Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCCCCCCCCCCC.NC(N)=[O:23].C(=O)(O)[O-].[Na+].OO>O>[CH2:1]1[O:23][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(N)=O
Reactant: C=Cc1ccccc1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CCCCCCCCCCCC
Solvent: O
Product: c1ccc(C2CO2)cc1

Procedure:
To a mechanically stirred solution of styrene (0.1 mol), dodecane (0.01 mol), urea (2.08 mol), sodium bicarbonate (0.03 mol) in 50.0 ml of water at 20° C. is added 30% aqueous hydrogen peroxide (0.22 mol) drop-wise over a period of 5 h. After 5 h the organic layer of the reaction mixture was separated by a separating funnel. The aqueous layer was extracted with 4×20 mL diethyl ether. The combined organic layer was distilled to yield styrene oxide. The conversion to epoxide is 99% with selectivity 95%.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(O[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:35]=[O:36])(=O)=O>CN(C)C=O>[C:42]1([CH2:41][O:40][C:39]2[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][C:32]=2[CH2:31][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: c1ccc(CCNCc2ccccc2)cc1
Reactant: CS(=O)(=O)OCc1cc(C=O)ccc1OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccc(OCc2ccccc2)c(CN(CCc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a solution of N-benzyl-N-(2-phenylethyl)amine (351 mg) and diisopropyl-ethylamine (145 mg) in dimethylformamide (1.5 ml) was added 3-[[(methylsulfonyl)oxy]methyl]-4-phenylmethoxybenzaldehyde (355 mg). After stirring at room temperature for 3 hours, the reaction mixture was partially concentrated under reduced pressure and the residue was purified by flash chromatography column using petroleum ether:diethyl ether (1:3) as eluant. The pure fractions were combined and evaporated under reduced pressure to give 4-phenylmethoxy-3-[[N-phenylmethyl-N-(2-phenylethyl)amino]methyl]benzaldehyde (420 mg) as a gum. 1H NMR (CDCl3) δ9.89 (s, 1H, CHO); 5.20 (s, 2H); 3.88 (s, 2H); 3.85 (s, 2H); 2.92 (m, 4H, CH2CH2).
Reaction SMILES: Br[C:2]1[C:18]([F:19])=[CH:17][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[S:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[CH:22]=1>>[F:19][C:18]1[C:2]([C:29]#[C:28][C@@:26]([OH:30])([C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH3:27])=[CH:3][C:4]2[C:10]3[S:11][C:12]([C:14]([NH2:16])=[O:15])=[CH:13][C:9]=3[CH2:8][CH2:7][O:6][C:5]=2[CH:17]=1
Reactant: NC(=O)c1cc2c(s1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2cc3c(cc2F)OCCc2cc(C(N)=O)sc2-3)no1
Yield: 41 %

Procedure:
Methyl 9-bromo-8-fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate was subjected to General Procedure L to afford 484 mg 9-bromo-8-fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide in quantitative yield. 9-bromo-8-fluoro-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (0.1 g) was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similarly to as described in General Procedure F with non-critical modifications to afford 50 mg (41%) of 8-fluoro-9-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-4,5-dihydrothieno[3,2-d][1]benz oxepine-2-carboxamide. M+1=413; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.59 (s, 1H), 7.43 (s, 1H), 7.03 (d, J=10.4 Hz, 1H), 6.55 (s, 1H), 6.35 (d, J=1.0 Hz, 1H), 4.34 (t, J=5.6, 4.5 Hz, 2H), 3.18 (t, J=5.1 Hz, 2H), 2.41 (d, J=1.0 Hz, 3H), 1.80 (s, 3H).
Reaction SMILES: [CH3:1]N(C=O)C.[Cl:6][C:7]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([Cl:35])[C:8]=1[O:9][C:10]1[CH:26]=[CH:25][C:13]2[NH:14][C:15](=[O:24])[C:16](C)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:17][C:12]=2[CH:11]=1.[H-].[Na+].Cl[CH:39]([F:41])[F:40]>O>[Cl:6][C:7]1([CH3:1])[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[C:27]([Cl:35])[CH:8]1[O:9][C:10]1[CH:26]=[CH:25][C:13]2[N:14]([CH:39]([F:41])[F:40])[C:15](=[O:24])[CH:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[O:17][C:12]=2[CH:11]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1(C)Oc2cc(Oc3c(Cl)cc(C(F)(F)F)cc3Cl)ccc2NC1=O
Reactant: FC(F)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1Oc2cc(OC3C(Cl)=CC(C(F)(F)F)=CC3(C)Cl)ccc2N(C(F)F)C1=O
Reaction time: 1 h

