Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([C:5]1[C:6]([Cl:11])=[N:7][CH:8]=[CH:9][CH:10]=1)=[N:3][OH:4].[CH3:12][O:13][C:14](=[O:18])[C:15]#[C:16][CH3:17].C(N(CC)CC)C>C(OCC)C>[CH3:12][O:13][C:14]([C:15]1[C:2]([C:5]2[C:6]([Cl:11])=[N:7][CH:8]=[CH:9][CH:10]=2)=[N:3][O:4][C:16]=1[CH3:17])=[O:18]
Reactant: ON=C(Cl)c1cccnc1Cl
Reactant: CC#CC(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2cccnc2Cl)noc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine chloro(2-chloro(3-pyridyl))(hydroxyimino)methane (2.90 g, 0.015 mol) with methyl-2-butynoate (1.19 mL, 0.012 mol) in diethyl ether (75 mL). Cool the mixture in an ice bath under a nitrogen atmosphere. Add a solution of triethylamine (1.77 mL, 0.013 mol) in diethyl ether (10 mL) in a dropwise manner. Stir the mixture overnight while warming to ambient temperature. Quench the mixture with water and extract with diethyl ether. Concentrate the combined extracts and elute over silica gel with 10% methanol/dichloromethane to give the desired isoxazole along with a co-eluting impurity (2.30 g, 60%). MS(ES): (M+1)+ 253.0, 255.0 m/z.
Reaction SMILES: [Si]([O:8][C@H:9]([C:49]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]2[C:50]=1[CH:51]=[CH:52][C:53](=[O:60])[NH:54]2)[CH2:10][NH:11][CH2:12][C:13]1[CH:48]=[CH:47][C:16]2[N:17]([CH2:21][CH2:22][CH2:23][N:24]([CH3:46])[C@H:25]3[CH2:30][CH2:29][C@H:28]([O:31][C:32]([C:41]4[S:42][CH:43]=[CH:44][CH:45]=4)([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)[C:33]([O-:35])=[O:34])[CH2:27][CH2:26]3)[C:18](=[O:20])[NH:19][C:15]=2[CH:14]=1)(C(C)(C)C)(C)C.[FH:61].F.F.C(N(CC)CC)C.C(#N)C>C1COCC1>[FH:61].[FH:61].[OH:8][C@H:9]([C:49]1[CH:58]=[CH:57][C:56]([OH:59])=[C:55]2[C:50]=1[CH:51]=[CH:52][C:53](=[O:60])[NH:54]2)[CH2:10][NH:11][CH2:12][C:13]1[CH:48]=[CH:47][C:16]2[N:17]([CH2:21][CH2:22][CH2:23][N:24]([CH3:46])[C@H:25]3[CH2:30][CH2:29][C@H:28]([O:31][C:32]([C:36]4[S:37][CH:38]=[CH:39][CH:40]=4)([C:41]4[S:42][CH:43]=[CH:44][CH:45]=4)[C:33]([OH:35])=[O:34])[CH2:27][CH2:26]3)[C:18](=[O:20])[NH:19][C:15]=2[CH:14]=1
Reactant: CN(CCCn1c(=O)[nH]c2cc(CNC[C@H](O[Si](C)(C)C(C)(C)C)c3ccc(O)c4[nH]c(=O)ccc34)ccc21)[C@H]1CC[C@H](OC(C(=O)[O-])(c2cccs2)c2cccs2)CC1
Agent: F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCCn1c(=O)[nH]c2cc(CNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)ccc21)[C@H]1CC[C@H](OC(C(=O)O)(c2cccs2)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
95 mg (0.12 mmol) of 71% pure trans-4-[{3-[5-({[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]propyl}(methyl)amino]cyclohexylhydroxy(di-2-thienyl)acetate (Intermediate 17) are dissolved in 2 ml THF. 0.05 ml (0.31 mmol) of triethylamine trihydrofluoride are added and the system stirred overnight at room temperature. The supernatant is discarded and the residue is washed with 2×10 additional ml of THF and the supernatant is again discarded. Acetonitrile (5 ml) is added to the residue and the solid is stirred for 2 hr, aged overnight, filtered and washed with acetonitrile. The residue is chromatographically purified with C-18 reversed phase column silica from MERCK, using water to acetonitrile/MeOH as eluents with a gradient from 0% to 100%. 31.8 mg of pure title compound are thus obtained (51% yield).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(C(F)(F)F)c2)C1
Solvent: C1CCOC1
Product: FC(F)(F)c1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 55.1 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-trifluoromethylphenyl)piperidin-1-yl]methanone (30 mg, 0.077 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave 16 mg of the title compound.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]#[N:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl.O1CCCC1>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH2:37][C:38]#[N:39])[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC#N)c3csc(N)n3)[C@H]2SC1
Yield: 70 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.1 g.) and conc. hydrochloric acid (1.6 g.) in methanol 21 ml.) and tetrahydrofuran (5 ml.) was treated in a similar manner to that of Example 9-(2) to give 7-[2-(2-aminothiazol-4-yl)-2-cyanomethoxyiminoacetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 1.40 g.).
