Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4ccc(C(C)(C)C)cc4)c3)c2cc1OC
Yield: 26.7 %

Procedure:
3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) was reacted with 4-tert-butylphenyl isocyanate (54 uL, 0.3 mmol) as described in Example 173 to give 1-(4-tert-butylphenyl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (40 mg, 0.08 mmol, 27%). 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.70 (s, 1H), 8.65 (s, 1H), 7.84 (s, 1H), 7.51 (d, 1H), 7.45-7.20 (m, 8H), 3.99 (s, 6H), 1.25 (s, 9H); LC-MS (ESI) m/z 489 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20].[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36](Cl)=[C:37]([NH:42][CH:43]([CH3:45])[CH3:44])[N:38]=2)[CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:25]([N:32]1[CH2:41][CH2:40][C:39]2[C:34](=[N:35][C:36]([N:9]3[CH2:8][CH2:7][CH:6]([O:5][C:4]4[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=4[F:2])[CH2:11][CH2:10]3)=[C:37]([NH:42][CH:43]([CH3:45])[CH3:44])[N:38]=2)[CH2:33]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1.[C:19]([OH:20])([C:21]([F:24])([F:23])[F:22])=[O:18]
Reactant: COc1ccc(OC2CCNCC2)c(F)c1
Reactant: CC(C)Nc1nc2c(nc1Cl)CN(Cc1ccccc1)CC2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CCN(Cc3ccccc3)C4)CC2)c(F)c1
Temperature: 100 °C

Procedure:
A mixture of 4-(2-fluoro-4-methoxyphenoxy)piperidine hydrochloride (72.9 mg, 0.279 mmol), 6-benzyl-3-chloro-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (100 mg, 0.232 mmol), sodium tert-butoxide (66.9 mg, 0.696 mmol), BINAP (21.7 mg, 0.035 mmol), and Pd2(dba)3 (10.6 mg, 0.012 mmol) in toluene (1.16 mL) was heated at 100° C. in a sealed tube for 14 h. The mixture was purified by HPLC Method A to give the title compound as a TFA salt (122.1 mg, 85%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.6 Hz, 6H), 1.86-1.97 (m, 2H), 2.03-2.12 (m, 2H), 2.95 (br s, 2H), 3.01-3.12 (m, 2H), 3.33-3.38 (m, 2H), 3.53 (br s, 2H), 3.75 (s, 3H), 4.13-4.24 (m, 3H), 4.31-4.38 (m, 1H), 4.52 (s, 2H), 6.63-6.69 (m, 1H), 6.73 (dd, J=12.8, 2.9 Hz, 1H), 7.06 (t, J=9.2 Hz, 1H), 7.51-7.60 (m, 5H); ESI-MS m/z [M+H]+ 506.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1B(O)O.[NH2:16][C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:21]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:16])[CH:22]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COc1ccc(C(F)(F)F)cc1B(O)O
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: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1-c1ccnc(N)c1
Temperature: 85 °C
Yield: 120 %

Procedure:
Argon was bubbled through a suspension of 2-methoxy-5-trifluoromethylphenylboronic acid (2.3 g, 10 mmol), 2-amino-4-bromopyridine (2.0 g, 12 mmol), and sodium carbonate (4.4 g, 42 mmol) in 1,4-dioxane (30 mL) and water (9 mL) for 15 minutes, then tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol) was added. The resulting mixture was heated at 85° C. for 18 hours. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate and water. The phases were separated and the aqueous phase extracted with ethyl acetate then choloroform. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (0% to 10% methanol in chloroform gradient elution) to afford the title compound as yellow oil (3.22 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13].[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>N1C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[CH2:11][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[C:6]([O:8][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:18])=[O:16])=[CH:7][C:2]=1[Cl:1]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)Cc1cc(OC)c(O)cc1Cl
Solvent: c1ccncc1
Product: COC(=O)Cc1cc(OC)c(OS(=O)(=O)C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl (2-chloro-4-hydroxy-5-methoxyphenyl)acetate (570 mg, 2.468 mmol) in 10 mL of pyridine was added Tf2O (853 mg, 2.962 mmol) dropwise at 0° C. The resulting mixture was stirred at rt overnight and concentrated to dryness. The residue was dissolved in EtOAc (50 mL), washed with 1 N HCl (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated to give methyl(2-chloro-5-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}phenyeacetate.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][C:9]#[C:10][CH:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[CH:14][C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]1=2.Cl.[OH-].[NH4+]>CC(C)=O>[OH:7][CH2:8][C:9]#[C:10][CH:11]1[C:12]2[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=2[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1=2
Reactant: C(#CC1c2ccccc2C=Cc2ccccc21)COC1CCCCO1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OCC#CC1c2ccccc2C=Cc2ccccc21

