organic layer was washed with brine, dried (Na2SO4) and concentrated. Chromatography of the residue on silica gel (8 g; eluent 2.5% methanol/DCM) gave 1-(5-methyl-1,3,4-thiadiazol-2-yl)-4-(2-hydroxyethyl)piperidine (41 mg, 32%), 1H nmr; 1.33 (m, 2H), 1.54 (q, 2H), 1.7 (m, 1H), 1.79 (m, 2H), 2.54 (s, 3H), 3.08 (m, 2H), 3.71 (t, 2H), 3.88 (m, 2). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With hydrogen bromide; sodium nitrite; | Step 1 2-Bromo-5-methyl-1,3,4-thiadiazole To a solution of aqueous hydrobromic acid (48%, 40 mL) containing a trace amount of copper powder at -10 C. is added a mixture of 2-amino-5-methyl-1,3,4-thiadiazole (2.88 g) and sodium nitrite (7.76 g) portionwise over 45 mins with vigorous stirring. The resulting mixture is stirred at -10 C. for 1.5 hrs and at ambient temperature for an additional 1.5 hrs and is then cooled in an ice bath, neutralized with aqueous sodium hydroxide (50%), diluted with saturated aqueous sodium hydrogensulfite till the mixture no longer turns potassium iodide-starch test paper blue and filtered to remove insoluble material (rinsing with hot water). The filtrate is extracted with methylene chloride (4*100 mL), and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude produce which is then chromatographed on silica gel (70-230 mesh, 75 g), eluding with ethyl acetate/hexane (50/50). Pooling and concentration of those fractions with an Rf =0.78 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 107-108 C. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

 [ 188974-29-0 ]
                                                    
                                                    [ 188974-29-0 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| In dimethyl sulfoxide; | Step 2 (S)-(-)-N-[[3-[4-[1-(5-Methyl-1,3,4-thiadiazol-2-yl)-3,6-dihydro-2H-pyridin-4-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide A mixture of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 550 mg), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (EXAMPLE 87, Step 1, 323 mg) and potassium hydrogenphosphate (571 mg) in dimethyl sulfoxide (16 mL) is stirred under N2 at 100 C. for 2 hrs, cooled to ambient temperature, diluted with water (20 mL) and extracted with methylene chloride (3*20 mL). The combined organic phase is washed with water (20 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated to give the crude product which is then chromatographed on silica gel (230-400 mesh, 45 g), eluding with a gradient of methanol/methylene chloride (2/98-3/97). Pooling and concentration of those fractions with an Rf =0.44 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 193-195 C. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

 [ 67-66-3 ]
                                                    
                                                    [ 67-66-3 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 1.23 parts (13.2%) | With sodium carbonate; In methanol; ethanol; N,N-dimethyl acetamide; | Example 30 A mixture of 2.4 parts of <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong>, 5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-amine, 1.6 parts of sodium carbonate and 47 parts of N,N-dimethylacetamide was stirred overnight at 120 C. After cooling, the reaction mixture was poured into water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in ethanol. The salt was filtered off and dried, yielding 1.23 parts (13.2%) of 3-(2-ethoxyethyl)-N-[1-[2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]ethyl]-4-piperidinyl]-3H-imidazo[4,5-b]pyridin-2-amine ethanedioate(1:2), hemihydrate; mp. 197.3 C. (compound 129). In a similar manner there is also prepared: | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]
 [ 132995-55-2 ]
                                                    