Reaction SMILES: C[O-].[Na+].CO.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[NH:14][S:15]([C:18]1[N:29]=[C:21]2[CH:22]=[C:23](Cl)[CH:24]=[C:25]([O:26][CH3:27])[N:20]2[N:19]=1)(=[O:17])=[O:16].[C:30](O)(=[O:32])C>CS(C)=O.ClCCl>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[NH:14][S:15]([C:18]1[N:29]=[C:21]2[CH:22]=[C:23]([O:32][CH3:30])[CH:24]=[C:25]([O:26][CH3:27])[N:20]2[N:19]=1)(=[O:17])=[O:16]
Reactant: CC(=O)O
Reactant: COc1cc(Cl)cc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2c1

Procedure:
Sodium methoxide in methanol (3.0 mL of 25 percent solution, 0.71 g, 0.013 mol) was added to a solution of N-(2,6-dichlorophenyl)-5-methoxy-7-chloro[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide (0.66 g, 0.0016 mol) in dimethyl sulfoxide (30 mL) with stirring over several hours. The mixture was allowed to react and was then acidified with acetic acid and diluted with dichloromethane. The resulting organic phase was recovered and washed with water and the volatiles were removed by evaporation under reduced pressure. The residue obtained was chromatographed on silica gel starting with 0.5 percent acetic acid in dichloromethane and gradually increasing the strength to 0.5 percent acetic acid plus 1.0 percent ethanol in dichloromethane. The product fractions were concentrated by evaporation under reduced pressure to obtain 118 mg (13 percent of theory) of the title compound as a pale yellow powder melting at 252°-253° C.(d).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](Cl)=[O:6].[CH2:14]([N:16](CC)[CH2:17]C)C.CNC.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([N:16]([CH3:17])[CH3:14])=[O:6]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN(CC)CC
Agent: CNC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 49.9 %

Procedure:
Into a solution of 3 (1.50 g, 7.36 mmol) in CH2Cl2 (30 mL) at 0° C. was added triethylamine (1.5 mL, 10.9 mmol) and dimethylamine 40% in water (0.83 mL, 7.36 mmol) dropwise. The solution was stirred and allowed to warm to RT overnight before concentrating under reduced pressure and adding EtOAc. The solution was washed sequentially with saturated NaHCO3, water, and brine, before drying over MgSO4 and concentrating under reduced pressure to give impure 4 (0.78 g, 50%). MS: APCI (AP+): 213.1 (M)+, (AP−): 212.1 (M)−.
