Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([N:26]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]4)[CH2:27][CH3:28])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:43])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:46]1(B(O)O)[CH2:48][CH2:47]1>C(=O)([O-])[O-].[K+].[K+].C1COCC1.O>[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([N:26]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]4)[CH2:27][CH3:28])=[CH:24][CH:23]=[C:22]([C:46]([CH3:48])=[CH2:47])[N:21]=3)[C@H:14]2[CH3:43])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)C[C@H]1CC[C@H](CN(CC)c2ccc(Cl)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)c1ccc(N(CC)C[C@H]2CC[C@H](CC(=O)OCC)CC2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Temperature: 85 °C

Procedure:
A mixture of ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-chloropyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate, cyclopropylboronic acid and 1,1′-bis(di-t-butylphosphinoferrocene) palladium dichloride in 1N aqueous potassium carbonate and THF was heated at 85° C. in a sealed tube overnight. The reaction was diluted with water (10 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-30% EtOAc in hexanes gradient) to afford ethyl (trans-4-{[[2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-6-isopropenylpyridin-3-yl](ethyl)amino]methyl}cyclohexyl)acetate. Rf=0.44 (20% EtOAc/hexanes). LCMS calc.=670.3; found=670.4 (M+1)+. 1H NMR (600 MHz, CDCl3): δ 7.87 (s, 1 H); 7.78 (s, 2 H); 7.40 (s, 2 H); 5.85 (s, 1 H); 5.75 (d, J=8.6 Hz, 1 H); 5.25 (s, 1 H); 4.96 (d, J=16.7 Hz, 1 H); 4.42-4.36 (m, 2 H); 4.08 (q, J=7.1 Hz, 2 H); 2.98-2.92 (m, 2 H); 2.85 (dd, J=6.5, 13.0 Hz, 1 H); 2.76 (dd, J=7.5, 13.0 Hz, 1H); 2.20 (s, 3 H); 2.12 (d, J=6.8 Hz, 2 H); 1.83-1.65 (m, 5 H); 1.36-1.30 (m, 1 H); 1.22 (t, J=7.1 Hz, 3 H); 0.99 (t, J=7.0 Hz, 3 H); 0.95-0.83 (m, 4 H); 0.72 (d, J=6.7 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[NH:18][C:19]1([CH3:23])[CH2:22][NH:21][CH2:20]1.[CH3:24]C(O)=O.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[NH:18][C:19]1([CH3:23])[CH2:20][N:21]([CH3:24])[CH2:22]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CNC4)cc3N21
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C)C4)cc3N21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of (R)-7-bromo-4-methyl-6-(3-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4.0 g, 10.4 mmol) and polyformaldehyde (0.78 g, 26 mmol) in MeOH (10 mL) was stirred at ambient temperature for 10 min followed by the addition of AcOH (0.5 mL). The mixture was stirred at ambient temperature for 30 min before the addition of sodium cyanoborohydride (1.4 g, 22.8 mmol). The mixture was stirred at 40° C. overnight. The mixture was cooled to ambient temperature and concentrated in vacuo to give the residue, which was purified by chromatography on silica gel (eluting with 1% methanol in dichloromethane) to give (R)-7-bromo-6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.8 g, 62%). 1H NMR (400 MHz, CDCl3) δ=8.77 (s, 1H), 7.14 (s, 1H), 6.01 (s, 1H), 4.63 (q, J=6.8 Hz, 1H), 4.56 (d, J=12.8, 2H), 4.46 (s, 1H), 3.87 (m, 2H), 3.46 (m, 2H), 2.57 (s, 3H), 1.65 (s, 3H), 1.55 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 25) Rt=0.659 min.; MS m/z: 394 [M+H]+ and 396 [M+H+2]+.
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](/[CH:9]=[CH:10]\[S:11][C:12]2[C@H:13]([CH3:26])[C@@H:14]3[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]3[C:16]=2[C:17]([O-:19])=[O:18])=[CH:7][N:8]=1)(=[O:3])[NH2:2].[Na+].[C:28]([O:34][CH2:35]I)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>>[C:1]([C:4]1[S:5][C:6](/[CH:9]=[CH:10]\[S:11][C:12]2[C@H:13]([CH3:26])[C@@H:14]3[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]3[C:16]=2[C:17]([O:19][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:18])=[CH:7][N:8]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)C(=O)OCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3cnc(C(N)=O)s3)[C@H](C)[C@H]12
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(S/C=C\c3cnc(C(N)=O)s3)[C@H](C)[C@H]12

