Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:3]([CH2:4][O:5][C:6]2[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH:16]3[CH:23]4[CH2:24][CH:19]5[CH2:20][CH:21]([CH2:25][CH:17]3[CH2:18]5)[CH2:22]4)=[O:12])=[CH:9][N:10]=2)[CH2:2]1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>C(O)C>[CH:26]([NH:29][CH2:2][CH:3]([OH:1])[CH2:4][O:5][C:6]1[S:7][C:8]([C:11]([NH:13][CH2:14][CH2:15][CH:16]2[CH:17]3[CH2:25][CH:21]4[CH2:20][CH:19]([CH2:24][CH:23]2[CH2:22]4)[CH2:18]3)=[O:12])=[CH:9][N:10]=1)([CH3:28])[CH3:27]
Reactant: CC(C)N
Reactant: O=C(NCCC1C2CC3CC(C2)CC1C3)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: CC(C)NCC(O)COc1ncc(C(=O)NCCC2C3CC4CC(C3)CC2C4)s1
Temperature: -20 °C
Reaction time: 12 h

Procedure:
This example illustrates methods for preparing the compounds of the present invention. In this example a mixture containing 12 g. (0.0314 mole) of 1,2-epoxy-3-(5-[2-(adamant-2-yl)ethylaminocarbonyl]thiazol-2-yloxy)-propane, 12 g. (0.203 mole) of isopropylamine and 20 ml. of ethanol is allowed to stand at room temperature for 12 hours. The mixture is then evaporated under vacuum to remove the solvent and the resulting residue dissolved in 50 ml. of ethyl acetate and cooled to -20° C, and maintained at this temperature for 2 hours. The mixture is then filtered and the resulting filter cake washed with cold (about 0° C) ethyl and then recrystallized from ethyl acetate affording 1-isopropylamino-3-(5-[2-(adamant-2-yl)ethylaminocarbonyl]thiazol-2-yloxy)-propan-2-ol.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([Br:13])=[C:11]([Br:14])[N:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].CO>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[C:12]([Br:13])=[C:11]([Br:14])[N:10]=[C:9]1[C:20]1[CH:19]=[CH:18][C:17]([F:16])=[CH:22][C:21]=1[F:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1nc(Br)n(Cc2ccccc2)c1Br
Reactant: OB(O)c1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nc(Br)c(Br)n2Cc2ccccc2)c(F)c1
Temperature: 25 °C
Yield: 37.6 %

Procedure:
Reflux a mixture of 1-benzyl-2,4,5-tribromoimidazole (1.043 g, 2.42 mmol), 2,4-difluorophenyl boronic acid (0.682 g, 4.32 mmol), palladium acetate (0.027 g, 0.12 mmol), R(+)-2,2′-bis(di-p-tolyl-phosphino)1,1′-binaphthyl (0.098 g, 0.14 mmol), 2 M sodium carbonate (3.6 mL, 4.83 mmol), methanol (3.6 mL) and toluene (36 mL) for 18 hours. Cool to ambient temperature and dilute with ethyl acetate. Wash with saturated sodium carbonate, saturated sodium chloride, dry with magnesium sulfate and purify the residue on silica gel eluting with hexane/ethyl acetate mixtures to provide 1-benzyl-4,5-dibromo-2-(2,4-difluoro-phenyl)-1H-imidazole (0.39 g). MS(ES+): m/z=461.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]([F:24])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:14]([O-])=O.[Na+].C[Si](OP(=O)=O)(C)C.O>CCOC(C)=O>[F:24][C:13]([F:12])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=1)[C:14]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([CH3:11])=[CH:8][CH:7]=2)[N:1]=1
Reactant: Cc1ccc(C(N)=O)c(N)c1
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc2c(O)nc(C(F)(F)c3ccc(F)cn3)nc2c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a mixture of 2-amino-4-methylbenzamide (804 mg, 5.36 mmol) and sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (1.25 g, 5.89 mmol) was added trimethylsilyl polyphosphate (ca. 10 mL) and the mixture was heated at 130° C. in a sand bath overnight. The mixture was allowed to cool to rt, and then water (75 mL) and EtOAc (75 mL) were added and the mixture was stirred at rt for 1 h. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-60% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-7-methylquinazolin-4-ol (1.09 g, 66%). LCMS (ESI) m/z 306 (M+H)+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])(=O)C.[Na+].[OH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[OH-].[Na+]>ClCCl>[N:6]1[CH:11]=[CH:10][C:9]([N:21]2[CH2:22][CH2:23][C:18](=[O:17])[CH2:19][CH2:20]2)=[CH:8][CH:7]=1
Reactant: c1cc[nH+]cc1
Reactant: OC1CCNCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.3 %