Reaction SMILES: [OH:1][C@H:2]([CH3:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11]CC)=[O:10])[N:6]=[C:5]1[CH3:14].[OH-].[Na+].Cl>CO.C1COCC1>[OH:1][C@H:2]([CH3:15])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[N:6]=[C:5]1[CH3:14]
Reactant: CCOC(=O)c1cn(C[C@@H](C)O)c(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(C(=O)O)cn1C[C@@H](C)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
(R)-Ethyl 1-(2-hydroxypropyl)-2-methyl-1H-imidazole-4-carboxylate (2.474 mmol, 525 mg) was dissolved in methanol (1 ml) and THF (8 ml). NaOH 2 M (7.42 mmol, 3.71 ml) was added and the resulting mixture was stirred overnight at RT. The pH of the mixture was adjusted to about 5 with 1M HCl and the solvents were evaporated. Ethanol was added and the salts were removed by filtration. The filtrate was evaporated. 393 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.03 (m, 6H), 2.30 (s, 3H), 3.71-3.80 (m, 1H), 3.81-3.97 (m, 2H), 4.95 (bs), 7.67 (s, 1H).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[CH:12]=[CH:11][O:10][N:9]=1)=O.OC[C@@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[CH2:18]1.C(P(CCCC)CCCC)CCC.C1CCN(C(/N=N/C(N2CCCCC2)=O)=O)CC1>O1CCCC1>[O:10]1[CH:11]=[CH:12][C:8]([NH:7][CH2:5][C@@H:17]2[O:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:25]([F:35])[CH:24]=3)[CH2:18]2)=[N:9]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Nc1ccon1)OCC(Cl)(Cl)Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(/N=N/C(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CNc2ccon2)CN1c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 331.2 %

Procedure:
To a stirred solution of 3-(2,2,2-trichloroethyloxycarbonylamino)isoxazole (260 mg, 1.0 mmol), 5(R)-hydroxymethyl-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (see WO 95/07271; 293 mg, 1 mmol) and tributylphosphine (303 mg, 1.5 mmol) in dry tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere, was added 1,1-(azodicarbonyl)dipiperidine (378.5 mg, 1.5 mmol) in dry tetrahydrofuran (3 ml). The reaction allowed to warm to room temperature and was stirred for 4 days by which time a white suspension had formed. The reaction mixture was filtered and the residue washed with tetrahydrofuran. The filtrate was concentrated by rotary evaporation to give a yellow oil (1.2 g) which was purified by MPLC (30% ethyl acetate/hexane, ICN Alumina N 32–63) and further MPLC (100% CH2Cl2, ICN Alumina N 32–63). Concentration of the fractions by rotary evaporation gave the title compound as a crisp white foam (296 mg, 55%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Cr+3:4].[CH2:5]([N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Li])[CH2:8][CH3:9])[CH3:6]>>[CH2:5]([N:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cr:4]([C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:10][N:7]([CH2:8][CH3:9])[CH2:5][CH3:6])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:7]([CH2:8][CH3:9])[CH2:5][CH3:6])[CH2:8][CH3:9])[CH3:6]
Reactant: [Cr+3]
Reactant: [Li]c1ccccc1CN(CC)CC
Agent: [Cl-]
Product: CCN(CC)Cc1ccccc1[Cr](c1ccccc1CN(CC)CC)c1ccccc1CN(CC)CC

Procedure:
In Angew. Chem., 75, 94 (1963), Bahr and Zohm disclose reaction of chromium trichloride with 2-diethylaminomethylphenyllithium to give tris(2-diethylaminomethylphenyl)chromium. The product was highly unstable to atmospheric oxygen.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([I:12])[C:3]=1N.Cl.N([O-])=O.[Na+].[PH2](O)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[C:4]([I:12])[CH:3]=1
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1I
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: FC(F)(F)c1cc(Cl)cc(I)c1
Temperature: 57.5 °C
Reaction time: 1.17 h
Yield: 66 %

Procedure:
2-Chloro-6-iodo-4-(trifluoromethyl)benzenamine (i.e. the product of Example 4) (31.8 g, 98.9 mmol) was added to hydrochloric acid (36%, 190 mL) and the mixture was warmed to 55-60° C. for 20 min. The mixture was cooled to 0° C. Sodium nitrite (13.6 g, 197 mmol) in water (36 mL) was added over 30 min. When the addition was complete the mixture was stirred at 0-5° C. for 70 min. Hypophosphorous acid (50%, 36.5 mL, 351 mmol) was added dropwise at 5-10° C. over 40 min. When the addition was complete the mixture spontaneously warmed briefly to 35° C., and was then cooled to 10-20° C. After stirring at 10-20° C. for 2 h, the mixture was stored in a refrigerator overnight. Then the mixture was warmed to room temperature and was stirred for 1 h. The mixture was diluted with water (400 mL) and extracted with ether (2×250 mL). The combined extracts were dried and evaporated. Distillation gave the product as an oil (19.93 g, 66% yield), b.p. 98-112° C. at 2.0 kPa.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=[O:7].C(#N)C.[OH-].[Na+:17]>O>[C:1]([O-:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].[Na+:17].[Na+:17]