Procedure:
This preparation illustrates methods according to step 2 of the process for preparing the compounds of formula A. In this preparation a solution containing 18.3 g. of crude 5-[3-(2-tetrahydropyranyloxy)-prop-1-ynyl]-5H-dibenzo[a,d]cycloheptene in 200 ml. of acetone and 20 ml. of concentrated hydrochloric acid is stirred at room temperature until thin-layer chromatographic analysis of a representative sample indicates hydrolysis to be complete (about 2 hours). The reaction mixture is neutralized by the addition of concentrated ammonium hydroxide and then evaporated under vacuum to remove acetone. The concentrated mixture is extracted with methylene chloride. The methylene chloride extract is washed consecutively with water and saturated brine, then dried over sodium sulfate. The dried extract is evaporated to dryness under vacuum affording a residue of crude 5-(3-hydroxyprop-1-ynyl)-5H-dibenzo[a,d]cycloheptene which is then further purified by column chromatography over silica gel, deactivated by the addition of 10%, by wt., of water, eluting with acetone-hexane mixtures.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([O:32]C)=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.[OH-].[K+]>CO>[C:1]([NH:8][C@H:9]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:27])[CH2:22][CH2:23][S:24][CH3:25])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 0.5 h

Procedure:
6.02 Grams of methyl Boc-L-tyrosyl-D-methionyl-glycinate is dissolved in 30 ml of methyl alcohol and water is added until the solution becomes cloudy. A 4 M solution of potassium hydroxide is added to maintain the pH at 12-13. When the pH is stable at 13 for 30 minutes, the methanol is removed under reduced pressure. The aqueous solution is filtered and adjusted to pH 3 with concentrated hydrochloric acid. The product crystallizes and is removed by filtration and washed with water to give Boc-L-tyrosyl-D-methionyl-glycine which is represented by the following formula
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:16]=1[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([O:5][C:6]([N:8]([CH2:14][C:15]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:16]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH2:9][C:10]([F:11])([F:12])[F:13])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CCc1ccc(OC)cc1CN(CC(F)(F)F)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(CCC(=O)O)c(CN(CC(F)(F)F)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 106.5 %

Procedure:
To a stirred solution of methyl 2-[N-(tert-butoxycarbonyl)-N-(2,2,2-trifluoroethyl)aminomethyl]-4-methoxydihydrocinnamate (43.71 g, 108 mmol) in dioxane (200 mL) was added aqueous 1 N NaOH (130 mL, 130 mmol). The cloudy reaction was stirred at RT for 4 h. The resulting a homogeneous solution was neutralized with 1 N HCl (130 mL, 130 mmol) and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with brine (250 mL), dried (MgSO4), and concentrated to give the title compound (45.01 g, 100%) as a thick clear oil: TLC (95:4:1 CHCl3, MeOH, HOAc) Rf 0.49.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([C:22]([F:25])([F:24])[F:23])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:26]([NH:30][S:31]([C:34]1[S:35][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:38]=1)(=[O:33])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[C:26]([NH:30][S:31]([C:34]1[S:35][C:36]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([C:22]([F:24])([F:23])[F:25])[CH:11]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=4)[N:13]=3)[CH:3]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:33])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.37) (0.40 g, 0.89 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.40 g, 1.16 mmol) according to the general procedure VI. Obtained as white foam (0.45 g), which was subsequently deprotected.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>CN(C)C=O.ClCCl>[C:12]([C:10]1[C:9]([N:15]2[CH2:16][CH2:17][N:18]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH2:19][CH2:20]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(CC(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a mix of 1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) and potassium carbonate (0.043 g, 0.31 mmol) in N,N-dimethylformamide (1 mL) was added 2-chloro-N,N-dimethylacetamide (0.012 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 4 hrs, and then diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (19 mg, 49%). LCMS calculated for C19H24ClN4O2 (M+H)+: m/z=375.2; Found: 375.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:18]1([CH3:23])OCC[O:19]1)[C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:24].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH:13]([C:18](=[O:19])[CH3:23])[C:14]([O:16][CH3:17])=[O:15])[C:5]2=[O:24]
Reactant: COC(=O)C(CN1C(=O)c2ccc(F)cc2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: COC(=O)C(CN1C(=O)c2ccc(F)cc2C1=O)C(C)=O

Procedure:
Methyl 2-(5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (84 mg, 15%) in the same manner as described in the above example 6 (1) from methyl 3-(5-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.63 g, 1.87 mmol) and pyridinium p-toluenesulfonate (51 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:24]=[N:25][C:26](Cl)=[CH:27][C:28]=2[C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[C:18]([C:36]#[N:37])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[C:36]([C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:24]=[N:25][C:26]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=2)=[CH:27][C:28]=1[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)#[N:37]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1ccc(Oc2cnc(Cl)cc2-c2cccnc2)c(C#N)c1
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
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2cscn2)ccc1Oc1cnc(-c2cccc(F)c2)cc1-c1cccnc1
Reaction time: 0.08 h
Yield: 31.5 %