                                                    [ 132995-55-2 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 1.3 parts (23.8%) | With sodium carbonate; In water; | EXAMPLE 11 A mixture of 2.6 parts of <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong>, 4.0 parts of intermediate 2 and 1.6 parts of sodium carbonate was stirred for 6 hours at 140 C. After cooling, the reaction mixture was taken up in water and dichloromethane. The separated organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CHCl3 /CH3 OH 99:1). The eluent of the desired fractions was evaporated and the residue was crystallized from 2-propanol. The product was filtered off, washed with 2-propanol and 2,2'-oxybispropane and dried at 60 C., yielding 1.3 parts (23.8%) of ethyl 4-[[4-(5-methyl-1,3,4-thiadiazol-2-yl)-2-morpholinyl]methoxy]benzoate; mp. 112.4 C. (compound 15). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 2.5 parts (35.8%) | With sodium carbonate; In methanol; N,N-dimethyl acetamide; | EXAMPLE 35 A mixture of 2.41 parts of <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong>, 5.5 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 1.6 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred and heated overnight at 120 C. The reaction mixture was cooled and poured onto water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.5 parts (35.8%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(5-methyl-1,3,4-thiadiazol-2-yl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 190.6 C. (compound 15). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 80℃; for 12h; | To a stirred and degassed solution of 2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5-ethynyl-3,4 difluorobenzaldehyde (Intermediate 47, 0.35 mmol) in dry acetonitrile (5 mL) was added copper iodide (0.01 mmol), dichoro bis(triphenylphosphine)palladium (0.01 mmol), triethylamine (3.58 mmol), and 2-bromo-5 -methyl- 1, 3, 4-thiadiazole (77 mg, 0.43 mmol), sequentially. The reaction mixture was heated at 80 0C in a sealed tube for 12 hours, cooled to room temperature, filtered through a Celite pad, and concentrated. The residue was purified by flash chromatography over a silica gel column using a gradient of ethyl acetate in petroleum ether to give the title product. The product was taken for next step without further purification. MS (ES) MH+: 378 for Ci8Hi7F2N3O2S. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 150℃; for 0.166667h;Microwave irradiation;Product distribution / selectivity; | In a microwave vial, 2-bromo-5-methyl-1 ,3,4-thiadiazole (0.6 g, 3.26 mmol), [2,4- bis(methyloxy)-5-pyrimidinyl]boronic acid (0.780 g, 4.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.754 g, 0.652 mmol) in 1 ,2-Dimethoxyethane (DME) (12 ml) were stirred until dissolution of reactants, then sodium carbonate 1 M (9.78 ml, 9.78 mmol) was added and the mixture microwaved for 10 min at 15O0C. In another microwave vial, 2-bromo-5-methyl-1 ,3,4-thiadiazole (commercially available from Akos, 0.522 g, 2.84 mmol), [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (0.780 g, 4.36 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.656 g, 0.568 mmol) in 1 ,2- Dimethoxyethane (DME) (12 ml) were stirred until dissolution of reactants, then sodium carbonate 1 M (8.51 ml, 8.51 mmol) was added and the mixture microwaved for 10 min at 15O0C. The two reaction mixtures were combined, water and AcOEt (50 +50 ml.) were added and organic layer separated. Combined organic layers were washed by water (3 x 50 ml_), dried upon sodium sulphate and concentrated under reduced pressure. Residue was purified by flash chromatography (Cy: EtOAc 1 :1 ) to give the title compound (637 mg, 2.272 mmol). 1H NMR (CHLOROFORM-d) delta ppm 9.30 (s, 1 H) 4.18 (s, 3 H) 4.1 1 (s, 3 H) 2.84 (s, 3 H) | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With potassium phosphate; (S,S)-1,2-diaminocyclohexane;copper(l) iodide; In 1,4-dioxane; at 20 - 120℃; | Example 4-18 (Trans)-8-([6-(2-fluorophenyl)-3-pyridazinyl]amino}methyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)-1-oxa-3-azaspiro[4.5]decan-2-one Hydrochloride (Trans)-8-([6-(2-fluorophenyl)-3-pyridazinyl]amino}methyl)-1-oxa-3-azaspiro[4.5]decan-2-one (prepared in a similar fashion to Intermediate 47, 22 mg, 0.062 mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (11.05 mg, 0.062 mmol), potassium phosphate (65.5 mg, 0.309 mmol), copper(I) iodide (11.76 mg, 0.062 mmol) and trans-1,2-diaminocyclohexane (7.42 mul, 0.062 mmol) in 1,4-dioxane (2 ml) were stirred in a closed vial at 120 C. for 5 hours then further <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (11.05 mg, 0.062 mmol) was added and the mixture was stirred at 120 C. for 3 hours, left standing at r.t. overnight and stirred again at 120 C. for 3 hours. The mixture was dried (vacuo) then the solid was taken up with DCM and filtered over a filter tube. The organic phase was dried (vacuo) to afford a crude that was purified by KP-NH chromatography (Biotage SP1 12+M) eluding in gradient with 0%-100% EtOAccyclohexane to afford a white solid (8.3 mg). UPLC-MS: 0.55 min, 455 [M+H]+ | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 28.8% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 100℃; for 2.25h;Inert atmosphere; | Example 681 -Methylethyl [(2S,4 ?)-1 -acetyl-2-methyl-6-(5-methyl-1 ,3,4-thiadiazol-2-yl)-1 ,2,3,4- tetrahydro-4-quinolinyl]carbamateA flask was charged with 1 -methylethyl [(2S,4R)-1 -acetyl-2-methyl-6-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (223 mg, 0.536 mmol), potassium carbonate (222 mg, 1.607 mmol), tetrakis(triphenylphosphine)palladium(0) (61 .9 mg, 0.054 mmol) and 2-bromo-5-methyl- 1 ,3,4-thiadiazole (125 mg, 0.696 mmol) then filled with ethanol (3 mL) and toluene (3 ml_). The resulting mixture was degassed for 15 min under house vacuum (with several quenches with nitrogen) then stirred at 100C for 2 h before being cooled to room temperature and left stand still for 16 h. The insoluble material was filtered off and rinsed with AcOEt. Most of the solvent was removed in vacuo and the residue was dissolved in AcOEt. The organic phase was washed with brine, dried over MgS04 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 25 to 100% AcOEt in hexanes) gave a material which was then further purified by MDAP (modifier: ammonium bicarbonate) to give 1 -methylethyl [(2S,4R)-1 -acetyl-2-methyl-6-(5- methyl-1 ,3,4-thiadiazol-2-yl)-1 ,2,3,4-tetrahydro-4-quinolinyl]carbamate (60 mg, 0.154 mmol, 28.8 % yield) as a white foam.LCMS (method A): Retention time 0.89 min, [M+H]+ = 389.06. | 
| 28.8% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 20 - 100℃; for 18h;Inert atmosphere; | A flask was charged with 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 52) (223 mg, 0.536 mmol), potassium carbonate (222 mg, 1.607 mmol), tetrakis(triphenylphosphine)palladium(0) (61.9 mg, 0.054 mmol) and <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (125 mg, 0.696 mmol) then filled with ethanol (3 mL) and toluene (3 mL). The resulting mixture was degassed for 15 min under house vacuum (with several quenches with nitrogen) then stirred at 100 C. for 2 h before being cooled to room temperature and left stand still for 16 h. The insoluble material was filtered off and rinsed with AcOEt. Most of the solvent was removed in vacuo and the residue was dissolved in AcOEt. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 25 to 100% AcOEt in hexanes) gave a material which was then further purified by MDAP (modifier: ammonium bicarbonate) to give 1-methylethyl [(2S,4R)-1-acetyl-2-methyl-6-(5-methyl-1,3,4-thiadiazol-2-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (60 mg, 0.154 mmol, 28.8% yield) as a white foam.LCMS (method A): Retention time 0.89 min, [M+H]+=389.06. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 58% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 20 - 100℃; | To a solution of 2-bromo-5-methyl- l,3,4-thiadiazole (150 mg, 0.84 mmol) in 1,2- dimethoxyethane (5 mL) are added 2-formylphenylboronic acid (190 mg, 1.26 mmol), Pd(PPh3)4 (97 mg, 0.08 mmol) and Na2C03 (sat., 0.10 mL) at room temperature. The solution is heated to 100 C for 18 hours then cooled and poured into water and EtOAc. Layers are separated and the aqueous phase extracted with EtOAc (lx 10 mL). The combined organics are dried (MgS04), filtered and concentrated to give the crude product which is purified via flash chromatography (12g silica gel, 5-60% EtOAc/hexanes). The product-containing fractions are combined and concentrated to give 2-(5-methyl- 1,3,4- thiadiazol-2-yl)-benzaldehyde (100 mg, 58%) which is used without further purification. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

 [ 1329669-50-2 ]
                                                    
