Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[CH3:13][Si:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][OH:17].[H-].[Na+].S([O-])(O)(=O)=O.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10])[O:17][CH2:16][CH2:15][Si:14]([CH3:19])([CH3:18])[CH3:13]
Reactant: C[Si](C)(C)CCO
Reactant: Fc1ccc(C(F)(F)F)c(Cl)c1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOc1ccc(C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 870.4 %

Procedure:
To 2-chloro-4-fluoro-(trifluoromethyl)benzene (2.39 g, 1.2 mmol) and 2-(trimethylsilyl)ethanol (2.13 g, 1.8 mmol) in anhydrous tetrahydrofuran (100 mL) was added sodium hydride (0.72 g, 1.8 mmol, 60% in mineral oil). The resulting mixture was stirred at room temperature for 18 hours under nitrogen. The reaction mixture was poured onto water and acidified with aqueous potassium hydrogen sulfate and extracted with ethyl acetate (3×30 mL), dried (MgSO4), filtered and concentrated in vacuo to afford 3.1 g (87%) of the title compound as a colourless oil.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:11][P:12]([CH2:15][C:16]([OH:18])=O)([OH:14])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[NH:43]1[CH2:57][CH2:56][CH2:55][C@H:44]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].[NH4+].[OH-].O>O1CCCC1.C(O)(C)C.C(O)(=O)C.CO.ClCCl>[C:1]([NH:9][CH:10]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:11][P:12]([CH2:15][C:16]([N:43]1[CH2:57][CH2:56][CH2:55][C@H:44]1[C:45]([O:47][CH2:48][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:46])=[O:18])([OH:14])=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@@H](CP(=O)(O)CC(=O)O)NC(=O)c1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Solvent: CO
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)CC(CP(=O)(O)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (S)-[[2-(benzoylamino)-4-methylpentyl]hydroxyphosphinyl]acetic acid (0.85 g., 2.60 mmole) in dry tetrahydrofuran (10 ml.) at 0° (ice bath) under argon was treated with carbonyldiimidazole (0.50 g., 3.08 mmole). After one hour, the mixture was treated with triethylamine (1.0 ml., 7.23 mmole), and L-proline, phenylmethyl ester, hydrochloride salt (0.75 g., 3.1 mmole), allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between ethyl acetate-5% potassium bisulfate. The ethyl acetate layer was washed successively with 5% potassium bisulfate, 5% sodium biphosphate (pH 4.5 buffer) and saturated sodium chloride, dried (MgSO4) and evaporated. The residue (1.3 g.) was taken up in 1N lithium hydroxide (2.5 ml.), diluted with saturated sodium bicarbonate (30 ml.) and washed with ether (twice). The aqueous phase was acidified with concentrated hydrochloric acid (pH 1) and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with saturated sodium chloride, dried (MgSO4) and evaporated to give 0.9 g. of (S)-1-[[[2-(benzoylamino-4-methylpentyl]hydroxyphosphinyl]acetyl]-L-proline, phenylmethyl ester as a white foam. Rf (acetic acid/methanol/dichloromethane; 1:1:20)=0.25; Rf (isopropanol/conc. NH4OH/water; 7:2:1)=0.74.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[N:7][C:6]=12.[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH3:33])=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>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.CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH3:33])=[C:22]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[N:7][C:6]=23)[CH:23]=1)=[O:18]
Reactant: FC(F)Oc1cnc2c(Br)cnn2c1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cnn3cc(OC(F)F)cnc23)c(C)s1
Temperature: 85 °C
Yield: 66.5 %

