Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:61])[CH2:7][NH:8][C:9](=[O:60])[CH2:10][NH:11][C:12](=[O:59])[CH2:13][NH:14][C:15](=[O:58])[CH2:16][CH2:17][S:18][CH2:19][CH:20]([O:40][C:41](=[O:57])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH2:21][O:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(C)(C)C.FC(F)(F)C(O)=O>>[C:41]([O:40][CH:20]([CH2:21][O:22][C:23](=[O:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][S:18][CH2:17][CH2:16][C:15]([NH:14][CH2:13][C:12]([NH:11][CH2:10][C:9]([NH:8][CH2:7][C:6]([OH:61])=[O:5])=[O:60])=[O:59])=[O:58])(=[O:57])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)NCC(=O)NCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)NCC(=O)NCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
(6,7-bis(palmitoyloxy)-4-thiaheptanoyl)glycylglycylglycine t-butyl ester as obtained in Example 5 (110 mg) was mixed with trifiuoroacetic acid (5 ml), followed by stirring at room temperature for 1 hour. The mixture was concentrated to yield the title compound (81 mg, yield 86%) as a colorless crystal.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH:14]1([CH2:17][NH:18][C:19](=[O:36])[C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](B3OC(C)(C)C(C)(C)O3)[CH:21]=2)[CH2:16]C1>CC(O)C>[CH:17]1([NH:18][C:19]([C:20]2[CH:21]=[C:22]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)=[CH:4][CH:3]=3)[C:23]([CH3:26])=[CH:24][CH:25]=2)=[O:36])[CH2:14][CH2:16]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc2)o1

Procedure:
Example 39 was prepared using 2-(4-iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and N-cyclopropyl-4methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 17) with propan-2-ol as the solvent.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([O:10][CH3:19])=[O:9])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(C)(=O)=O)c1
Yield: 81 %

Procedure:
To a solution of 3-methylsulfonylbenzoic acid (10 g, 50 mmol) in anhydrous methanol (100 mL) was added conc. sulfuric acid (10 mL). The mixture was refluxed for 4 hours and then concentrated to one-third volume. Water (200 mL) was added, and the mixture was extracted with diethyl ether. The organic extract was washed with 10% sodium carbonate solution, and dried over Na2SO4. After concentration, 8.6 g (81%) of methyl 3-methylsulfonylbenzoate was obtained.
Reaction SMILES: C1N2CN3[CH2:10][N:4](C2)CN1C3.BrC[C:13]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH:23]([CH3:25])[CH3:24])=[O:14].Cl>C(Cl)(Cl)Cl>[ClH:21].[NH2:4][CH2:10][C:13]([C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[O:22][CH:23]([CH3:25])[CH3:24])=[O:14]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)Oc1ccc(Cl)cc1C(=O)CBr
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(Cl)cc1C(=O)CN
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Add hexamethylenetetramine (36.14 g, 258 mmol) to a solution of 2-bromo-1-(5-chloro-2-isopropoxyphenyl)ethanone (75.17 g, 258 mmol) in chloroform (400 mL) at room temperature under nitrogen and stir for 2 days. Collect the solids by filtration, wash with diethyl ether, and dry overnight under reduced pressure. Suspend the solids in methanol (350 ml), cool to 0° C., and treat slowly with concentrated HCl (113 ml, 1365 mmol). Warm the mixture to room temperature and stir for 40 hours. Then heat the mixture to 55° C. for an additional 4 hours. Remove the solids by filtration, and remove the filtrate solvent under reduced pressure to provide a solid. Triturate the solid with diethyl ether. Collect the resulting material by filtration to provide 2-amino-1-(5-chloro-2-isopropoxyphenyl)ethanone hydrochloride, which is used in the next step without purification.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[F:8][C:9]([F:46])([F:45])[C:10]1[CH:11]=[C:12]([C:20]2[N:24]=[CH:23][N:22](/[CH:25]=[CH:26]\[C:27]([NH:29][NH:30][C:31](=[O:44])[C@H:32]([NH:36]C(=O)OC(C)(C)C)[CH:33]([CH3:35])[CH3:34])=[O:28])[N:21]=2)[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>ClCCl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:36][C@H:32]([CH:33]([CH3:35])[CH3:34])[C:31]([NH:30][NH:29][C:27](=[O:28])/[CH:26]=[CH:25]\[N:22]1[CH:23]=[N:24][C:20]([C:12]2[CH:11]=[C:10]([C:9]([F:45])([F:46])[F:8])[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=2)=[N:21]1)=[O:44]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H](N)C(=O)NNC(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
In a 10 mL round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.05 g, 1.0 eq.) was dissolved in THF (5 mL) and cooled to −60° C. where (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.038 g, 1.3 eq.) was introduced dropwise. T3P (50% in EtOAc) (0.16 mL, 2 eq.) was added dropwise followed by DIPEA (0.095 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (R,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate (0.017 g, yield: 26%). In a 10 mL round-bottom flask, (R,Z)-tert-butyl (1-(2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)hydrazinyl)-3-methyl-1-oxobutan-2-yl)carbamate was then dissolved in dichloromethane (2 mL). TFA (0.2 mL) was added and the reaction mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product (0.02 g), which was triturated with petroleum ether and dried under reduced pressure to yield (R,Z)-2-amino-N′-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-methylbutanehydrazide 2,2,2-trifluoroacetate (0.007 g, yield: 35%).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH2:14]([NH2:16])[CH3:15]>>[CH:9]1([C:6]2[S:7][CH:8]=[C:4]([CH2:3][NH:16][CH2:14][CH3:15])[N:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: ClCc1csc(C2CCCC2)n1
Reactant: CCN
Agent: Cl
Product: CCNCc1csc(C2CCCC2)n1