                                                    [ 1329669-50-2 ]| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 28% | With N-ethyl-N,N-diisopropylamine; sodium t-butanolate;palladium diacetate; CyJohnPhos; In 1,4-dioxane; at 200℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Example 24[1-(5-Methyl-[1,3,4]thiadiazol-2-yl)-piperidin-4-yl]-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine; Palladium (II) acetate (3.6 mg, 0.016 mmol) and 2-(dicyclohexylphosphino)biphenyl (11.6 mg, 0.032 mmol) were stirred under nitrogen at room temperature in dioxane (1.8 mL) for 10 minutes. Sodium tert-butylat (29 mg, 0.3 mmol), (4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-piperidin-4-yl-amine dihydrochloride (77.3 mg, 0.2 mmol), N,N-diisopropylethylamine (69 L, 0.4 mmol) and <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (40.2 mg; 0.22 mmol) were added and the reaction was heated to 200 C. for 30 minutes in a microwave oven. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc as eluent. The title compound was obtained as a yellow solid (23 mg, 28%).MS ISP (m/e): 412.2 (100) [(M+H)+].1H NMR (DMSO-D6, 300 MHz): (ppm)=7.33 (d, 1H), 7.26 (d, 2H), 7.16 (t, 1H), 7.06 (d, 2H), 3.89 (m, 1H), 3.67 (m, 2H), 3.52 (m, 1H), 3.17 (m, 2H), 2.59 (m, 1H), 2.04 (m, 1H), 1.92 (m, 3H), 1.68 (m, 3H), 1.46 (m, 2H). | 
| 28% | With sodium t-butanolate;palladium diacetate; CyJohnPhos; In 1,4-dioxane; at 200℃; for 0.5h;Microwave irradiation; Inert atmosphere; | Palladium (II) acetate (3.6 mg, 0.016 mmol) and 2-(dicyclohexylphosphino)biphenyl (11.6 mg, 0.032 mmol) were stirred under nitrogen at room temperature in dioxane (1.8 mL) for 10 minutes. Sodium tert-butylat (29 mg, 0.3 mmol), (4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)- piperidin-4-yl- amine dihydrochloride (77.3 mg, 0.2 mmol), N,N-diisopropylethylamine (69 L, 0.4 mmol) and 2-bromo-5-methyl-l,3,4-thiadiazole (40.2 mg; 0.22 mmol) were added and the reaction was heated to 200 C for 30 minutes in a microwave oven. The reaction was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using EtOAc as eluent. The title compound was obtained as a yellow solid (23 mg, 28%).MS ISP (m/e): 412.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): (ppm) = 7.33 (d, 1H), 7.26 (d, 2H), 7.16 (t, 1H), 7.06 (d, 2H), 3.89 (m, 1H), 3.67 (m, 2H), 3.52 (m, 1H), 3.17 (m, 2H), 2.59 (m, 1H), 2.04 (m, 1H), 1.92 (m, 3H), 1.68 (m, 3H), 1.46 (m, 2H). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 85% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 55 - 80℃; for 18h;Inert atmosphere; | A mixture of 2-bromo-5-methyl-l,3,4-thiadiazole A2-1 (13.1 g, 73.3 mmol), (4-formylphenyl)boronic acid Al (10.0 g, 66.7 mmol), 2M K3PO4 (66.7 mL, 133.4 mmol) in toluene (150 mL) and ethanol (38 mL) was heated to 55 C under nitrogen then degassed by alternately putting under vacuum and nitrogen three times for several minutes each. Tetrakis(triphenylphosphine)palladium (1.54 g, 1.33 mmol) was added, and then the mixture was degassed again. After heating for 18 hours at 80 C and cooling to room temperature, the aqueous layer was separated. The mixture was washed with brine and the remaining organic layer was reduced in volume by distillation. Addition of heptane provided a solid which was collected by filtration to give 4-(5-methyl-l,3,4-thiadiazol-2-yl)benzaldehyde Bl-1 as a solid in 85% yield. | 
| 85% | A mixture of 2-bromo-5-methyl-l,3,4-thiadiazole A2-1 (13.1 g, 73.3 mmol), (4-formylphenyl)boronic acid Al (10.0 g, 66.7 mmol), 2M K3PO4 (66.7 mL, 133.4 mmol) in toluene (150 mL) and ethanol (38 mL) was heated to 55 C under nitrogen then degassed by alternately putting under vacuum and nitrogen three times for several minutes each. Tetrakis(triphenylphosphine)palladium (1.54 g, 1.33 mmol) was added, and then the mixture was degassed again. After heating for 18 hours at 80 C and cooling to room temperature, the aqueous layer was separated. The mixture was washed with brine and the remaining organic layer was reduced in volume by distillation. Addition of heptane provided a solid which was collected by filtration to give 4-(5-methyl-l,3,4-thiadiazol-2-yl)benzaldehyde Bl-1 as a solid in 85% yield. | |
| 85% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 55 - 80℃; for 18h;Inert atmosphere; | A mixture of <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> A2-1 (13.1 g, 73.3 mmol), (4-formylphenyl)boronic acid Al (10.0 g, 66.7 mmol), 2M K3P04 (66.7 mL, 133.4 mmol) in toluene (150 mL) and ethanol (38 mL) was heated to 55 C under nitrogen then degassed by alternately putting under vacuum and nitrogen three times for several minutes each. Tetrakis(triphenylphosphine)palladium (1.54 g, 1.33 mmol) wasadded, and then the mixture was degas sed again. After heating for 18 hours at 80 Ccooling to room temperature, the aqueous layer was separated. The mixture was washed with brine and the remaining organic layer was reduced in volume by distillation. Addition of heptane provided a solid which was collected by filtration to give 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde B1-1 as a solid in 85% yield. | 
| 51% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water;Inert atmosphere; Reflux; | Example 34 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone To a solution of <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (2.0 g, 11.17 mmol) in dioxane (40 ml) was added 4-formylbenzeneboronic acid (3.35 g, 22.34 mmol) and 2M Na2CO3 (23 ml). This mixture was degassed with a stream of argon for 2 min. Tetrakis(triphenylphosphine)palladium (0.636 g, 0.55 mmol) was added and this mixture was heated at reflux overnight under argon. After cooling to room temperature, H2O (30 ml) and EtOAc (50 ml) were added and stirred for 5 min. The organic layer was separated and washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (10 to 20% EtOAc/hexanes) gave 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde as a pale yellow liquid (1.16 g, 51% yield). | 

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 58% | With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; | To a solution of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole(Compound IB, 600 mg, 1.916 mmol) and 2-bromo-5-methyl-l,3,4-thiadiazole (480 mg, 2.68 mmol) in DMF (15 mL) was added potassium carbonate (794 mg, 5.75 mmol). The reaction mixture was stirred at 110 C overnight. The reaction mixture was cooled to rt, diluted with water (20 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were dried (Na2S04), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 100% EtOAc) to afford 6-bromo-2-(l-(5-methyl-l,3,4-thiadiazol-2-yl)piperidin- 4-yloxy)benzo[d]thiazole (455 mg, 1.106 mmol, 58% yield) as a yellow solid. lH NMR (500 MHz, chloroform-d) delta ppm 7.78 (1H, d, J=1.9 Hz), 7.50 - 7.56 (1H, m), 7.45 - 7.50 (1H, m), 5.40 - 5.52 (1H, m), 3.77 - 3.88 (2H, m), 3.54 - 3.66 (2H, m), 2.61 (3H, s), 2.19 - 2.29 (2H, m), 2.07 - 2.17 (2H, m). LCMS (m/z) =412 (M+H)+. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]
 [ 87-69-4 ]
                                                    