Procedure:
To a DMF solution (50 ml) of ethyl 7-(2,6-dichloro-4-trifluoromethylphenoxy)-2-methyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-2-carboxylate (Compound 3) (1.5 g) was added 60% sodium hydride (0.2 g), and the mixture was stirred for one hour. Then, while cooling in a dry ice-acetone bath, chlorodifluoromethane gas was introduced for one hour, and the mixture then stirred for 2 days and nights. Thereafter, water (50 ml) was added and the mixture was extracted twice with ethyl acetate (50 ml), and the extract was washed with water and then with saturated aqueous sodium chloride, and then dried over magnesium sulfate. The solvent was evaporated under a reduced pressure, and the residue was purified by silica gel chromatography (eluant: n-hexane/ethyl acetate=9/1) to give 0.6 g of the title compound (colorless oil).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[SH2:12]>N1C=CC=CC=1>[NH:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1](=[S:12])[NH2:2])=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: S
Reactant: N#Cc1ccc2[nH]ccc2c1
Solvent: c1ccncc1
Product: NC(=S)c1ccc2[nH]ccc2c1

Procedure:
A solution of 5-cyanoindole (Aldrich) (2.84 g, 20.0 mmol) in 20 mL of pyridine and 8.35 mL of TEA was purged with H2S gas for 1.5 h. Solvents were removed under vacuum. The residue was dissolved in 100 mL of EtOAc, washed with H2O, 0.3 N HCl (aq.), and H2O. The EtOAc layer was separated, dried (Na2SO4), and concentrated to yield the corresponding 5-indole-thiocarboxamide that was used directly in the next step. A solution of 5-indole-thiocarboxamide (150 mg, 0.85 mmol) and 3-(2-bromoacetyl)hydroquinolin-2-one (Example 27, 120 mg, 0.45 mmol) in 50 mL of MeOH was heated at reflux for 4 h. The mixture was then concentrated. The residue was treated with CH2Cl2 and the precipitates were collected by filtration to provide the title compound as a pale orange solid. MS m/z: 344 (M+1). Anal. Calc'd for C20H13N3OS.H2O.0.8HBr: C, 56.37; H, 3.74; N, 9.86; O, 7.51; S, 7.52. Found: C, 56.64; H, 3.80; N, 9.64; O, 7.30; S, 7.44.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([NH:22]C=O)/[CH:5]=[C:6](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH2:7][P:8]([O:13]CC)([O:10]CC)=[O:9]>Cl>[NH2:22][CH:4](/[CH:5]=[C:6](\[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)/[CH2:7][P:8]([OH:13])([OH:10])=[O:9])[C:3]([OH:25])=[O:2]
Reactant: CCOP(=O)(C/C(=C/C(NC=O)C(=O)OC)c1ccccc1)OCC
Agent: Cl
Product: NC(/C=C(/CP(=O)(O)O)c1ccccc1)C(=O)O

Procedure:
0.15 g of E-2-formylamino-4-phenyl-5-diethylphosphono-3-pentenoic acid methyl ester are dissolved in 10 ml of 4.5 N hydrochloric acid and heated at 75° for 192 hours. After concentration in vacuo, the foamy residue is dissolved in a small amount of ethanol and 1 ml of ethanol/propylene oxide (1:1) is added dropwise thereto. The resulting white precipitate is filtered off and recrystallised from water/acetone (1:2). E-2-amino-4-phenyl-5-phosphono-3-pentenoic acid is thus obtained in the form of colourless needles, m.p. 230°-233°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12]C(C)(C)C(C)(C)[O:9]2)=[CH:4][CH:3]=1.[C:17](=O)([O-])[O-].[K+].[K+].[C:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])[CH3:24]>CN(C=O)C>[C:23]([N:26]1[CH2:31][CH2:30][N:29]([CH2:17][C:2]2[CH:3]=[CH:4][C:5]([B:8]([OH:9])[OH:12])=[CH:6][CH:7]=2)[CH2:28][CH2:27]1)(=[O:25])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(Br)cc2)OC1(C)C
Reactant: CC(=O)N1CCNCC1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.120 g, 0.4 mmol) and potassium carbonate (0.056 g, 0.4 mmol) in DMF (3 mL) was added N-acetylpiperazine (0.052 g, 0.4 mmol) and the resulting reaction mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was suspended in MeOH and purified by SPE using an MP-TsOH resin (1000 mg) cartridge to afford 4-((4-acetylpiperazin-1-yl)methyl)phenylboronic acid as an oil which was used without further purification. LCMS (1) Rt: 1.04 min; m/z (ES+) 263.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]([NH2:26])([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[CH:18]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH3:16])[CH:8]=1.[N:27]#[C:28]Br>C(Cl)(Cl)Cl>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([C:6]2([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][CH3:16])[CH:8]=3)[C:2]3=[N:1][CH2:5][CH2:4][N:3]3[C:28]([NH2:27])=[N:26]2)=[CH:18][C:19]=1[CH3:25]
Reactant: CCCOc1cccc(C(N)(C2=NCCN2)c2ccc(OC)c(C)c2)c1
Reactant: N#CBr
Solvent: ClC(Cl)Cl
Product: CCCOc1cccc(C2(c3ccc(OC)c(C)c3)N=C(N)N3CCN=C32)c1
Temperature: 60 °C