Procedure:
Using the procedure of Example 1Q, but replacing 4-(chloromethyl)-2-isopropylthiazole hydrochloride with 4-(chloromethyl)-2-cyclopentylthiazole hydrochloride and replacing 40% aqueous methylamine with 70% aqueous ethylamine provided, after purification of the residue by silica gel chromatography using 5% methanol in chloroform, 1.08 g (50%) of the desired compound.
Reaction SMILES: [C:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)#[CH:2].[CH2:12]([O:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)[CH2:13][CH2:14][CH2:15][CH3:16].[Cl-].[OH-].[Na+]>O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C)C=O.C(N(CC)CC)C>[CH2:12]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:2]#[C:1][C:3]2([OH:11])[CH:8]3[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]3)[CH2:4]2)=[CH:22][CH:23]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: CCCCCOc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCOc1ccc(C#CC2(O)CN3CCC2CC3)cc1
Yield: 61.1 %

Procedure:
A mixture of 3-ethynyl-3-hydroxyquinuclidine (750 mg), 4-n-pentyloxyiodobenzene (1.45 g), bis(triphenylphosphine)-palladium. (II) chloride (175 mg), copper (I) iodide (90 mg), triethylamine (5 ml) and dimethylformamide (10 ml) was stirred at 80° C. under an atmosphere of argon for 4 hours. The mixture was cooled, diluted with water (50 ml) and basified with 2M aqueous sodium hydroxide solution (10 ml). The mixture was extracted with ethyl acetate containing 10% methanol (3×30 ml). The organic extracts were combined, and filtered through a short column of silica gel (Varian Bond--elut S1 silica gel). The eluent was evaporated and the residue was crystallised from acetonitrile to give 3-[2-(4-n-pentyloxyphenyl)ethynyl]-3-hydroxyquinuclidine (950 mg) as a solid, m.p. 153°-154° C.; microanalysis, found: C, 76.4; H, 8.9; N, 4.4%; C20H27NO2 requires: C, 76.6; H, 8.68; N, 4.47%; NMR: 0.82-0.95(3H,t), 1.22-1.48(5H,m), 1.6-1.76(3H,m), 1.8-2.0(3H,m), 2.6-2.9(6H,m), 3.9-4.0(2H,t), 5.5(1H,s), 6.85-6.95(2H,d), 7.3-7.4(2H,d); m/z 314(M+H).
Reaction SMILES: N1C=CC=CC=1.S(=O)(=O)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:21]=[C:20]([CH2:22][OH:23])[O:19][N:18]=1.C(N(CC)CC)C>CS(C)=O.ClCCl.C(OCC)(=O)C>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:21]=[C:20]([CH:22]=[O:23])[O:19][N:18]=1
Reactant: OCc1cc(-c2ccccn2)no1
Agent: O=S(=O)=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cc(-c2ccccn2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Sulfur trioxide pyridine (10.0 g, 62.8 mmol) was dissolved in dimethylsulfoxide (50 mL) and cooled to near 0° C. A solution of the compound prepared in Example 124 (5.05 g, 28.7 mmol) and triethylamine (16.0 mL, 115 mmol) in dichloromethane (40 mL) was added to the solution over 45 minutes. The reaction was warmed to room temperature and stirred overnight. The reaction was diluted with ethyl acetate and washed with sodium hydrogen carbonate aqueous solution. The organic phase was washed with water and dried over magnesium sulfate. The crude mixture was purified by column chromatography using an eluant of 1 to 3% ethyl acetate/dichloromethane to provide the title compound (0.90 g) with the following physical data.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:10][C:11]([NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:13])=[CH:5][C:4]=1[C:18]([F:21])([F:20])[F:19])#[N:2]
Reactant: NCc1ccccc1
Reactant: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Product: N#Cc1ccc(N(CC(=O)NCc2ccccc2)CC2CC2)cc1C(F)(F)F