                                                    [ 87-69-4 ]
 [ 1360440-16-9 ]
                                                    
                                                    [ 1360440-16-9 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 11% | Example 25 Preparation of 2-(5-(4-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-5-methyl-1,3,4-thiadiazole, L-tartrate Salt A mixture of 5-(4-chlorophenyl)-2,5-ethano-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-2-benzoazepine (80 mg, 0.19 mmol) from Step B of Example 14, <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (35 mg, 0.19 mmol) and potassium carbonate (81 mg, 0.58 mmol), in N,N-dimethylformamide (2 mL), was degassed with argon. Next, tetrakis(triphenylphosphine)palladium(0) (33 mg, 0.028 mmol) was added, the mixture was degassed again and heated to 100 C. After stirring for 17 h, the reaction mixture was cooled to ambient temperature, diluted with ethyl acetate (25 mL), washed with water (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (90:9:1 methylene chloride/methanol/ammonium hydroxide). To the obtained material (6.3 mg, 0.016 mmol) in acetonitrile (1.5 mL) was added L-tartaric acid (2.5 mg, 0.016 mmol) in water (6 mL). The resultant solution was lyophilized to give 24544-chlorophenyl)-2,5-ethano-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-yl)-5-methyl-1,3,4-thiadiazole, L-tartrate salt (11 mg, 11%, AUC HPLC 98.7%) as a white solid: 1H NMR (CD3OD, 500 MHz) delta 7.90 (s, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.47 (d, J=9.0 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 6.53 (d, J=8.5 Hz, 1H), 4.90 (s, 2H), 4.43 (s, 2H), 3.65-3.61 (m, 2H), 3.46-3.39 (m, 2H), 2.83-2.78 (m, 5H), 2.48-2.43 (m, 2H); ESI MS m/z 382 [M+H]+. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With potassium phosphate;1,1'-bis(di-tertbutylphosphino)ferrocene; palladium diacetate; In ISOPROPYLAMIDE; at 95℃; for 1.41667h;Inert atmosphere; sealed tube; | A stirred mixture of impure 4-(2-fluoro-2-methylcyclopentylamino)-6- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[l,2-b]pyridazine-3-carboxamide (13 mg, from Step 1), 2-bromo-5-methyl-l,3,4-thiadiazole (6.94 mg, 0.039 mmol), potassium phosphate (35.9 mg, 0.169 mmol), palladium(II) acetate (2.53 mg, 0.01 1 mmol), l, l'-bis(di-tert-butylphosphino)ferrocene (5.41 mg, 0.011 mmol) and ,N- dimethylformamide (0.5 mL) was pumped under vacuum and backfilled with nitrogen twice. The reaction vial was sealed and heated to 90 C for 45 min.Additional 2-bromo-5-methyl-l,3,4-thiadiazole (7 mg) was added. Heating continued for another 40 min. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge CI 8, 19 x 10 mm, 5-muiotaeta particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (1.5 mg). XH NMR (500 MHz, 1 : 1 mixture of methanol- | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 96% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 18h;Inert atmosphere; | General procedure: To an oven-dried round-bottom flask containing tert-butyl 2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 3 (1.0 mmol) was added bis(pinacolato)diboron (1.1 mmol), potassium acetate (4.0 mmol) and 10 mL of anhydrous 1,4-dioxane. The resulting mixture was purged with N2 for three times. Pd(dppf)Cl2 (0.05 mmol) was added, the reaction mixture was purged with N2 again three times and heated under N2 at 110 C for 46 h. The course of the reaction was followed by TLC (5% MeOH in CH2Cl2) and LCMS. The reaction mixture was cooled to room temperature, and the aryl halide 5 (1.1 mmol)], Pd(dppf)Cl2 (0.05 mmol) and 3.5 mL of 2M aqueous solution of potassium carbonate (de-oxygenated by bubbling through N2 for 15 minutes before addition) were added. The reaction mixture was purged with N2 three times and then heated under N2 for 618 h at 110 C. The course of the reaction was followed by LCMS. The reaction mixture was cooled to room temperature, and the solvent removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and 1N NaOH solution (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4 and the solvent was removed under reduced pressure to afford the crude product as a dark brown oil. The crude product was purified by silica gel chromatography, eluting with 010% MeOH in CH2Cl2 to afford the desired product. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; at 150℃; for 0.0833333h;Inert atmosphere; Microwave irradiation; | A solution of intermediate (76) (0.45 g, 1.34 mmol) and 2-bromo-5-methyl-l,3,4- thiadiazole (0.288 g, 1.61 mmol) in K2C03 (2 M, 1.34 mL, 2.69 mmol) and ethylene glycol dimethyl ether (5ml) was stirred and degassed with N2 for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.155 g, 0.134 mmol) was added and the reaction mixture was heated at 150C using a single mode microwave (Biotage Initiator EXP 60) with a power output ranging from 0 to 400W for 5 minutes. Water and EtOAc were added, the organic layer was separated, washed with brine, dried (MgS04) and evaporated till dryness. The obtained residue was purified by flash chromatography over silica gel (cartridge 30 g, 15-40muiotaeta, DCM to DCM/MeOH/NH4OH : 98/2/0.1) The pure fractions were collected and evaporated to dryness, yielding intermediate (77). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 21% | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 24h;Inert atmosphere; | [000101] To a stirring solution of 2-bromo-5-methyl-l, 3, 4-thiadiazole 57 (2.7 g, 15.08 mmol) in CC (50 mL) under inert atmosphere were added N-bromosuccinimide (2.68 g, 15.08 mmol) and AlphaIotaBetaNu (247 mg, 1.50 mmol) at RT; heated to 80 C and stirred for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered. The filtrate was concentrated in vacuo to obtain the crude. The residue was diluted with water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to the crude. The crude was purified through silica gel flash column chromatography using 5-7% EtOAc/ hexanes to afford compound 58 (800 mg, 21%) as an off-white solid. TLC: 10% EtOAc/ hexanes (Rf. 0.8); NMR (400 MHz, DMSO-rfs): delta 5.14 (s, 2H) | 