Procedure:
To a suspension of pyridinium chlorochromate (24.1 g) and sodium acetate (18.3 g) in dichloromethane (500 ml) was added small portionwise 4-hydroxypiperidine (9.7 g), and the mixture was stirred at room temperature for 5 hours. To the reaction solution was added 1N sodium hydroxide solution, and insoluble materials were dissolved. The separated aqueous layer was extracted with dichloromethane, and combined dichloromethane solution was washed with brine, dried, concentrated and crystallized from toluene to give colorless crystals of 1-(4-pyridyl)-4-piperidinone (9.0 g).
Reaction SMILES: S1C=CC=C1N([C@@H]1C(=O)N2C(C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=O)=C(CSC3N(C)N=NN=3)CS[C@H]12)C(C)=O.S1C=CC=C1N([C@@H:52]1[C:82](=[O:83])[N:54]2[CH:55](C(OC(C3C=CC=CC=3)C3C=CC=CC=3)=S)[C:56]([C:60]3[N:64]([CH3:65])[N:63]=[N:62][N:61]=3)(C)[CH2:57][S:58][C@H:53]12)C(C)=O.CSC1(CCl)CN2C(=O)C[C@H]2SC1.ClC1C=CC=C(C(OO)=O)C=1>>[CH3:65][N:64]1[C:60]([C:56]2[CH2:57][S:58][C@@H:53]3[CH2:52][C:82](=[O:83])[N:54]3[CH:55]=2)=[N:61][N:62]=[N:63]1
Reactant: CC(=O)N(c1cccs1)[C@@H]1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)C(C)(c3nnnn3C)CS[C@H]12
Agent: CC(=O)N(c1cccs1)[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnnn3C)CS[C@H]12
Agent: CSC1(CCl)CS[C@@H]2CC(=O)N2C1
Agent: O=C(OO)c1cccc(Cl)c1
Product: Cn1nnnc1C1=CN2C(=O)C[C@H]2SC1

Procedure:
Finally, T. Aoki et al. (Tetrahedron 1983, 34/15, 2515-2556—in particular pages 2520-2525) disclose the synthesis of diphenylmethyl 7β-(2-thienylacetamino)-3-(1-methyl-1H-tetrazol-5-yl)thiometyl-3-cephem-4-carboxylate, which involves the preparation of diphenylmethyl 7β-(2-thienylacetamino)-3-(l-methyl-1H-tetrazol-5-yl)-3-methylthiocepham-4-carboxylate via the corresponding 3-methylthio-3-chloromethylcepham analog and the reaction of said diphenylmethyl 7β-(2-thienylacetamino)-3-(1-methyl-1H-tetrazol-5-yl)-3-methylthiocepham-4-carboxylate with m-chloroperbenzoic acid in order to remove methylmercaptan and form a 3-(1-methyl-1H-tetrazol-5-yl)-3-cephem structure via the corresponding 1-oxide. However, the method described by Aoki et al. is not transposable to the preparation of third-generation-cefalosporins because the reactants employed affect the amino group which is present on the thiazole ring and is sensitive thereto.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=O)=[C:4](F)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:19][NH2:20]>CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]2[NH:19][N:20]=[C:11]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:3]=12
Reactant: COc1ncc(Br)c(C(=O)C2CCCC2)c1F
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1ncc(Br)c2c(C3CCCC3)n[nH]c12
Reaction time: 3 h