Procedure:
To a flask containing DMF (40.6 mL) was added 3-bromo-6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidine (1.07 g, 4.06 mmol), methyl-5-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (1.20 g, 4.27 mmol), palladium tetrakis (235 mg, 0.203 mmol), and 2 M sodium carbonate (aq) (6.10 mL, 12.2 mmol). The reaction mixture was sealed and degassed with N2 for 5 min. The reaction mixture was then heated to 85° C. for 16 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane. The organic layer was washed twice with saturated sodium bicarbonate (aq) twice and once with brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-80% EtOAc/Hex) to afford the title compound (0.916 g, 2.70 mmol). LRMS (APCI) calc'd for (C14H11F2N3O3S) [M+H]+, 340.1; found 340.0.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:12][C@@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C1COCC1.N1C=CC=CC=1.N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][OH:15])[O:12][C@@H:11]([N:23]2[C:27]3[N:28]=[CH:29][N:30]=[C:31]([NH:32][C:33](=[O:40])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1CO
Temperature: 25 °C
Reaction time: 30 h
Yield: 31 %

Procedure:
To a solution of N-{7-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-2-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}benzamide (1.06 g, 1.82 mmol) in 18 mL THF/pyridine (1:1) was added approximately 20 drops of hydrofluoridic acid in pyridine. The mixture was stirred at r.t. for 30 h. The reaction was quenched by slowly adding to saturated aq NaHCO3 (100 mL) and the solution was extracted with EtOAc (3×50 mL). The combined organics were washed with saturated aq Cu(SO4)2 (50 mL) and saturated aq EDTA.Na2. The combined organics were dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography (15 to 50% EtOAc/hexanes) to isolate the title compound as a white foam (0.264 g, 31%).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)=[O:24]>CN(C=O)C.O>[Cl:20][C:21]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:22]=1[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)=[CH:31][CH:32]=1)=[O:24]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
To a solution of theophylline (1.80 g) in DMF (20 ml) were added potassium carbonate (1.66 g) and 4-(2,4-dichlorobenzoyl)benzyl bromide (3.33 g) and the mixture was stirred at room temperature for 24 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was recrystallized (ethyl acetate) to provide the title compound as white powder (3.38 g, 76%). 1H-NMR (CDCl3) δ: 3.39(3H,s), 3.60(3H,s), 5.58(2H,s), 7.25-7.84(8H,m).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C@@:14]4([CH3:19])[C:16]([CH3:18])([CH3:17])[C@H:11]([CH2:12][CH2:13]4)[C:10]=3[C:9](=[O:20])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH2:21]([N:8]1[C:9](=[O:20])[C:10]2[C@@H:11]3[C:16]([CH3:17])([CH3:18])[C@@:14]([CH3:19])([CH2:13][CH2:12]3)[C:15]=2[N:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)[nH]n1-c1ccccc1
Reactant: BrCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(Cc2ccccc2)n1-c1ccccc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture of (4S,7R)-1-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 8; 1.00 g, 3.7 mmol) and benzyl bromide (0.9 mL, 7.6 mmol) in N,N-dimethylformamide (30 mL) was heated at 100° C. overnight. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an Isco 80 g column, eluting with 5-75% ethyl acetate/hexanes to give (4S,7R)-2-benzyl-7,8,8-trimethyl-1-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (1.01 g, 76%) as a brown oil. ES(+)-MS (M+H) 359.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].Br.Br.[CH:22]12[CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][NH:23]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:22]12[CH2:28][CH:25]([NH:26][CH2:27]1)[CH2:24][N:23]2[C:10]1[C:11]([F:13])=[C:12]2[C:7]([C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4][N:3]2[CH2:1][CH3:2])=[CH:8][C:9]=1[F:15]
Reactant: C1NC2CNC1C2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CC3CN4)c(F)c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 0.54 g (2.0 mmol) of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.57 g (2.2 mmol) of 2,5-diazabicyclo(2.2.1)heptane dihydrobromide [P. S. Portoghese and A. A. Mikhail, J. Org. Chem., 31, 1059 (1966)], 0.90 ml (6.0 mmol) of 1,8-diazabicyclo(5.4.0)undec-7ene, and 20 ml of acetonitrile was heated under reflux for one hour and stirred at room temperature for two hours. The reaction mixture was filtered and the solid was washed with ethanol to give 0.60 g of the title compound, mp 275° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29][Si:30]([CH3:37])([CH3:36])[CH2:31][CH2:32][O:33][CH2:34]Cl>CN(C=O)C.C1COCC1.CC(=O)OCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:34][O:33][CH2:32][CH2:31][Si:30]([CH3:37])([CH3:36])[CH3:29])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:14]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(Br)cc3)[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(Br)cc3)n2COCC[Si](C)(C)C)cc1
Reaction time: 2 h
Yield: 0 %