| 0.150 g | With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃; for 3h; | Step 1 Preparation of 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole To a solution of <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (0.50 g, 2.79 mmol) in CCl4 (8 mL) is added N-bromosuccinamide (0.543 g, 3.067 mmol) and azobis-isobutyronitrile (0.022 g, 0.139 mmol) and reaction mixture is heated to 70 C. for 3 hours. Reaction mixture is cooled to 0 C. and the solvent evaporated in vacuo to give the crude material, which is purified by column chromatography eluting in 5% ethylacetate in hexane to afford give the title compound (0.150 g): 1H-NMR (400 MHz, CDCl3) delta 4.75 (s, 2H). LC-MS (m/z): [M+H]=260.8. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 44% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 80 - 100℃; | a) 6-(5-Methyl- 1 ,3,4-thiadiazol-2-yl)-8-((2-(trimethylsilyl)ethoxy)methoxy)-3-((2- (trimethylsilyl)ethoxy)methyl)guinazolin-4(3H)-oneA suspension of <strong>[54044-79-0]2-bromo-5-methyl-[1,3,4]thiadiazole</strong> (0.02 g, 0.1 mmol), (6-(4,4,5,5- tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 8- ((2- (trimethylsilyl)ethoxy)methoxy)-3-((2-5 (trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (0.05 g, 0.08 mmol, example 28), bis (diphenylphosphino)feffocene-palladium(II)dichloride (0.01 g, 0.01 mmol), potassium carbonate (0.03 g, 0.25 mmol) and water (0.2 ml) in dimethylformamide (1 ml) was stirred insealed tube at 100 C for 2 hours and then at 80 C overnight. Filtration and chromatography (C18 reverse phase HPLC, methanol / water = 40:60 to 100:0) yielded the title compound as10 white solid (0.02 g, 44 %). MS: mle = 521.7 [M+Hf?. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 87 mg | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; water; at 115℃; for 2.5h;Inert atmosphere; Sealed tube; | Example 72 1,3,3-Trimethyl-6-(5-methyl- 1,3,4-thiadiazol-2-yl)indolin-2-one In a pressure tube 1,3,3 -trimethyl-6-(4,4, 5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)indolin-2-one (example 29a, 0.1 g, 332 imol) and <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (71.3 mg, 398 tmol) were suspended in dioxane (2.66 ml) and a 2M aqueous sodium carbonate solution (664 tl) was added. Argon was bubbled through the mixture for 5 minutes, thenbis(triphenylphosphine)palladium(II) chloride (23.8 mg, 33.2 tmol) was added, the tube was sealed and the reaction mixture was heated to 115 C for 2.5 hours. The reaction mixture was diluted with ethyl acetate and methanol, 2 spoons silica gel were added and the mixture was concentrated in vacuo. The material was purified by silica gel chromatography using heptane/ ethyl acetate as eluent. The title compound was obtained as light brown solid (87 mg).MS ESI (m/z): 247.5 [(M+H)j.1H NMR (CDC13, 300 MHz): oe = 7.56 (d, J=1.4 Hz, 1H), 7.50 (dd, J=1.6, 7.7 Hz, 1H), 7.29 -7.26 (m, 1H), 3.29 (s, 3H), 2.83 (s, 3H), 1.41 (s, 6H). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 4.2% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 2h;Inert atmosphere; | Example 292 N-(2',4'-difluoro-5-(5-(5-methyl-1,3,4-thiadiazol-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1'-biphenyl]-3-yl)cyclopropanesulfonamide A solution of N-(2',4'-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1'-biphenyl]-3-yl)cyclopropanesulfonamide (0.15 g, 0.272 mmol) in 1,2-dimethoxyethane (5 ml) was degassed by N2 bubbling for 5 min. <strong>[54044-79-0]2-Bromo-5-methyl-1,3,4-thiadiazol</strong>e (0.058 g, 0.326 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.011, 0.013 mmol, 0.05 eq.) and aqueous sodium carbonate (0.072, 0.680 mmol, 2.5 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexane) to yield the desired title product in 4.2% yield (0.006 g). 1H NMR (400 MHz, DMSO-d6): delta 10.21 (s, 1H), 8.81 (s, 1H), 8.34-8.33 (s, 1H), 8.00-7.98 (dd, 1H), 7.84 (d, 1H), 7.79-7.73 (m, 1H), 7.54 (s, 1H), 7.49-7.42 (m, 2H), 7.29-7.24 (m, 1H), 3.17-3.16 (d, 2H), 2.85-2.84 (m, 1H), 2.79 (s, 3H), 1.01-0.99 (m, 4H); LC-MS (ESI): Calculated mass: 523.58; Observed mass: 523.7 [M+H]+ (rt: 1.50 min). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 13% | With tetrakis(triphenylphosphine) palladium(0); hexamethyldistannane; In N,N-dimethyl-formamide; at 130℃; for 2h;Inert atmosphere; Sealed tube; | [0317] To a stuffed, dry DMF solution of compound LX (50 mg; 0.11 mmol; 1 eq) in a reaction tube were added 2-bromo-5-methyl-[1,3,4lthiadiazole (20 mg; 0.11 mmol; 1 eq), hexamethylditin (50 mg; 0.16 mmol; 1.5 eq), and the resulting mixture was degassed with argon for 5 mm. To the mixture was added Pd(PPh3)4 (10 mg; 0.01 mmol; 0.1 eq) and degassing with argon was repeated for about 5 mm, and the reaction tube was sealed then heated at 130C for 2 h. The mixture was quenched with ice cold water (50 mL) and the organic components were extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, aqueous ammonium chloride solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was initially purified by silica gel (100-200 mesh) column chromatography eluting with 0-2% methanol/CH2C12 and further purified using preparative TLC to obtain the title compound (20 mg, 13%) as off white solid. 1H NMR (DMSO-d6) oe 10.27 (s, 1H), 9.47 (t, 1H, J = 6 Hz), 8.53 (s, 1H), 8.49 (s, 1H), 8.45 (m, 2H), 7.66 (dd, 1H, J = 8, 2 Hz), 7.41 (t, 1H, J = 53 Hz), 7.23 (d, 1H, J = 8 Hz), 4.53 (d, 2H, J = 6 Hz), 2.84 (s, 3H), 2.44 (s, 3H). LCMS: m/z = 482.2 [M+Hj , RT = 2.94 minutes, (Program P1, Column Y). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| With azobisisobutyronitrile; In chloroform; for 4.5h;Reflux; | To the mixture of <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (3.6 g, 20 mmol) in CC14 (320 ml) was added 1-bromopyrrolidine-2,5-dione (3600 mg, 20 mmol) and (E)-2,2?-(diazene- 1,2-diyl)bis(2-methylpropanenitrile) (190 mg, 1.2 mmol). The resulting mixture was heated at reflux for 4.5 hrs. After filtration through celite and washing of the pad with DCM, the combined filtrate was concentrated and the residue was purified on silica gel column usingEtOAc/hexane as eluting solvents to give 2-bromo-5-(bromomethyl)-1,3,4-thiadiazole. LC/MS:(M+1): 256.83, 258.84, 260.88. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 23% | With dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); sodium t-butanolate; In 1,4-dioxane; at 120℃; for 16h;Inert atmosphere; | tetrahydropyrazolo [4,3 -cpyridin-3 -yl)-3 ,4-dihydro-2H-quinoline (Intermediate XX, 30.3 mg, 0.0724 mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (27.3 mg, 0.145 mmol), dichloro[1,3- bis(2,6-di-3 -pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(1I) (12.1 mg,0.0145 mmol), t-BuONa (13.9 mg, 0.145 mmol), then 1,4-dioxane (0.4 mL). The mixture was sparged with an argon ballon, and then heated to 120 C for 16 h under argon atmosphere. After cooling the reaction to room temperature, DCM (1 mL) was added and the reaction was filtered through celite and concentrated in vacuo to give crude product that was purified by reverse phase preparative HPLC (acetonitrile 20-60% / 0.1 % ammonium hydroxide inwater) to give the title compound (10.3 mg, 23% yield) as a white solid. ?H NMR (400 MHz,DMSO-d6) 67.92 (d, J= 0.8 Hz, IH), 7.68 (d, J? 0.8 Hz, IH), 7.21 (d, J 2.1 Hz, 1H), 7.11(dd, J= 8.4, 2.2 Hz, 1H), 6.44 (d, Jr 8.4 Hz, IH), 4.34-4.24 (m, IH), 4.11 (s, 2H), 3.95 (d,J 11.6 Hz, 2H), 3.82 (d, J 1.3 Hz, 3H), 3.78 (t, J= 5.8 Hz, 2H), 3.62- 3.53 (m, 2H), 3.49-3.41 (m, 2H), 2.92 (t, J= 5.9 Hz, 2H), 2.81 (t, J= 6.2 Hz, 2H), 2.48 (s, 3H), 1.97 (tt, J11.7,5.2Hz, 4H), 1.81 (d,J= 12.3 Hz, 2H). LCMS M/Z(M+H) 517. | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]
 [ 615-16-7 ]
                                                    