Procedure:
To a solution of (5-bromo-3-fluoro-2-methoxypyridin-4-yl)(cyclopentyl)methanone (440 mg) in methanol (10 mL) was added hydrazine monohydrate (2.06 mL) at room temperature, the mixture was stirred for 3 hr, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane) to give the title compound (100 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+].C1COCC1.[CH2:26]([O:28][C:29](=[O:34])[C:30](=O)[CH2:31]Br)[CH3:27].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[CH2:26]([O:28][C:29]([C:30]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:8][CH:7]=2)[O:12][CH:31]=1)=[O:34])[CH3:27]
Reactant: NC(=O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(C=Cc2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of 3-(4-trifluoromethyl-phenyl)-acrylamide (5.0 g, 23.2 mmol) and NaHCO3 (7.80 g, 92.9 mmol) in THF (90 ml) 3-bromo-2-oxo-propionic acid ethyl ester (5.53 g, 25.6 mmol) is added under an argon atmosphere. The mixture is heated to reflux for 15 h when another portion of 3-bromo-2-oxo-propionic acid ethyl ester (5.53 g, 25.6 mmol) is added and stirring continued for 5 h. After cooling to r.t. the mixture is filtered, concentrated in vacuo and the resulting residue suspended in THF (20 ml). At 0° C. trifluoroacetic acid anhydride (16.3 g, 77.9 mmol) is added and the mixture stirred at room temperature for 16 h. The mixture is neutralized with sat. NaHCO3, the aqueous layer extracted with ethyl acetate (2×200 ml) and the combined organic phases dried over Na2SO4 and concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate/heptane 4:1) yielding 2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazole-4-carboxylic acid ethyl ester as a colorless solid. Yield 5.84 g (81%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.CO>O>[N:1]1[CH:2]=[CH:3][C:4]([S:7][C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(Sc2ccncc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Sc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.6 %

Procedure:
A mixture of ethyl 4-(4-pyridylthio)benzoate (400 mg, 1.54 mmol) and 5 N aqueous sodium hydroxide (2 mL) in 1:1 tetrahydrofuran/methanol (2 mL) was stirred at room temperature for 18 h. The mixture was diluted with water and washed with diethyl ether. The aqueous layer was acidified to pH 6 with concentrated hydrochloric acid. The resulting precipitate was collected via vacuum filtration to provide 280 mg (78%) of the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]1([C:28]2[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:29]=2[OH:38])[CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:29]3[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:35])([F:36])[F:37])[C:28]=3[CH:25]3[CH2:26][CH2:27]3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc(C(F)(F)F)c1C1CC1
Product: CC(NC(=O)c1coc(Oc2cccc(C(F)(F)F)c2C2CC2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 57.8 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 2-cyclopropyl-3-trifluoromethyl-phenol (53 mg, 0.26 mmol) to give the title compound (41 mg, 58%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[CH2:9][CH2:8][CH:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]([CH3:34])[C:31]([NH2:33])=[O:32])[C:19]([C:35]([F:38])([F:37])[F:36])=[CH:18][N:17]=3)[CH:12]=[N:11]2)[CH2:6][CH2:5]1>CCO>[CH2:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH:30]([CH3:34])[C:31]([NH2:33])=[O:32])[C:19]([C:35]([F:37])([F:36])[F:38])=[CH:18][N:17]=3)[CH:12]=[N:11]2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCNCC3)c2)ncc1C(F)(F)F
Reactant: CC=O
Solvent: CCO
Product: CCN1CCC(n2cc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C(C)C(N)=O)n3)cn2)CC1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
Acetaldehyde (17 μL, 0.31 mmol) was added to a solution of 2-(2-(2-(2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanamide A67 (50 mg, 0.10 mmol) in EtOH (20 mL). After 10 minutes, NaHB(OAc)3 (86 mg, 0.41 mmol) was added and the mixture was stirred for 3 hours. The reaction was quenched with water (20 mL) and the volatiles were removed in vacuo. The resultant solid was suspended in water (25 mL), sonicated for 10 minutes, collected by filtration and then dissolved in acetone (3 mL). Addition of petroleum benzine 40-60° C. gave a precipitate that was collected by filtration to give the title compound 59 as a tan solid (42 mg, 79%). LCMS-A: rt 4.808 min; m/z 516.3 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8]/[C:9](=[C:12]1\[CH2:13][O:14][C:15]2[C:20]([C:21]\1=[O:22])=[CH:19][C:18]([F:23])=[CH:17][CH:16]=2)/SC.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCOCC>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8]/[C:9](=[C:12]1\[CH2:13][O:14][C:15]2[C:20]([C:21]\1=[O:22])=[CH:19][C:18]([F:23])=[CH:17][CH:16]=2)/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CS/C(CCC1OCCCO1)=C1/COc2ccc(F)cc2C1=O
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: O=C1/C(=C(/CCC2OCCCO2)c2ccccc2)COc2ccc(F)cc21
Reaction time: 0.5 h