Procedure:
A solution of [4,5-dihydro-1H-imidazol-2-yl(4-methoxy-3-methylphenyl)(3-propoxyphenyl)methyl]amine (0.6 g) in chloroform is treated with cyanogen bromide (0.581 g), heated at 60° C. for 5 days and filtered through a pad of silica. The silica pad was eluted with ethyl acetate, followed by elution with (40:5:5) ethyl acetate: methanol: ammonium hydroxide. The eluents were combined and concentrated in vacuo to give a thick yellow oil, which was purified by Gilson preparative reverse phase HPLC system YMC Pro C18, 20 mm×50 mm ID, 5 uM column; 2 mL injection; Solvent A: 0.02% NH4OH/water; Solvent B:0.02% NH4OH/acetonitrile; Gradient: Time O: 95% A; 2 min: 95% A; 14 min: 10% A, 15 min: 10% A, 16 min: 95% A; Flow rate 22.5 mL/min; Detection: 254 nm DAD to afford the title compound was as an off-white, amphorous solid (0.131 g), characterized by LCMS analysis. LCMS Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm (i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0 mL/min; Solvent A: 0.02% NH4OH in water; Solvent B 0.02% NH4OH in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sample concentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254 nm DAD; retention time: 2.34 min, [M−H] 377, [M+H] 379.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([C:25]#[CH:26])(C)C.CCN(CC)CC>[Cu]I.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.CN(C=O)C>[C:25]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[CH:26]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A microwave vial was charged with tert-butyl 4-(4-iodophenyl)piperazine-1-carboxylate (300 mg, 0.773 mmol), trimethylsilylacetylene (0.22 mL, 1.54 mmol), NEt3 (3.0 mL), DMF (1.5 mL), CuI (15 mg, 0.080 mmol), and PdCl2(PPh3)2 (27 mg, 0.039 mmol). The vial was capped and heated in the microwave at 100° C. for 1 h. After removing the NEt3 in vacuo, the residue was extracted with EtOAc (15 mL). The organic layer was then washed with NaHCO3 (sat.) (5 mL), H2O (5 mL), brine (5 mL) and then dried over MgSO4. The solvent was removed and then the material was dissolved into MeOH (4 mL) and THF (2 mL). K2CO3 (1.0 mL of a 1M solution) was added and the reaction stirred for 3 h. The solvent was removed and the residue extracted with EtOAc (15 mL). The organic layer was washed with brine (5 mL) and then dried over MgSO4. The solvent was removed and the product dried under high vacuum to give the title compound as a brown solid (212 mg, 96%); MS ESI 287.0 [M+H]+, calcd for [C17H22N2O2+H]+ 287.18.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[S:8]1[C:4]2[CH:3]=[C:2]([NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])[CH:10]=[CH:9][C:5]=2[N:6]=[CH:7]1
Reactant: Nc1ccc2ncsc2c1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc2ncsc2c1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 6-amino-1,3-benzothiazole (1.00 g, 6.66 mmol) and pyridine (0.633 ml, 7.99 mmol) in tetrahydrofuran (22 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.11 ml, 7.99 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.45 g (66.7%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[N:18]=[N:19][NH:20][N:21]=3)=[CH:13][N:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.Br[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>C1COCC1>[Br:1][C:2]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][N:20]([CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[N:21]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: Fc1ccc(Br)c(OC2CCN(c3cnc(-c4nn[nH]n4)cn3)CC2)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cn1nnc(-c2cnc(N3CCC(Oc4cc(F)ccc4Br)CC3)cn2)n1
Reaction time: 1 h