Procedure:
To a solution of 2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1H-imidazole (370 g, 900 mmol) in DMF (4 ml) was added NaH (40 mg, 980 mmol). After 2 h, 2-(trimethylsilyl)ethoxymethyl chloride (160 g, 990 mmol) in THF (2 ml) was added dropwise and reaction mixture was stirred overnight. The reaction mixture was diluted with EA and washed with aq. NaHCO3. The organics were dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The crude product was purified by chromatography (EA/hexane) to afford 32 mg (65%) of 2-(4-bromophenyl)-5-(4-(heptyloxy)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole as a tan solid. LCMS-ESI (m/z) calculated for C28H39BrN2O2Si: 542.2. found 543.3 [M+H]+, tR=3.35 min (Method 8).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:37]=[C:36]([OH:38])[C:30]3[CH2:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[CH:28]=2)=[O:26])=[N:20]1.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:18][N:19]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]2[CH:37]=[C:36]([O:38][C:9]3[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=3)[C:30]3[CH2:31][C:32]([CH3:35])([CH3:34])[O:33][C:29]=3[CH:28]=2)=[O:26])=[N:20]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)nc3)c3c(c2)OC(C)(C)C3)n1
Yield: 47.5 %

Procedure:
A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinonitrile (634 mg, 2.76 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (396 mg, 1.33 mmol), Et3N (0.96 mL, 6.89 mmol), and Cu(OAc)2 (501 mg, 2.76 mmol) in CH2Cl2 (15 mL) was stirred at room temperature with 4A molecular sieves for 4 days, then filtered through celite, washed with CHCl3, concentrated, and purified by column chromatography with 30-60% EtOAc in hexanes to give a white foam (246 mg, 46% yield). 1H NMR (400 MHz, CDCl3) δ 9.23 (s, 1 H) 8.45 (d, J=2.53 Hz, 1 H) 7.65 (d, J=8.59 Hz, 1 H) 7.21-7.35 (m, 2 H) 7.10 (d, J=111.37 Hz, 2 H) 6.78 (d, J=2.02 Hz, 1 H) 3.73 (s, 3 H) 2.89 (s, 2 H)) 1.48 (s, 6 H); LCMS for C21H19N5O3 m/z 390.00 (M+H+).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH2:7][CH2:8][CH:9]([CH:17]([OH:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])[CH3:3].ClC(Cl)(Cl)C(=N)O[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1>O1CCCC1.B(F)(F)F.CCOCC>[CH3:4][C:2]([Si:5]([CH3:28])([CH3:29])[O:6][CH2:7][CH2:8][CH:9]([CH:17]([O:27][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])([CH3:1])[CH3:3]
Reactant: COc1ccc(COC(=N)C(Cl)(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CCO[Si](C)(C)C(C)(C)C)C(O)CCc1ccc(I)cc1
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(COC(CCc2ccc(I)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
Boron trifluoride etherate (5.0 μL, 39 μmol) was added to a stirred solution of 1,1-dimethylethyl 2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-hydroxy-5-(4-iodophenyl)pentanoate (5.14 g, 9.63 mmol) and 4-methoxybenzyl 2,2,2-trichloroethanimidoate (4.05 g, 14.4 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature at which stirring was continued for 2 h. A further portion of boron trifluoride etherate (5.0 μL, 39 μmol) was then added and stirring was continued at room temperature for a further 2 h. Two further additions of boron trifluoride etherate (5.0 μL, 39 μmol) followed by stirring at room temperature for 2 h were carried out before evaporation of the solvent. The residue was chromatographed on silica gel (0% to 10% diethyl ether: cyclohexane) to give the title compound (4.14 g, 66%) as a yellow oil which was a mixture of diastereomers. LC/MS: 4.78 min; z/e 655, calcd (M+1) 655. 1H NMR (400 MHz: CDCl3): 7.55 (2H), 7.25 (2H), 6.90 (2H), 6.80 (2H), 4.55 (1H), 4.35 (1H), 3.80 (3H), 3.65 (1H), 3.55 (1H), 2.95 (1H major), 2.80 (1H minor), 2.70 (1H), 2.55 (1H), 1.95-1.60 (4H), 1.45 (9H), 0.85 (9H), 0.5 (6H).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].Cl(O)(=O)(=O)=O.C1C=[C:20]2C(C(O)(O)[C:25](=O)[C:19]2=[CH:18]C=1)=O.CCO.C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+]>C(OC(C)(C)C)(=O)C.C(OCC)C.C1(C)C=CC=CC=1.CCOC(C)=O.CO.C(Cl)Cl>[CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([O:8][C:19]([CH3:25])([CH3:20])[CH3:18])=[O:7])[NH2:5]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)C[C@H](N)C(=O)OC(C)(C)C
Yield: 96 %