                                                    [ 615-16-7 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 70.7% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 135℃; for 2h;Inert atmosphere; Microwave irradiation; | A stirring mixture of 2-hydroxybenzimidazole (500 mg, 3.73 mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (801 mg, 4.47 mmol), copper iodide (71 mg, 0.37 mmol) andpotassium carbonate (1030 mg, 7.46 mmol) in 1,4-dioxane (10 ml.) was degassed by bubblingnitrogen through the mixture for 5 min. Trans-A/,/V-dimethylcyclohexane-1,2-diamine (118 pl_,0.745 mmol) was added and the mixture heated to 135 eC for 2 h in a microwave. The mixture10 was added to 10%MeOH/DCM (200 ml.) and saturated aqueous sodium bicarbonate (200ml.) and the mixture stirred for 5 min. The DCM layer was separated and the aqueousextracted with 10%MeOH/DCM (100 ml_). The combined DCM extracts were concentratedunder reduced pressure and purified by column chromatography (DCM->10%MeOH/DCM)yielding 3-(5-methyl-1,3,4-thiadiazol-2-yl)- 7/-/-benzimidazol-2-one (612 mg, 2.64 mmol,15 70.7%) as a white solid.[00373] 1H NMR (300MHz, DMSO-d6) 5 = 11.98 - 11.67 (m, 1H), 8.26 (s, 1H), 7.29 -7.13 (m, 3H), 2.72 (s, 3H) | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]
 [ 405211-51-0 ]
                                                    