Procedure:
To a mixture of 2-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-5-(2H-tetrazol-5-yl)pyrazine from Step 6 (5.00 g, 11.9 mmol) and triethylamine (3.32 mL, 23.8 mmol) in THF (50 mL) at 60° C. was added tert-butyl bromoacetate (3.48 g, 17.9 mmol). After a period of 1 h at 60° C., the reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated. To the solid was added 50 mL of acetone followed by slow addition of 100 mL of hexane. The resulting solid was filtered to provide tert-butyl (5-{5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazin-2-yl}-2H-tetrazol-2-yl)acetate.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=1)#[N:2].C(OC([N:19]1[CH2:24][CH2:23][O:22][C@H:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20]1)=O)(C)(C)C>>[ClH:32].[Cl:32][C:27]1[CH:26]=[C:25]([C@H:21]2[O:22][CH2:23][CH2:24][NH:19][CH2:20]2)[CH:30]=[CH:29][C:28]=1[NH:31][C:9](=[O:11])[C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[N:8]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)c(Cl)c2)C1
Reactant: N#Cc1cccc(C(=O)O)n1
Product: Cl
Product: N#Cc1cccc(C(=O)Nc2ccc([C@@H]3CNCCO3)cc2Cl)n1

Procedure:
In analogy to example 79, step a) using 6-cyano-2-pyridinecarboxylic acid (CAS 872602-74-9) instead of 4-cyanopicolinic acid (CAS 640296-19-1) and (+)-(R)-2-(4-Amino-3-chloro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (example 29a) instead of (−)-(S)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester. White solid. MS (ISP): 341.1 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:23][C:24]3[CH:32]=[CH:31][C:30](Br)=[C:29]4[C:25]=3[C:26](=[O:35])[N:27]([CH3:34])[CH2:28]4)[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Si]([O:47][CH2:48][CH2:49][N:50]1[CH:54]=[CH:53][C:52](B(O)O)=[N:51]1)(C(C)(C)C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[OH:47][CH2:48][CH2:49][N:50]1[CH:54]=[CH:53][C:52]([C:30]2[CH:31]=[CH:32][C:24]([NH:23][C:21]3[C:20]([C:36]([F:39])([F:38])[F:37])=[CH:19][N:18]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([CH2:9][P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])=[CH:11][CH:12]=4)[N:22]=3)=[C:25]3[C:29]=2[CH2:28][N:27]([CH3:34])[C:26]3=[O:35])=[N:51]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)c4c3C(=O)N(C)C4)n2)cc1)OCC
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(B(O)O)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4ccn(CCO)n4)c4c3C(=O)N(C)C4)n2)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared according to the procedure for Compound 97A diethyl[4-({4-[(7-bromo-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)benzyl]phosphonate (30.0 mg, 0.0477 mmol) and [1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazol-3-yl]boronic acid (Compound 142A, 46.7 mg, 0.173 mmol). The afforded intermediate, diethyl (4-{[4-({7-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1H-pyrazol-3-yl]-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate, was purified using an ISCO Combiflash system (eluting with 0-100% EtOAc:CH2Cl2). The product thus obtained was dissolved in CH2Cl2 (2 mL), treated with 4.0 M of HCl in dioxane (0.5 mL) and stirred at rt for 2 h. The solid was filtered off and rinsed with a mixture of CH2Cl2/heptane, giving the title material as an off-white solid, 24.6 mg (77%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (s, 1H), 10.03 (br s, 1H), 8.89 (br s, 1H), 8.49 (s, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.81 (d, J=2.3 Hz, 1H), 7.57 (br s, 2H), 7.30 (br d, J=6.6 Hz, 2H), 6.93 (br s, 1H), 4.72 (s, 2H), 4.21 (t, J=5.6 Hz, 2H), 3.97 (quin, J=7.4 Hz, 4H), 3.81 (t, J=5.7 Hz, 2H), 3.25 (d, J=21.5 Hz, 2H), 3.13 (s, 3H), 1.16 (t, J=7.1 Hz, 6H). MS (ES+): m/z 660.22 (100) [MH+]. HPLC: tR=2.72 min (ZQ3, nonpolar—5 min).
Reaction SMILES: [CH:1]1[N:5]=[C:4]([NH2:6])[S:3][CH:2]=1.[C:7](N1C=CN=C1)(N1C=CN=C1)=[O:8].[CH:19]1([NH:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl.C(OCC)(=O)C>[CH:26]1([N:25]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:7]([NH:6][C:4]2[S:3][CH:2]=[CH:1][N:5]=2)=[O:8])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nccs1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1nccs1)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of aminothiazole (50 mg, 0.5 mmol) in dichloromethane was added carbonyldiimidazole (81 mg, 0.5 mmol) and the solution stirred 2 h at room temperature. Dicyclohexylamine (1 eq) was then added and the reaction stirred overnight at room temperature. The reaction mixture is then diluted with ethyl acetate (8 mL), washed successively with 10% sodiumhydrogensulphate (3 mL), water (3 mL), dried over magnesium sulphate, concentrated in vacuo, and the residue purified by HPLC (Gilson 1, X-terra column; 0-100% CH3CN/H2O/0, 1% TFA; 15 min; flow 50 ml/min) to give the title product (52 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH2:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)NC(CN)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 79.3 %