Procedure:
In the same manner as in Example 81, 78 mg of the title compound was prepared from 74 mg of sodium (1R,5S,6S)-2-[[(Z)-2-(2-carbamoylthiazol-5-yl)ethen-1-yl]thio]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate prepared in Example 62 and 0.031 ml of iodomethyl pivalate.
Reaction SMILES: C([O:9][C:10]1[C:11]([C:35]([O:37]C)=O)=[N:12][C:13]([CH:17]([NH:27]C(OC(C)(C)C)=O)[CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:14][C:15]=1[OH:16])(=O)C1C=CC=CC=1.[F:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44][NH2:45])=[CH:42][CH:41]=1>>[NH2:27][CH:17]([C:13]1[N:12]=[C:11]([C:35]([NH:45][CH2:44][C:43]2[CH:46]=[CH:47][C:40]([F:39])=[CH:41][CH:42]=2)=[O:37])[C:10]([OH:9])=[C:15]([OH:16])[N:14]=1)[CH2:18][O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: COC(=O)c1nc(C(COCc2ccccc2)NC(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Product: NC(COCc1ccccc1)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a methanolic solution of methyl 5-(benzoyloxy)-2-{2-(benzyloxy)-1-[(tert butoxycarbonyl)amino]ethyl}-6-hydroxypyrimidine-4-carboxylate prepared as described in Step 2, 4-fluorobenzylamine (2.15 eq.) was added. The resulting solution was refluxed for 24 hours (100% conversion by LC-MS). After cooling to room temperature, the crude was concentrated under reduced pressure and the solvent switched to CH2Cl2. To the solution, trifluoroacetic acid was added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and diethyl ether (100 mL) was added. The resulting slurry was stirred for 1 hour at room temperature and the product was collected by filtration. The cake was washed with cold diethyl ether and dried under reduced pressure to afford title compound as trifluoroacetic salt. MS (ES) C21H21FN4O4 requires 412. Found: 413.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>C(=O)(O)[O-].[Na+]>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[N+:15]([O-:17])=[O:16])=[CH:22][CH:21]=1
Reactant: COc1ccc(O)cc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(Oc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (14 g), p-methoxyphenol (9.3 g), and 1N sodium bicarbonate (200 ml) was stirred at 90°C for 5 hours. After cooling, the resulting 4-(p-methoxyphenoxy)-3-nitro-5-sulphamyl-benzoic acid was precipitated by the addition of 4N hydrochloric acid until the pH was 1, and collected by suction. The crude acid was dissolved in hot methanol (100 ml) and precipitated by the addition of water (100 ml) and cooling. After collection and drying in vacuo, the melting point was 229°-230°C.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:20][CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: Cc1nc(-c2ccccc2)n[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccccc2)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
5-Methyl-3-phenyl-1H-1,2,4-triazole (120 mg, 754 μmol) was dissolved in DMF (2.4 mL) and potassium carbonate (208 mg, 1.51 mmol) was added. After 20 min tert-butyl 2-bromoethylcarbamate (186 mg, 829 μmol) was added at 0-5° C. and the reaction mixture was stirred at RT for 25 h. The reaction mixture was extracted with ethyl acetate (30 mL) and washed with water (3×50 mL). The aqueous layers were back-extracted with ethyl acetate (20 mL) and the combined organic layer was dried over MgSO4 and concentrated in vacuo. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as white solid (237 mg, 784 μmol, 83.2%).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)#[N:6]>O.C(O)(=O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:7](=[N:1][OH:3])[C:5]#[N:6]
Reactant: O=N[O-]
Reactant: N#CCc1nc2ccccc2s1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=NO)c1nc2ccccc2s1