                                                    [ 405211-51-0 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 35.4% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 135℃; for 2h;Inert atmosphere; Microwave irradiation; | A stirring mixture of 3-(2-methoxyethyl)- 7/-/-benzimidazol-2-one (0.2 g, 1.04mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (466 mg, 2.6 mmol), copper iodide (20 mg, 0.100mmol) and potassium carbonate (575 mg, 4.16 mmol) in 1,4-dioxane (10 ml.) was degassed5 by bubbling nitrogen through the mixture for 5 min. Trans-A/,/V-dimethylcyclohexane-1,2-diamine (0.03 ml_, 0.21 mmol) was added and the mixture heated to 135 eC for 2 h in amicrowave. The mixture was added to 10%MeOH/DCM (200 ml.) and saturated aqueoussodium bicarbonate (200 ml.) added and the mixture stirred for 5 min. The DCM layer wasseparated and the aqueous extracted with 10%MeOH/DCM (100 ml_). The combined DCMio extracts were passed through a hydrophobic frit, concentrated under reduced pressure andpurified by column chromatography (Hex -> EtOAc) yielding 1-(2-methoxyethyl)-3-(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one (107 mg, 0.369 mmol, 35.4%) as a white solid.[00381] 1H NMR (300MHz, DMSO-d6) 5 = 8.38 - 8.28 (m, 1H), 7.43 (s, 1H), 7.30 (s,2H), 4.14 (t, J=5.3 Hz, 2H), 3.68 (t, J= 5.3 Hz, 2H), 3.24 (s, 3H), 2.73 (s, 3H) | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 41% | With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere; | A stirred suspension of 4-fluoro-3-methyl-1 H-benzimidazol-2-one (200. mg, 1.2mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (646.6 mg, 3.61 mmol), potassium carbonate (499.1 mg, 3.61 mmol), and copper (I) iodide (45.85 mg, 0.24 mmol) in 1,4-dioxane (8 ml.)was purged with nitrogen for 5 min. trans-N,N'-Dimethylcyclohexane-1,2-diamine (94.91 uL,0.60 mmol) was then added to the reaction mixture and then heated at 80 C under nitrogenfor 16 h. The reaction mixture was filtered (hot) through celite and the cake was washed with5 1,4-dioxane ( 2 x 5 ml_). The combined filtrates were distilled to dryness and the crude productwas purified by automated column chromatography, S i0 2 (RediSep 24 g) eluent 0-100%EtOAc in iso-hexane to yield 4-fluoro-3-methyl-1 -(5-methyl-1,3,4-thiadiazol-2-yl)benzimidazol-2-one (130 mg, 0.49 mmol, 41%).[00298] 1H NMR (300MHz, DMSO-d6) 5 = 8.17 (dd, J= 1.5, 7.4 Hz, 1H), 7.31 - 7.18 (m,10 2H), 3.58 (d, J= 2.1 Hz, 3H), 2.73 (s, 3H) | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 6% | With copper(l) iodide; potassium carbonate; trans-1,2-cyclohexanediamine; In acetonitrile; for 2h;Inert atmosphere; Reflux; | [00321] A mixture of 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1 H-indazole-6-sulfonamide (45. mg, 0.13 mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (0.04 mL, 0.31mmol), copper (I) iodide (2.38 mg, 0.01 mmol) and potassium carbonate (43.26 mg, 0.315 mmol) in MeCN (2 mL) was degassed with nitrogen. (+/-)-trans,1,2-Diaminocyclohexane (3.0jxL, 0.03 mmol) was added and the reaction mixture heated at reflux for 2 h. The reactionmixture was allowed to cool, DCM (5 mL) and saturated aq. NaHC03 were added and themixture stirred for 5 min. The DCM layer was isolated and the aqueous washed with DCM.The combined DCM extracts were concentrated under reduced pressure and purified by10 automated column chromatography, S i0 2, eluent 0-100% EtOAc in iso-hexane, and then byprep. HPLC (high pH) to yield 3-[(4-fluorophenyl)methyl]-N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indazole-6-sulfonamide (4 mg, 0.0078 mmol, 6%). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 11% | With copper(l) iodide; potassium carbonate; trans-1,2-cyclohexanediamine; In acetonitrile; for 2h;Inert atmosphere; Reflux; | A mixture of N-(1-methylcyclopropyl)-1 H-indole-6-sulfonamide (40. mg, 0.16mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (57.22 mg, 0.32 mmol), copper (I) iodide (3.04 mg,0.02 mmol) and potassium carbonate (55.21 mg, 0.40 mmol) in MeCN (2 ml.) was degassedwith nitrogen. (+/-)-trans-1,2-Diaminocyclohexane (3.8 jxL, 0.03 mmol) was added and thereaction mixture heated at reflux for 2 h. The reaction mixture was allowed to cool, DCM (5ml.) and saturated aq. NaHC03 were added and the mixture stirred for 5 min. The DCM layerwas isolated and the aqueous washed with DCM. The combined DCM extracts wereconcentrated under reduced pressure and the residue purified by automated columnchromatogrpahy S i0 2, eluent 0-100% EtOAc in iso-hexane, and then by prep. HPLC (highpH) to yield N-(1-methylcyclopropyl)-1-(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide (6mg, 0.017 mmol, 11%). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 11% | With copper(l) iodide; potassium carbonate; trans-1,2-cyclohexanediamine; In acetonitrile; for 2h;Inert atmosphere; Reflux; | stirring mixture of 3-acetyl-N-(1 -methylcyclopropyl)-1 H-indole-6-sulfonamide(60. mg, 0.21 mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (0.04 mL, 0.41 mmol), copper (I)20 iodide (3.91 mg, 0.02 mmol) and potassium carbonate (85.1 mg, 0.62 mmol) in MeCN (4 mL)was degassed with nitrogen. (+/-)-trans,1,2-Diaminocyclohexane (4.9 jxL, 0.040 mmol) wasadded and the mixture heated at reflux for 2 h. The reaction mixture was allowed to cool, DCM(5 mL) and saturated aq. NaHC03 were added and the mixture stirred for 5 min. The DCMlayer was isolated and the aqueous washed with DCM. The combined DCM extracts were25 concentrated under reduced pressure and the residue purified by automated column chromatography, S i0 2, 0-100% EtOAc in iso-hexane, and then by prep. HPLC (high pH) toyield 3-acetyl-N-(1 -methylcyclopropyl)-1 -(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide(4.4 mg, 0.0108 mmol, 5%). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 25% | With copper(l) iodide; potassium carbonate; trans-1,2-cyclohexanediamine; In acetonitrile; for 2h;Inert atmosphere; Reflux; | A suspension of 3-benzyl-N-(1-methylcyclopropyl)-1H-indole-6-sulfonamide(80. mg, 0.23 mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (84.15 mg, 0.47 mmol), copper (I)iodide (4.48 mg, 0.02 mmol) and potassium carbonate (81.19 mg, 0.59 mmol) in MeCN (3 ml.)was degassed with nitrogen. (+/-)-trans,1,2-Diaminocyclohexane (0.01 ml_, 0.05 mmol) wasadded and the reaction mixture heated at reflux for 2 h. The reaction mixture was allowed to25 cool, DCM (5 ml.) and saturated aq. NaHC03 were added and the mixture stirred for 5 min. The DCM layer was isolated and the aqueous washed with DCM. The combined DCM extractswere concentrated under reduced pressure and the residue purified by automated columnchromatography, S i0 2, 0-100% EtOAc in iso-hexane, and then by prep. HPLC (high pH) toyield 3-benzyl-N-(1 -methylcyclopropyl)-1 -(5-methyl-1,3,4-thiadiazol-2-yl)indole-6-sulfonamide5 (26 mg, 0.059 mmol, 25%). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 65% | With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 1h;Microwave irradiation; | A solution of Intermediate 3 (250 mg, 1.0 mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (270 mg, 1.5 mmol) and cesium carbonate (654 mg, 2.0 mmol) in DMF(5 mL) was heated in the microwave at 120 C for lh. The reaction mixture partitioned between brine (10 mL) and EtOAc (10 mL). The layers were separated and the aqueous layer was extracted with further EtOAc (2 x 10 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified by Biotage lsolera chromatography (silica gel, eluting with heptane-EtOAc, 4:1 to 1:4) to afford 226.6 mg (65% yield) of the title compound as a yellow gum.1H NMR (500 MHz, Chloroform-d): 6 [ppm] 8.39 (t, J = 1.4 Hz, 1H), 8.09 (dd, J =2.3, 1.7 Hz, 1H), 7.98 (dd, J = 2.4, 1.4 Hz, 1H), 7.54 (d, J = 1.1 Hz, 1H), 3.95 (5, 3H), 2.69 (5, 3H), 2.54 (d, J = 1.0 Hz, 3H).LCMS (Analytical Method A) Rt = 1 .23 mm, MS (ESipos): m/z = 347.9 (M+H). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 51.9% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 100℃; for 2h;Microwave irradiation; Inert atmosphere; Sealed tube; | To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one (120 mg, 0.292 mmol), <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (104.5 mg, 0.584 mmol), 1,2-dimethoxyethane (2 mL), 1 N Na2CO3 aqueous solution (0.96 mL, 0.96 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (33.7 mg, 0.029 mmol) was added. The tube was sealed and heated in an oil bath at 100 C. for 2 hrs. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH: DCM=5:95) to give light yellow solids, 58.1 mg (yield 51.9%). | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 7.83% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; at 90℃; for 16h;Inert atmosphere; | To a solution of 2-bromo-5-methyl-l,3,4-thiadiazole (0.62 g, 3.47 mmol, 1.0 eq) in DME (lOmL) was added compound 1.3 (l .Og, 4016mmol, 1.2eq) followed by addition of Na2C03 (0.735 g, 6.94 mmol, 2.0 eq). Reaction mixture was degassed with argon for 10 min and (dppf)PdCl2(0.253 g, 0.347 mmol, O. leq) was added. Reaction mixture was stirred at 90 C for 16 hours. After completion of the reaction, mixture was transferred into water and extracted with EtOAc. Organic layers were combined, washed with brine, dried over Na2S04and concentrated under reduced pressure to obtain crude which was purified by preparative HPLC to furnish 7.1. (0.08 g, 7.83 %). MS(ES): m/z 295.7 [M]+ | 
 [ 891785-28-7 ]
                                                    