Reactant: COC(=O)CCCCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C([O-])CCCCC(=O)[O-]

Procedure:
17.4 Grams (0.1 mole) of dimethyl adipate are dissolved in 100 mls. of acetonitrile and heated to 70° C. 8.2 Grams (0.2 mole) of sodium hydroxide dissolved in 6.0 g. of water are added to the reaction mixture. The reaction mixture is stirred at reflux temperature for 18 hours. The resulting solution is filtered hot and the solids are air dried to yield disodium adipate as the reaction product.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[O:23]C(C)(C)[N:21]([C:26](=[O:30])[CH:27]([F:29])[F:28])[C@H:20]3[CH2:31][F:32])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][CH:2]([C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C@@H:19]([OH:23])[C@H:20]([NH:21][C:26](=[O:30])[CH:27]([F:29])[F:28])[CH2:31][F:32])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([F:4])([F:5])[F:6]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(C(N)C(F)(F)F)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
To a stirred solution of 1-((4R,5R)-5-{4-[6-(1-Amino-2,2,2-trifluoro-ethyl)-pyridin-3-yl]-phenyl}-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl)-2,2-difluoro-ethanone (35 mg, 0.076 mmol) in CH2Cl2 (1 mL) is added trifluoroacetic acid (1 mL) at 0° C. then stirred to room temperature for 3 hours. The solvent evaporated in vacuo and the crude material is diluted with ammonia solution and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by preparative TLC using in 70% ethyl acetate in hexane to afford the title compound (0.013 g): 1H-NMR (400 MHz, DMSO-d6) δ: 2.66 (d, J=7.28 Hz, 2H), 4.30-4.36 (m, 1.5H), 4.40-4.44 (m, 0.5H), 4.54-4.55 (m, 0.5H), 4.61-4.68 (m, 1.5H), 4.89 (t, J=3.8 Hz, 1H), 5.93 (d, J=4.36 Hz, 1H), 6.19 (t, J=53.8 Hz, 1H), 7.45 (d, J=8.32 Hz, 2H), 8.00 (d, 1.16 Hz, 2H), 8.05 (d, J=8.28 Hz, 2H), 8.73 (s, 1H), 8.84 (d, J=8.56 Hz, 1H). LC-MS (m/z): [M+H]=422.0.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([CH2:20][O:21][CH3:22])[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CCO>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][CH:17]=[C:18]([CH2:20][O:21][CH3:22])[N:19]=2)=[CH:13][CH:14]=1
Reactant: COCc1c[nH]c(-c2ccc(OCc3ccccc3)cc2)n1
Agent: [Pd]
Solvent: CCO
Product: COCc1c[nH]c(-c2ccc(O)cc2)n1
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A suspension of 59 (4.6 g, 0.016 mol), EtOH (150 ml) and 10% Pd/C (1.5 g) was hydrogenated on a Parr shaker at 60.5 psi. After shaking overnight, the suspension was filtered under N2 through super cel. The solution was concentrated to dryness to Yield 3.2 g (100%) of 60; m.p. 191°-2° C. (CH3CN).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([OH:13])[C:10]([NH2:12])=[O:11].[C:14](=O)(OC)[O:15]C.CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][C:14](=[O:15])[NH:12][C:10]1=[O:11]
Reactant: NC(=O)C(O)c1c(F)cccc1Cl
Reactant: COC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C1NC(=O)C(c2c(F)cccc2Cl)O1
Temperature: 25 °C
Yield: 101.6 %

Procedure:
2-(2-Chloro-6-fluorophenyl)-2-hydroxyacetamide (3 g., 15 mmoles) was taken into 40 ml. of tert-butanol and dimethyl carbonate (2.7 g., 2.5 ml. 30 mmoles). Potassium tert-butoxide (3.4 g., 30 mmoles) was added portionwise and the reaction mixture heated to reflux for 65 minutes, cooled to room temperature, quenched by the portionwise addition of 60 ml. of 1 N hydrochloric acid, poured into 200 ml. of water and extracted with three portions of ethyl acetate. The combined organic extracts were washed with water, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 5-(2-chloro-6-fluorophenyl)oxazolidine-2,4-dione (3.5 g.). Purified product was obtained by recrystallization from toluene (3.0 g., m.p. 156°-158° C.).