Procedure:
A solution of 7.8 g (0.1 mol) of NaNO2 in 20 ml of water is added dropwise at room temperature to 17.4 g (0.1 mol) of 2-cyanomethyl-benzthiazole in 50 ml of glacial acetic acid. The end product is filtered off after 2 hours and washed with water: 19.5 g (96% of theory), melting point >170° (decomposition).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[F:13][C:14]([F:24])([CH2:20][CH2:21][CH2:22][CH3:23])[C:15](OCC)=[O:16].OS(O)(=O)=O>O1CCCC1.CCCCC>[CH3:4][O:3][P:2]([CH2:1][C:15](=[O:16])[C:14]([F:24])([F:13])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:7])[O:5][CH3:6]
Reactant: CCCCC(F)(F)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
A solution of dimethyl methylphosphonoate (6.5 g, 80 mmol, 2.2 equiv) in tetrahydrofuran (100 mL) was cooled to −78° C. and n-butyllithium (2.5 M in hexanes, 14 mL, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at −78° C. for 30 min and ethyl 2,2-difluorohexanoate (6.5 g, 36 mmol, 1 equiv) was added dropwise. The solution was stirred at −78° C. for 1 h and warmed to 0° C. over 1 h. Pentane (100 mL) was added followed by the dropwise addition of 2M H2SO4 to pH=6. The aqueous layer was separated and extracted with pentane (3×15 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated to dryness under vacuum on a rotary evaporator. The crude oil was purified by column chromatography using methyl tert-butyl ether as eluant to afford 4.1 g of 26 as a yellow oil (44%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[K+].Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(N)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])c(N)cc1C(=O)O

Procedure:
To a suspension of 13.57 g of methyl 5-amino-2-methoxy-4-nitrobenzoate in 250 ml of dioxane was added a solution of 4.36 g of potassium hydroxide in 25 ml of water, and the mixture was refluxed for 4 hours. To the reaction solution was added 7 ml of concentrated hydrochloric acid. The solvent was evaporated under reduced pressure, and the residue, after addition of dioxane, was refluxed for an hour. The insoluble was removed by filtration, and the filtrate was allowed to stand to give the title compound, m.p. 252°-255° C., yield of 10.99 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][C:10]2[N:11]([N:15]=[CH:16][N:17]=2)[C:12](=O)[CH:13]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[N:11]2[N:15]=[CH:16][N:17]=[C:10]2[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:13]=1
Reactant: O=c1cc(-c2ccccc2F)[nH]c2ncnn12
Reactant: O=P(Cl)(Cl)Cl
Product: Fc1ccccc1-c1cc(Cl)n2ncnc2n1
Yield: 46 %

Procedure:
5-(2-Fluoro-phenyl)-4H-[1,2,4]triazolo[1,5-a]pyrimidin-7-one (840 mg, 3.64 mmole) was suspended in phosphorous oxychloride (5 ml) and heated to reflux for 45 min. The excess phosphorous oxychloride was removed under vacuum, the residue was treated with ice, the product was extracted with chloroform, then the chloroform was washed with 10% sodium bicarbonate, dried over sodium sulfate and the solvent was removed under vacuum to give 420 mg of product (yield 46%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1.[CH3:28][SH:29].[Na]>O1CCCC1.C(OCC)(=O)C>[CH3:28][S:29][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=4)[C:12]=3[CH:27]=2)=[N:6][N:7]=1
Reactant: FC(F)(F)Oc1cccc(-c2coc3ccc(-c4nnc(CCl)o4)cc23)c1
Reactant: CS
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSCc1nnc(-c2ccc3occ(-c4cccc(OC(F)(F)F)c4)c3c2)o1
Yield: 77.6 %