                                                    [ 891785-28-7 ]
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]
 [ 73183-34-3 ]
                                                    
                                                    [ 73183-34-3 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 96.3% | To a mixture of 6-bromoisoquinolin-3-amine (XV) (4.52 g, 20.27 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (LIV) (5.62 g, 22.12 mmol), KOAc (5.43 g, 55.29 mmol), and Pd(dppf)Cl2 (3.0 g, 3.69 mmol) in dioxane (10 mL) was purged with nitrogen and then heated at 90 C. for 2 h. The reaction was cooled to room temperature before adding the <strong>[54044-79-0]2-bromo-5-methyl-1,3,4-thiadiazole</strong> (LV) (3.30 g, 18.43 mmol), K2CO3 (7.64 g, 55.29 mmol) and Pd(dppf)Cl2 (3.0 g, 3.69 mmol). The mixture was heated at 90 C. for another 4 h. The solvent was removed under high vacuum and the residue was purified by column chromatography (0?100% EtOAc/hexanes) to produce 6-(5-methyl-1,3,4-thiadiazol-2-yl)isoquinolin-3-amine (LVI) as a yellow solid (4.30 g, 17.75 mmol, 96.3% yield). ESIMS found for C12H10N4S m/z 243.0 (M+1). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 32.04% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 1h;Inert atmosphere; | A mixture of [l-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyridin-6-yl]boronic acid (4 g, 13.69 mmol, 1 eq), 2-bromo-5-methyl-l,3,4-thiadiazole (2.45 g, 13.69 mmol, 1 eq), CS2CO3 (8.92 g, 27.38 mmol, 2 eq), Pd(PPh3)4 (1.58 g, 1.37 mmol, 0.1 eq) in dioxane (50 mL) and fLO (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 C for 1 h under N2 atmosphere. The reaction mixture was diluted with H20 (300 mL) and extracted with EtOAc (100 mLx3). The combined organic layers were washed with brine (300 mLx2), dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (Si02, Petroleum ether/Ethyl acetate=l0/l to 4/1) to afford the title compound (1.6 g, 4.39 mmol, 32.04% yield, 95% purity) as a yellow solid. | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 78% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In ethanol; toluene; at 90℃; for 18h; | Og (49.8 mmol) of 4-Bromophenylboronic acid was mixed with 8.92g (49.8mmol) of 2-bromo-5-methyl-l,3,4-thiadiazole, and 3.64 g (4.98 mmol) of 1,1'- bis(diphenylphosphino)fenOcene-palladium(II) dichloride. 200 mL of toluene/ethanol mixture was added to the reaction mixture, followed by 100 mL of 1M sodium carbonate. Reaction mixture was heated at 90C for 18 hours. After the reaction was complete (followed by LCMS) additional lOOmL of water and 300 mL of Ethyl acetate were added and partitioned. Aqueous layer was washed two more times with l50mL of ethyl acetate. Combined organic layer was dried with magnesium sulfate, filtered through celite, concentrated and purified on silica using hexanes/ethyl acetate. 12.7g of 2-(4-bromophenyl)- 5-methyl-l,3,4-thiadiazole was isolated in 78% yield. If needed additional crystallization step can be performed using ethanol as a solvent. | 

 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 51% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 80℃; | lOg (54.2 mmol) of (4-chloro-2-formylphenyl)boronic acid was mixed with 9.7lg (54.2 mmol) of 2-bromo-5-methyl-l,3,4-thiadiazole, 3.97g (5.42 mmol) of l,T- bis(diphenylphosphino)fenOcene-palladium(II) di chloride, and 17.2 g (163 mmol) of sodium carbonate. l50mL of l,4-dioxane and 30 mL of water was added. The reaction mixture was heated at 80C until LCMS showed complete conversion. The mixture was diluted with additional 20 mL of water and extracted with ethyl acetate 3 times. Combined organic layer was dried over magnesium sulfate, filtered through celite, and purified on silica using ethyl acetate and hexanes. 5-Chloro-2-(5-methyl-l,3,4-thiadiazol-2-yl)benzaldehyde was isolated as yellow solid (6.6g, 51% yield). | 
 [ 54044-79-0 ]
                                                    
                                                    [ 54044-79-0 ]

| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 27% | With copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl acetamide; at 60℃; for 48h;Inert atmosphere; | A mixture of 2-bromo-5-methyl-l,3,4-thiadiazole (297 mg, 1.67 mmol), Cul (32 mg, 0.17 mmol) and Pd(PPh3)4 (96 mg, 0.084 mmol) in anhydrous DMA (6 mL) under a N2 atmosphere was treated with 1960-1 (2.0 mL). The resulting reaction mixture was stirred at 60 C for 48 h under a N2 atmosphere. The mixture was then diluted with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by Prep-TLC (EtOAc : PE = 1 : 1) to give 2124-1 (120 mg, 27%) as a yellow solid. MS 270.3 [M + H]+, 214.2 [M - 55]+ | 
| Yield | Reaction Conditions | Operation in experiment | 
|---|---|---|
| 39% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere; | A mixture of 2-bromo-5-methyl-l, 3, 4-thiadiazole (700 mg, 3.89 mmol), ie/t-butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,5-dihydro-lH- pyrrole-l-carboxylate (1.15 g, 3.89 mmol) and Na2C03 (l.2 g, 11.7 mmol) in dioxane (40 mL) was treated with PdCl2(dppf)2 (l59 mg, 0.2 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at 90 C for 3 h and then concentrated in vacuo. The residue was dissolved with EtOAc (30 mL) and the solution was washed with brine (10 mL x 3). The combined organic layer was dried over anhydrous Na2S04 and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE : EtOAc = 10 : 1 to 1 : 1) to give 1985-A (400 mg, 39%) as a yellow solid. MS 268.1 [M + H]+. | 

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