Procedure:
4-Methylleucine (500 mg, 3.44 mmol) was suspended in 10 ml t-butyl acetate. Perchloric acid (0.2 ml, 3.49 mmol) was added and the flask was stopped with a septum and stirred over night. Analysis was performed using TLC DCM:MeOH, 9:1; staining with a ninhydrine/EtOH solution). The solution was poured into a flask containing 30 ml EtOAc and 30 ml 5% Na2CO3. The aq-layer turned acidic and 2M NaOH was added until pH was approximately 7. The phases were separated and the aq-phase was washed with 2×30 ml EtOAc. The combined organic phases were washed with brine, dried with Na2SO4 and evaporated. A oil was obtained which was co-evaporated with toluene and then with diethyl ether before being placed under vacuum for two days. Mass 665 mg (96% yield). NMR (CDCl3): 1.0 (s, 9H), 1.5 (s, 9H), 1.65–1.95 (m, 2H), 3.82 (t, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23][CH2:22][N:21]([S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:20][C:19]2[N:40]=[C:15]([CH:16]=[CH:17][CH:18]=2)[CH2:14]1)(=[O:12])=[O:11])([O-:3])=[O:2].[C:41]1([C:57](O)=[O:58])[C:54]2[C:55]3=[C:56]4[C:51](=[CH:52][CH:53]=2)[CH:50]=[CH:49][CH:48]=[C:47]4[CH:46]=[CH:45][C:44]3=[CH:43][CH:42]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.CN(C=O)C>[C:41]1([C:57]([N:25]2[CH2:24][CH2:23][CH2:22][N:21]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-:39])=[O:38])(=[O:30])=[O:29])[CH2:20][C:19]3[N:40]=[C:15]([CH:16]=[CH:17][CH:18]=3)[CH2:14][N:13]([S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH2:27][CH2:26]2)=[O:58])[C:54]2[C:55]3=[C:56]4[C:51](=[CH:52][CH:53]=2)[CH:50]=[CH:49][CH:48]=[C:47]4[CH:46]=[CH:45][C:44]3=[CH:43][CH:42]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCCNCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)C1
Reactant: O=C(O)c1ccc2ccc3cccc4ccc1c2c34
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(c1ccc2ccc3cccc4ccc1c2c34)N1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Yield: 85.5 %

Procedure:
The title compound was prepared following the procedures illustrated above in Example 75 using 3,10-bis(2-nitrobenzenesulfonyl)-3,6,10,16-tetraazabicyclo-[10.3.1]hexadeca-1(16),12,14-triene (0.59 g, 1.0 mmol), 1-pyrenecarboxylic acid (0.25 g, 1.0 mmol), DCC (0.21 g, 1.0 mmol), HOBT (0.14 g, 1.0 mmol) and 4-methylmorpholine (0.15 g, 1.5 mmol) in 20 mL of CH2Cl2 and 10 mL of DMF. The compound was purified by flash chromatography on a silica gel column using 200:1 CH2Cl2—MeOH as an eluent to give 0.7 g (86%) of the title compound as a pale yellow foam.
Reaction SMILES: [CH:1]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.FC1C=C(OC)C=CC=1>>[CH:1]1([C:8]([C:17]2[CH:16]=[CH:15][C:14]([OH:18])=[CH:13][C:12]=2[F:11])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc(F)c1
Reactant: O=C(Cl)C1CCCCCC1
Agent: COc1cccc(F)c1
Product: O=C(c1ccc(O)cc1F)C1CCCCCC1