Procedure:
A solution of 2-(chloromethyl)-5-[3-[3-(trifluoromethoxy)phenyl]-1-benzofuran-5-yl]-1,3,4-oxadiazole (1.40 g, 3.55 mmol) and sodium methyl mercaptan (95%, 0.42 g, 5.67 mmol) in tetrahydrofuran (15 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) and recrystallized from hexane/diisopropyl ether to give the title compound (1.12 g, yield 78%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[C:13]([C:21](O)=[O:22])=[CH:12]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:24][CH2:25][CH2:26][NH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([CH3:20])[CH:18]=3)[C:13]([C:21]([NH:27][CH2:26][CH2:25][F:24])=[O:22])=[CH:12]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: NCCF
Reactant: COc1ncc(F)cc1Cn1cc(C(=O)O)c2ncc(C)cc21
Product: COc1ncc(F)cc1Cn1cc(C(=O)NCCF)c2ncc(C)cc21
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
See FIG. 19(c). 1-((5-fluoro-2-methoxypyridin-3-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (60 mg, 0.19 mmol) and 2-fluoroethanamine (21.60 mg, 0.34 mmol), TEA (0.080 mL, 0.57 mmol) was added. After 3 min1-Propanephosphonic acid cyclic anhydride (151 mg, 0.48 mmol) was added. The resulting reaction mixture was stirred at rt for 50 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water.DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product 1-((5-fluoro-2-methoxypyridin-3-yl)methyl)-N-(2-fluoroethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (25.00 mg, 36.5%). ES+MS m/z: 361.33. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.44 (s, 3 H ) 3.65 (d, J=5.27 Hz, 1 H ) 3.75 (d, J=5.27 Hz, 1 H ) 3.90 (s, 3 H ) 4.49 (t, J=4.99 Hz, 1H ) 4.64 (t, J=4.99 Hz, 1 H ) 5.42 (s, 2 H ) 7.36 (dd, J=8.29, 3.01 Hz, 1 H ) 7.93 (s, 1H ) 8.12 (d, J=3.01 Hz, 1 H ) 8.23 (s, 1H ) 8.38 (s, 5 H ) 8.88 (t, J=5.65 Hz, 1 H ).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][C:8]1[S:9][C:10]([CH:14]=[O:15])=[C:11]([Br:13])[N:12]=1>O>[Br:7][C:8]1[S:9][C:10]([C:14]([OH:2])=[O:15])=[C:11]([Br:13])[N:12]=1
Reactant: O=Cc1sc(Br)nc1Br
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1sc(Br)nc1Br

Procedure:
Solid potassium permanganate (2.19 g, 13.85 mmol) was added portionwise to a hot suspension of 2,4-dibromo-thiazole-5-carbaldehyde (2.5 g, 9.23 mmol) in water (20 ml). The progress of the reaction was monitored by HPLC. More potassium permanganate was added until all of the aldehyde was consumed. The dark suspension was filtered while hot. The filtrate was cooled and acidified with conc. hydrochloric acid to pH=2 to 3. The resulting precipitate was filtered off to afford a white solid as the desired product. The filtrate was lyophilized and methanol was added to dissolve the remaining acid product. The suspension was filtered and the filtrate was concentrated in vacuo. Two crops were combined to give 2,4-dibromo-thiazole-5-carboxylic acid 1.8 g (68%). 1H NMR (300 MHz, DMSO-d6) δ 11.87 (s, 1H).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[C:3](=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C:7](=[O:14])[CH2:6][CH2:5]3)[O:2]1.[N+:15]([C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=1[CH:20]=O)([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=1[CH:20]=[C:8]1[C:9]2[C:4](=[C:3]3[O:2][CH2:1][O:13][C:12]3=[CH:11][CH:10]=2)[CH2:5][CH2:6][C:7]1=[O:14])([O-:17])=[O:16]
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: O=C1CCc2c(ccc3c2OCO3)C1
Product: COc1cc(C=C2C(=O)CCc3c2ccc2c3OCO2)c([N+](=O)[O-])cc1OC