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycine and benzyl amine: MS (APCI) m/z 388 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.C([N-]C(C)C)(C)C.[Li+].[CH3:25][C:26]([CH3:28])=[O:27].C(Cl)Cl>O1CCCC1.CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([C:26]([OH:27])([CH3:28])[CH3:25])=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Reactant: CC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCc1ccccc1
Product: CC(C)(O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
4-(5-Chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 was slurried in tetrahydrofuran and cooled to −78° C. under nitrogen. Two equivalents of 2M lithium diisopropylamide in heptane/tetrahydrofuran/ethylbenzene were added slowly and the solution was stirred for 30 minutes. Acetone (6 eq) was added and the solution was stirred at −78° C. for an additional one hour. Ice was added and the solution was warmed to room temperature before extraction with methylene chloride. The organic layer was dried with sodium sulfate and concentrated. The resulting residue was purified on silica gel to give the light yellow solid of 2-(5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)propan-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[NH:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C(=O)([O-])[O-].[K+].[K+].O=[C:26]([CH:32]1[C:37](=O)[CH2:36][CH2:35][O:34][CH2:33]1)[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:18]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:32]3[CH2:33][O:34][CH2:35][CH2:36][C:37]=3[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=O)C1COCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc2c1COCC2
Temperature: 50 °C

Procedure:
1-(3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)guanidine (418 mg, 1.36 mmol) and potassium carbonate (469 mg, 3.40 mmol) in EtOH (8mL) were stirred for 10min at 50° C. Ethyl 2-oxo-2-(4-oxotetrahydro-2H-pyran-3-yl)acetate (272 mg, 1.36 mmol) was added slowly and the reaction was stirred at 50° C. over night. The crude product was partitioned between DCM and water. The organic phase was dried and solvent evaporated and used as such in the next step. MS (ES+) m/z 410.0 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.C[O:18][B:19](OC)[O:20]C>C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([B:19]([OH:20])[OH:18])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COB(OC)OC
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
To a stirred solution of 4-tert-butyl-bromobenzene (21.3 g, 0.0999 mol) in THF (30 mL) at −78° C. under nitrogen was added dropwise a 2.1 M solution of n-butyl lithium in hexanes (45 mL, 0.095 mol), and the mixture was stirred for 1.5 hours. To the mixture was added dropwise neat trimethylborate (10.2 mL, 0.090 mol), and the mixture was allowed to slowly warm to room temperature. The mixture was stirred overnight, then quenched by dropwise addition of 1.0 M aqueous hydrochloric acid. Brine was added, and the organic layer was dried (Na2SO4) and rotary evaporated. The residue was crystallized from n-heptane to give 4.65 g of crude 4-tert-butyl-phenyl-boronic acid as white needles. This material was used directly in the next reaction without further characterization. Thus, in a manner similar to Example 12, Step (b), 4-tert-butyl-phenyl-boronic acid (0.4287 g, 0.00241 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (0.5443 g, 0.00200 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.0472 g, 0.0000408 mol) and 2.0 M aqueous sodium carbonate (2.4 mL, 0.0048 mol) in toluene (5 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with toluene then chloroform, 0.50 g. The material was dissolved in diethyl ether, washed with 0.10 M aqueous sodium hydroxide, water and brine. The organics were dried (K2CO3), and rotary evaporated to give 0.45 g of 4-(4′-tert-butyl-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester as a white solid; mp 58-62° C.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Sn](CCCC)(CCCC)CCCC)[N:26]=1>CN(C=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>[CH2:15]([NH:14][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[N:26]=3)=[CH:3][C:4]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:5][C:6]=2[N:7]=1)=[O:13])[CH3:16]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(OC)n1
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(Br)c2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3cccc(OC)n3)c2s1
Temperature: 120 °C
Yield: 11.2 %

Procedure:
To a solution of 1-(7-bromo-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (0.50 g, 1.32 mmol) in DMF (5.0 mL) was added 2-methoxy-6-tributylstannanyl-pyridine (1.05 g, 2.65 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was then degassed for half an hour followed by the addition of tetrakis(triphenylphosphine)palladium(0) (0.23 g, 0.20 mmol). The reaction mixture was then again degassed for half an hour and heated at 120° C. for 6 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), DMF was distilled off; water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The crude residue was purified by prep HPLC to get the title compound as white solid (0.06 g, 11%). M.P. 300.10° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=1>C(#N)C>[I:1][C:14]1[S:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[N:11][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(=O)Nc1nc(C)cs1
Solvent: CC#N
Product: CC(=O)Nc1nc(C)c(I)s1