Procedure:
Using the same procedure but replacing 1-adamantyl carbonyl chloride by cycloheptane carbonyl chloride and 3-fluorophenol by 3-fluoroanisole, the following compound was obtained:
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[NH:16][C:15](=[O:24])[N:14]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]3=[O:30])[CH:9]=1)=[O:4].[CH3:31][NH:32]C=O.C[O-].[Na+]>CN(C)C=O>[CH3:31][NH:32][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[NH:16][C:15](=[O:24])[N:14]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:13]3=[O:30])[CH:9]=1)=[O:4]
Reactant: CNC=O
Reactant: COC(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A solution of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro -quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methyl ester (800 mg, 1.79 mmol) and N-methylformamide (0.357 ml, 6 mmol) in 5 ml of dimethylformamide is heated to 120° C. and sodium methylate (100 mg, 1.79 mmol) is added under stirring. After two hours at 120° C. another 100 mg of sodium methylate is added and stirring at 120° C. continued for additional two hours. After cooling to room temperature the solution is evaporated in vacuo and the residue chromatographed to give 560 mg (1.25 mmol, 70%) of 1-(3-methanesulfonylamino-2,4-dioxo-7-trifluoromethyl-1,2,3,4-tetrahydro-quinazolin-6-yl)-1H-imidazole-4-carboxylic acid methylamide, m.p. 292 -295° C., ES-MS: m/z447 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([Cl:20])[CH:3]=1.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:20][C:4]1[CH:3]=[C:2]([NH:26][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=1
Reactant: NC1CCCC1
Reactant: O=C(Nc1nc2cc(Cl)cc(Cl)n2n1)c1cccnc1
Product: O=C(Nc1nc2cc(Cl)cc(NC3CCCC3)n2n1)c1cccnc1
Yield: 4.4 %

Procedure:
The title compound was prepared following procedure and work up described for example 118, but starting from N-(5,7-dichloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B10), 100 mg; 0.32 mmol; 1.0 eq) and cyclopentylamine (161 μL; 1.62 mmol; 5.0 eq) to give the title compound as a white solid (5 mg, 4%). HPLC, Rt: 3.20 min. (purity 92.3%). LC/MS, M+(ESI): 356.9, M−(ESI): 354.9.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C@@H:17]4[CH2:21][OH:22])=[O:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][NH:36][CH:37]=2)O1.C(=O)(O)[O-].[Na+].O.C(#N)C>C(OCC)(=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>[OH:22][CH2:21][C@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14]([C:8]1[S:9][C:10]2[CH2:11][CH2:12][O:13][C:4]3[CH:3]=[C:2]([C:33]4[CH:34]=[N:35][NH:36][CH:37]=4)[CH:24]=[CH:23][C:5]=3[C:6]=2[N:7]=1)=[O:15]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(c1nc2c(s1)CCOc1cc(Br)ccc1-2)N1CCC[C@@H]1CO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H]1CO
Temperature: 25 °C
Yield: 16.7 %

Procedure:
(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-((R)-2-hydroxymethyl-pyrrolidin-1-yl)-methanone (0.297 g, 0.726 mmol), 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (0.211 g, 1.09 mmol), 2 M Sodium bicarbonate in water (1 mL, 2.0 mmol) and acetonitrile (2 mL, 40 mmol) were combined in a microwave vial and thoroughly purged with nitrogen. Added Tetrakis(triphenylphosphine)palladium(0) (0.0838 g, 0.0726 mmol) and heated on the Emrys microwave at 150° C. for 10 minutes. Cooled to room temperature, diluted with ethyl acetate, washed with brine and concentrated the organic layer in vacuo. Purified by HPLC to give 101 (48 mg, 17% yield, M+1 397.1)