Procedure:
Prepared from 5,6-methylendioxy-2-tetralone and 2-nitro-4,5-dimethoxybenzaldehyde; mp 66-68° C.: IR (Nujol): 1710, 1553; 1H NMR: δ2.98 (2H, t), 3.19 (2H, t), 4.02 (3H, s), 4.03 (3H, s), 6.03 (2H, s), 6.82 (1H, d, J=8.1), 7.07 (1H, s), 7.29 (1H, d, J=8.1), 7.49 (1H, s), 8.20 (1H, s); 13C NMR: δ21.8, 30.8, 56.5, 56.7, 101.8, 105.7, 107.6, 117.9, 119.1, 123.9, 125.9, 126.9, 128.7, 143.4, 145.4, 147.7, 150.1, 152.9, 156.1, 176.4; Anal. (C20H17NO7) C, H, N.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:38]([C:40]1([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)#[CH:39]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:12]1([CH2:11][C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:39]#[C:38][C:40]3([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:7][N:6]=2)=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C#CC1(O)CCOCC1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)ccc1S(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC3(O)CCOCC3)cn2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.1 %

Procedure:
A mixture of N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (prepared as in Example 57, 154 mg, 0.33 mmol), N,N-diisopropylethylamine (0.6 mL, 3.44 mmol), and 4-ethynyl-tetrahydropyran-4-ol (prepared as in Example 46, 85 mg, 0.67 mmol) in toluene (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol) and copper(I) iodide (7 mg, 0.0367 mmol). The mixture was stirred at 25° C. for 17 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned with methylene chloride (50 mL) and a 0.2M aqueous hydrochloric acid solution (25 mL) and the layers were separated. The aqueous phase was back-extracted with methylene chloride (25 mL). Each organic layer was washed with a saturated aqueous sodium chloride solution (1 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with mixtures of ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[5-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 55%) as a yellow foam: (ES)+-HRMS m/e calcd for C27H33N3O5S (M+H)+ 512.2214, found 512.2219.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:4].Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:15][O:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Product: COc1ccc2cc(C(=O)O)n(Cc3cccc4ccccc34)c2c1

Procedure:
Using general procedure B, 6-methoxy-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 330.1 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][CH2:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ncsc1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ncsc1CCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
1 g (6.98 mmol) of 2-(4-methylthiazol-5-yl)ethanol is dissolved in 15 mL of dichloromethane. The solution is cooled to 0° C. When the temperature is reached, 1.85 g (6.98 mmol) of triphenylphosphine are added, followed by portionwise addition of 1.30 g (6.98 mmol) of N-bromosuccinimide. After stirring for 2 hours at 0° C., the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give 900 mg of 5-(2-bromoethyl)-4-methylthiazole, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[C:15]([CH:16]=2)=[N:14][N:13]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:12]=3[C:24]([NH:26][CH3:27])=[O:25])[CH:5]=[CH:6][CH:7]=1.[C:28]1(=[O:38])[O:33][C:31](=[O:32])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12>C(#N)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([N:13]2[C:12]([C:24](=[O:25])[NH:26][CH3:27])=[C:11]3[C:15]([CH:16]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:28]([C:29]5[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=5[C:31]([OH:33])=[O:32])=[O:38])[CH:7]=[CH:6][CH:5]=4)[CH:9]=[CH:10]3)=[N:14]2)=[CH:18][CH:19]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CNC(=O)c1c2ccc(-c3cccc(N)c3)cc2nn1-c1ccc(F)cc1
Solvent: CC#N
Product: CNC(=O)c1c2ccc(-c3cccc(NC(=O)c4ccccc4C(=O)O)c3)cc2nn1-c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 51.3 %

Procedure:
To a solution of Compound (16) (10 mg, 0.03 mmol) in ACN (3 mL) was added phthalic anhydride (8.2 mg, 0.06 mmol) and the reaction mixture was heated to 70° C. and stirred for 15 h. The reaction mixture was then cooled to RT and the resulting precipitate was collected by filtration. The residue was washed with cold ACN (5 mL) to afford Compound (17) as an off-white amorphous solid (7.83 mg, 55%). ESI-MS m/z calculated for [M+H]+: 509.15; found: 509.08. 1H NMR (400 MHz, d6-DMSO) δ 13.07 (brs, 1H), 10.47 (s, 1H), 8.77-8.71 (m, 1H), 7.99-7.87 (m, 3H), 7.77-7.38 (m, 12H), 2.85 (d, J=4.5 Hz, 3H).