Procedure:
2-tert-Butoxycarbonylamino-3-aminopropionic acid (10 g, 49 mmol), 2-fluoronitrobenzene (5.7 ml, 54 mmol), and sodium bicarbonate (8.25 g, 98 mmol) was taken into 130 ml of dimethylformamide and heated at 80° C. for 18 hours. The reaction was evaporated in vacuo to give a viscous orange residue that was dissolved in 300 ml of water and extracted with diethyl ether (3×150 ml). The aqueous solution was acidified to pH 5 with 10% sodium hydrogen sulfate and extracted with ethyl acetate (3×250 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to give 12.64 g (83%) of the title compound as an orange amorphous solid. 1H NMR (CD3OD) δ8.15-8.10 (1H,d), 7.54-7.48 (1H,t), 7.13-7.08 (1H, d), 6.73-6.65 (1H, t), 4.45-4.35 (1H, m), 3.9-3.8 (1H, dd), 3.65-3.55 (1H, dd), 1.45 (9H, s).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].CC(C)=O.[OH-].[K+].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:19]>O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([CH:17]2[CH:1]([OH:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[O:4]2)=[O:19])=[CH:21][CH:22]=1
Reactant: O=Cc1ccccc1O
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccc(Cl)cc1)C1Oc2ccccc2C1O

Procedure:
To a solution of 15.3 g. (0.125 mol.) of salicylaldehyde in 100 ml. of acetone was added 7.0 g. (0.125 mol.) of potassium hydroxide dissolved in a minimum amount of water. α-Bromo-p-chloroacetophenone (29.16 g., 0.125 mol.) was added dropwise with stirring and cooling (ice bath). After addition, the reaction mixture was stirred at 25° for 12 hours. The precipitate was collected by filtration, washed with water and combined with the residue remaining after concentration of the filtrate to give 2-(4'-chlorobenzoyl)-3-hydroxycoumaran which was immediately dehydrated in the presence of p-toluenesulfonic acid to yield 2-(4'-chlorobenzoyl)benzofuran.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:18][OH:19])=[C:6]([C:10](=[N:15][O:16][CH3:17])[C:11]([NH:13][CH3:14])=[O:12])[CH:7]=[CH:8][CH:9]=1.[Cl:20][C:21]1[C:22](Cl)=[N:23][CH:24]=[C:25]([CH:29]=1)[C:26]([OH:28])=[O:27].O>C1COCC1>[CH3:17][O:16][N:15]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([F:3])[C:5]=1[CH2:18][O:19][C:22]1[C:21]([Cl:20])=[CH:29][C:25]([C:26]([O:28][C:5]([CH3:18])([CH3:6])[CH3:4])=[O:27])=[CH:24][N:23]=1)[C:11]([NH:13][CH3:14])=[O:12]
Reactant: CNC(=O)C(=NOC)c1cccc(F)c1CO
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)C(=NOC)c1cccc(F)c1COc1ncc(C(=O)OC(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (60%, 0.15 g, 3.7 mmol) was added to a solution of 3-fluoro-2-hydroxymethyl-α-methyoxyimino-N-methyl-benzeneacetamide (0.54 g, 2.25 mmol) in dry THF (10 mL) and stirred for 10 minutes at 25° C. under N2 atmosphere. 5,6-Dichloronicotinic acid; t-butyl ester (0.59 g, 2.5 mmol) in 2-3 mL THF was added to this reaction mixture and stirred at 25° C. for about 2 hours. Water (40 mL) was added and the resulting mixture was extracted with ether (2×), dried (anhydrous Na2SO4), filtered and concentrated in vacuo to yield 1.2 g crude oil. Oil was chromatographed with dry pack silica gel (230-400 mesh) with descending solvent gradient from 100% petroleum ether to 80/20 pet ether/ethyl acetate as mobile phase. Elution and concentrated gave α-(methoxyimino)-N-methyl-2-[[[3-chloro-5-(t-butoxycarbonyl)-2-pyridinyl]oxy]methyl]-3-fluoro-benzeneacetamide (520 mg) as an oil. (98% E isomer; 2% Z isomer).