Procedure:
To a solution of 650 mg (1.92 mmol) 5-2 in 50 mL of Et2O cooled to 0° C. was added dropwise 670 μL (2.02 mmol) 3M PhMgBr in Et2O. This mixture was stirred for 30 min, quenched with a solution of saturated NH4Cl, dumped into a separatory funnel containing EtOAc, the layers were separated, and the organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography with EtOAc/hexanes to provide 5-3 as a yellow oil. Data for 5-3: 1HNMR (500 MHz, CDCl3) δ 7.65 (m, 1H), 7.5-7.3 (m, 4H), 7.15 (m, 2H), 6.85 (m, 1H), 4.8 (s, 2H), 4.55 (m, 1H), 4.05 (m, 2H), 3.7 (m, 2H), 3.0 (m, 2H), 2.0 (m, 1H), 1.7 (m, 2H), 1.3 (m, 1H) ppm, LC-MS: rt=2.9 min, m/z=369 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])=[O:4].Cl[C:39](=[O:44])[C:40]([O:42][CH3:43])=[O:41]>>[CH3:43][O:42][C:40](=[O:41])[C:39]([NH:1][C@H:2]([C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH2:8][C@H:9]([N:12]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10][OH:11])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:44]
Reactant: CC(C)CN([C@H](CO)CCCNC(=O)[C@@H](N)Cc1cccc2ccccc12)S(=O)(=O)c1ccc(N)cc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)NCCC[C@@H](CO)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1

Procedure:
The title compound was prepared from (2S,4S)-2-amino-N-{4-[(4-amino-benzenesulfonyl)-isobutyl-amino]-5-hydroxy-pentyl}-3-naphthalen-1-yl-propionamide (see example 8) as described in general procedure D using methyl chlorooxoacetate. The final product was obtained in 75% yield.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)=[C:4]([F:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:18][C:4]1[CH:3]=[C:2]([C:21]2[C:20]([NH2:19])=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:6]([F:8])[C:5]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]1
Reactant: Fc1cc(Br)cc(F)c1-n1ccc(C(F)(F)F)n1
Reactant: Nc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccccc1-c1cc(F)c(-n2ccc(C(F)(F)F)n2)c(F)c1
Temperature: 85 °C