Procedure:
N-Iodosuccinimide (4.75 g) is added portion wise to a solution of N-(4-methyl-thiazol-2-yl)-acetamide (3 g) in acetonitrile (60 ml) at room temperature. After 5 minutes a precipitate forms which is collected by filtration and washed with cold acetonitrile to give the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(F)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution of 1.00 g (2.86 mmol) of the product of Example 28 in 10 mL of DMF was added 0.14 g (3.57 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperature and then 0.42 mL (3.57 mmol) of benzyl bromide was added. This reaction mixture was stirred overnight at room temperature, poured into water and then extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from ethyl acetate (EtOAc)/Hexanes to provide 1.084 g (85%) of the desired product as a white solid. Electrospray Mass Spec: m/z 428.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:13]=[C:12]([O:24][CH:25]([CH3:27])[CH3:26])[CH:11]=2)=[N:6][CH:7]=1.[CH2:29]([O:31][PH:32]([CH3:34])=[O:33])[CH3:30].CCN(CC)CC>C1(C)C=CC=CC=1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:29]([O:31][P:32]([C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]3[CH:23]=[CH:22][S:21][CH:20]=3)[CH:13]=[C:12]([O:24][CH:25]([CH3:27])[CH3:26])[CH:11]=2)=[CH:4][CH:3]=1)([CH3:34])=[O:33])[CH3:30]
Reactant: CC(C)Oc1cc(OCCc2ccsc2)cc(C(=O)Nc2ccc(Br)cn2)c1
Reactant: CCO[PH](C)=O
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOP(C)(=O)c1ccc(NC(=O)c2cc(OCCc3ccsc3)cc(OC(C)C)c2)nc1
Temperature: 90 °C
Yield: 92.3 %

Procedure:
To a stirred solution of N-(5-bromo-pyridin-2-yl)-3-isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzamide (1.69 g, 3.66 mmol) in toluene (40 mL) was added a solution of methylphosphinic acid ethyl ester (0.475 g, 4.40 mmol), palladium tetrakis(triphenylphosphine) (0.846 g, 0.733 mmol), and Et3N (1.54 mL, 10.9 mmol) in DCM (5.0 mL) at rt. The mixture was heated at 90° C. overnight. Cooled to rt and concentrated. EtOAc and water were added and the mixture was filtered through a pad of Celite to remove the insoluble solids. The organic layer was separated, washed with brine (1×), dried with anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography (6×25 cm, hexane/EtOAc, v/v=1:3, EtOAc, 1% MeOH in EtOAc). Fractions containing the product were pooled and concentrated to give {6-[3-Isopropoxy-5-(2-thiophen-3-yl-ethoxy)-benzoylamino]-pyridin-3-yl}-methyl-phosphinic acid ethyl ester (1.65 g, 92%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.74 (br, 1H), 8.68 (ddd, J=6, 2, 1 Hz, 1H), 8.49 (ddd, J=9, 2, 1 Hz, 1H). 8.10 (ddd, J=11, 9, 2 Hz, 1H), 7.63-7.70 (m, 1H), 7.43-7.47 (m, 1H), 7.29 (dd, J=5.3 Hz, 1H), 7.09-7.10 (m, 1H), 7.04 (dd, J=5, 1 Hz, 1H), 6.99-7.03 (m, 2H), 6.64 (m, 1H), 4.60 (m, 1H), 4.22 (t, J=7 Hz, 2H), 4.07-4.15 (m, 1H), 3.84-3.92 (m, 1H), 3.14 (t, J=7 Hz, 2H), 1.70 (d, J=15 Hz, 3H), 1.35 (d, J=6 Hz, 6H), 1.23-1.31 (m, 3H).
Reaction SMILES: N[C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.P(=O)(O)(O)O.N([O-])=O.[Na+].[Cl-:22].[Na+]>Cl.O>[Cl:22][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: [Cl-]
Reactant: CCOC(=O)c1cn(C)nc1N
Agent: Cl
Agent: O=N[O-]
Agent: O=P(O)(O)O
Solvent: O
Product: CCOC(=O)c1cn(C)nc1Cl
Temperature: 0 °C
Yield: 49.2 %

Procedure:
A solution of 41.4 g (267 mmol) of ethyl 3-amino-1-methylpyrazole-4-carboxylate in a mixture of 150 mL of concentrated hydrochloric acid, 50 mL of 85 percent phosphoric acid, and 100 mL of water was prepared and cooled to about 0° C. A solution of 18.6 g (270 mmol) of sodium nitrite in 50 mL of water was added to this dropwise with cooling and stirring. After a short time the reaction mixture was added dropwise with stirring at ambient temperature to a solution of 46.5 g (484 mmol) of cupric sulfate and 60.0 g (1.03 mol) of sodium chloride in 200 mL of water. When the addition was complete, the mixture was heated to 50° C. with stirring for 1 hr. A solid formed. The mixture was extracted with methylene chloride and the extract was washed with water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure to obtain an impure solid. This was dried and recrystallized from ethanol to obtain 24.8 g of the title compound as a white solid melting at 76°-77° C.