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[CH3:8][N+:9](C)=[C:10](N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:34]([O:38][C:39]([NH:41][CH:42]([CH2:46][C:47]1[CH:48]=[N:49][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([F:59])[C:54]=2[F:60])=[CH:51][CH:52]=1)[C:43](O)=[O:44])=[O:40])([CH3:37])([CH3:36])[CH3:35].CNC.O1CCCC1>CN(C)C=O>[F:60][C:54]1[C:55]([F:59])=[CH:56][CH:57]=[CH:58][C:53]=1[C:50]1[N:49]=[CH:48][C:47]([CH2:46][CH:42]([NH:41][C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:37])[CH3:35])[C:43]([N:9]([CH3:10])[CH3:8])=[O:44])=[CH:52][CH:51]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(-c2cccc(F)c2F)nc1)C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol) and N,N-diisopropylethylamine (92 uL, 0.53 mmol) were added to a solution of 2-[(tert-butoxycarbonyl)amino]-3-[6-(2,3-difluorophenyl)pyridin-3-yl]propanoic acid (100 mg, 0.3 mmol) in N,N-dimethylformamide (5 mL). The reaction was stirred at r.t. for 10 min, and 2 M of dimethylamine in tetrahydrofuran (0.26 mL, 0.53 mmol) was added and stirred for 1 h. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give crude tert-butyl 3-(6-(2,3-difluorophenyl)pyridin-3-yl)-1-(dimethylamino)-1-oxopropan-2-ylcarbamate (0.06 g, 60%) as an oil. Analytical LCMS (M+H)+: m/z=406.0.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[N:16]1([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][NH2:31])(=[O:23])=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:31]([CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[S:21]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:23])=[O:22])[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: NCc1ccccc1S(=O)(=O)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=c1c(C(N)=O)cc(Cl)cn1Cc1ccccc1S(=O)(=O)N1CCCC1
Yield: 67.5 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (1.42 g), 1-[2-(pyrrolidin-1-ylsulfonyl)phenyl]methanamine hydrochloride obtained in Step 3 (2.0 g) and potassium carbonate (2.08 g) were stirred in ethanol (20 ml) at 90° C. for 8 hr. The reaction mixture was poured into 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=4:1). The obtained residue was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution (3 ml) was added, and the mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.88 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](N(OC)C)=[O:23])=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@H:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](=[O:23])[CH2:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[CH:18][CH:19]=1
Reactant: Cc1ccncc1
Reactant: CON(C)C(=O)C[C@H](c1ccc(Br)cc1)c1ccccc1C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccccc1[C@H](CC(=O)Cc1ccncc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 4-methylpyridine (308 mg, 3.31 mmol) in tetrahydrofuran at −78° C. was added dropwise n-butyllithium solution (1.6 M in hexane, 2.07 mL, 3.31 mmol). The reaction mixture was stirred for 1 hour at room temperature and cooled down again to −78° C. (R)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1; 400 mg, 1.1 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. A saturated solution of sodium hydrogencarbonate and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (10% methanol in dichloromethane) to yield the title compound as a yellow oil (51%), MS (ESI+): m/z=394.0 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C@H:38]2[CH2:43][NH:42][CH2:41][CH2:40][NH:39]2)=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C@@H:38]2[NH:39][CH2:40][CH2:41][N:42]([C:6]3[C:5]4[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:43]2)=[CH:32][CH:31]=1
Reactant: Fc1ccc(CC[C@H]2CNCCN2)cc1
Reactant: FC(F)(F)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Product: Fc1ccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)cc1
Yield: 77.8 %

Procedure:
Using a method similar to in Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.62, 3.0 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in ethanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (1.11 g): mass spectrum (APCI+, m/e): 476 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.67–8.36 (m, 2H), 7.27–7.16 (m, 2H), 7.13–7.03 (m, 2H), 7.01–6.86 (m, 3H), 6.75–6.68 (m, 1H), 4.24–3.96 (br. m, 2H), 3.39–2.91 (m, 5H), 2.75–2.51 (m, 2H), 1.88–1.73 (m, 2H).