Procedure:
A mixture of 1-(4-bromo-2,6-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole (i.e. the product of Step C, 1.83 g, 5.6 mmol), B-(2-aminophenyl)-boronic acid (0.90 g, 6.58 mmol), sodium carbonate (2.07 g, 19.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.33 g, 0.76 mmol) in 1,2-dimethoxyethane (46 mL) and water (11 mL) was heated at 85° C. for 16 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by medium pressure liquid chromatography on silica gel eluted with 0 to 100% ethyl acetate in hexanes to yield the title compound (1.02 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[N:34]=[C:33]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:32]=[CH:31][N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1nccc(-c2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4nccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-4-phenyl-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([C:15](=O)[NH:16][CH2:17][C:18]2[N:19]=[C:20]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:21]3=[N:22][CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1.FC(F)(F)C([O-])=O.[Hg+2].FC(F)(F)C([O-])=O>[CH3:14][C@@H:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]1[C:15]1[N:19]2[C:20]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=4)(=[O:28])=[O:29])[C:21]=3[N:22]=[CH:23][C:18]2=[CH:17][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)[C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)cnc32)cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [Hg+2]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2cnc([C@H]4CN(C(=O)OC(C)(C)C)CC[C@H]4C)n23)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of (3R,4R)-tert-butyl-4-methyl-3-((5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl-carbamoyl)-piperidine-1-carboxylate (53 g, 100 mmol) and Lawesson's reagent (22.4 g, 55.2 mmol) in 1,4-dioxane (500 mL) was heated at about 80° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then was partitioned between EtOAc (1000 mL) and saturated aqueous NaHCO3 (700 mL). The organic layer was washed with additional saturated aqueous NaHCO3 (700 mL), dried over anhydrous Na2SO4, filtered then concd in vacuo. The resulting residue was dissolved in 1,4-dioxane (500 mL) then mercury (II) trifluoroacetate (54.0 g, 127 mmol) was added. The reaction was stirred at about 25° C. for about 1 h. The reaction was partitioned with saturated aqueous Na2S2O3 (500 mL)/water (500 mL) with DCM (1000 mL). The layers were filtered through Celite® and the Celite® pad was washed with DCM (500 mL). The combined layers were separated then the organic layer was washed with saturated aqueous NaHCO3 (800 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and then concd in vacuo. The resulting residue was purified on silica gel (330 g) using 0-40% EtOAc in DCM to give (3R,4R)-tert-butyl 4-methyl-3-(6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)piperidine-1-carboxylate (40.5 g, 79%) as a yellow foam: LC/MS (Table 1, Method b) Rt=2.62 min; MS m/z: 510 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]O.CO.C(Cl)(Cl)[Cl:24]>O=S(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[N:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][Cl:24]
Reactant: OCc1cccc(OCc2ncc3ccccc3n2)c1
Reactant: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: ClCc1cccc(OCc2ncc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1.00 g (3.76 mmol) of 3-(2-quinazolinylmethoxy)benzyl alcohol in 10 ml of CHCl3, 0.5 ml of SOCl2 was added, followed by stirring at room temperature for 15 hours. A small amount of MeOH was added to the reaction mixture and the solvents were distilled off under reduced pressure, whereby 1.08 g of 3-(2-quinazolinylmethoxy) benzyl chloride were obtained as white powder.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)[N:3]=1.[OH:36][CH2:37][C:38](O)=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[OH:39][CH2:38][C:37]([N:17]1[CH2:16][CH2:15][N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:6]3[C:2]([CH3:1])=[N:3][C:4]([C:20]4[O:24][N:23]=[C:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31][C:32]([F:33])([F:35])[F:34])=[CH:27][CH:26]=5)[N:21]=4)=[N:5]3)[CH:9]=2)[CH2:19][CH2:18]1)=[O:36]
Reactant: O=C(O)CO
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCN(C(=O)CO)CC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(5-methyl-1-(3-(piperazin-1-yl)benzyl)-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Example 81; 110 mg, 0.23 mmol), 2-hydroxyacetic acid (21 mg, 0.28 mmol) and DIPEA (89 mg, 0.69 mmol) in DMF (5 mL) was added HATU (106 mg, 0.28 mmol). The resulting mixture was stirred at room temperature for 3 h, diluted with H2O (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by prep-HPLC (20% to 50% MeCN/H2O containing 0.1% trifluoroacetic acid) to give the title compound as a white solid; MS (ES+) C25H24F3N7O4 requires: 543. found: 544 [M+H]+; 1H-NMR (500 MHz, DMSO-d6) δ 8.23 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.24 (m, 1H), 6.95 (m, 2H), 6.69 (d, J=7.5 Hz, 1H), 5.49 (s, 2H), 4.12 (s, 2H), 3.56 (m, 2H), 3.15 (m, 4H), 2.58 (s, 3H), 2.50 (m, 2H).