Procedure:
10 mg (0.03 mmol) of tert-butyl((4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-3-cyanophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.7 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.6 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 5 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Cl)cnc1Oc1ccccc1F

Procedure:
This compound was prepared according to general procedure A using 2-bromo-5-chloro-3-nitro-pyridine (750 mg, 3.17 mmol), 2-fluorophenol (463 mmol, 4.13 mmol), K2CO3 (437 mg, 4.75 mmol) and DMF (5 mL). MS m/z: 269.0 (M+H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl.CO>[CH3:1][NH:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:20]=[C:19]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[N:12]2)=[CH:7][CH:6]=1
Reactant: CNC(=O)c1ccc(-n2cc3c(n2)CCN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl 2-{4-[(methylamino)carbonyl]phenyl}-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (184 mg, 0.50 mmol; may be prepared as described in Description 24) in dichloromethane (2 ml) was treated with trifluoroacetic acid (2 ml). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (D25); MS (ES+) m/e 271 [M+H]+.
Reaction SMILES: CS(O)(=O)=O.NC[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12](C1CCC(=O)NC1=O)C2.ClC1C=CC=CC=1C(Cl)=O.Cl>C(#N)C>[C:13]([NH2:12])(=[O:17])[C:14]1[CH:15]=[CH:16][CH:8]=[CH:9][CH:10]=1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: Cl
Agent: O=C(Cl)c1ccccc1Cl
Solvent: CC#N
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and chlorobenzoyl chloride (0.25 g, 1.4 mmol) in acetonitrile (30 ml) at 0° C. The mixture was stirred at 0° C. for 2 h, and then 4% aqueous HCl (30 ml) was added. The solid precipitate was filtered and dried in vacuo providing 2-chloro-N-[2,6-dioxo-piperidin-3yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid, (0.33 g, 59% yield); mp 194-196° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.33 (99.10%); 1H NMR (DMSO-d6) δ 1.98-2.04 (m, 1H), 2.33-2.43 (m, 1H), 2.46-2.63 (m, 1H), 2.86-2.98 (m, 1H), 4.33 (d, 1H, J=17.4 Hz), 4.46 (d, 1H, J=17.4 Hz), 4.57 (d, 2H, J=6.0 Hz), 5.12 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 7.38-7.53 (m, 5H), 7.58 (s, 1H), 7.71 (d, 1H, J=7.8 Hz), 9.09 (t, 1H, J=6.0 Hz), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 40.3, 42.5, 47.1, 51.6, 122.1, 122.9, 127.1, 127.2, 128.9, 129.6, 130.4, 130.8, 136.7, 142.4, 143.4, 166.5, 167.9, 170.9, 172.9; LCMS: MH=412, 414; Anal. Calcd for C21H18ClN3O4+0.1H2O: C, 60.98; H, 4.43; N, 10.16. Found: C, 60.76; H, 4.40; N, 10.11.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:16]([N:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=O)=[O:17])[CH3:15])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:42][CH:43]([CH:50]([CH3:52])[CH3:51])[CH:44]([OH:49])[C:45]([F:48])([F:47])[F:46]>C(#N)C.CN(C)C=O>[F:46][C:45]([F:47])([F:48])[CH:44]([OH:49])[CH:43]([NH:42][C:20](=[O:22])[C@@H:19]1[CH2:23][CH2:24][CH2:25][N:18]1[C:16](=[O:17])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[C@H:9]([CH3:10])[NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH:50]([CH3:51])[CH3:52]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)C(N)C(O)C(F)(F)F
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(O)C(F)(F)F
Temperature: -20 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
To a solution of Boc-L-alanyl-L-alanyl-L-proline (1.0 g, 2.80 mmol) in dry acetonitrile (25 ml) was added N-methylmorpholine (0.34 ml, 3.06 mmol). The solution was cooled to -20° C. and isobutylchloroformate (0.37 ml, 2.88 mmol) was added dropwise. To this solution, a pre-cooled (-20° C.) mixture of 3-amino-1,1,1-trifluoro-4-methyl-2-pentanol hydrochloride (0.61 g, 2.91 mmol), N,N-dimethylformamide (4 ml) and N-methylmorpholine (0.34, 3.06 mmol) was added. The reaction mixture was stirred at -20° C. for 4 hr, allowed to warm to room temperature and stirred overnight. Removal of the solvents in vacuo produced a pale yellow residue, which was purified by flash chromatography using ethyl acetate as an eluent to give 1,1,1-Trifluoro-3-[(N-tert-butyloxycarbonylalanyl)alanylprolylamino]-4-methylpentane-2-ol (1.09 g, 2.1 mmol) in 76% yield.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]2[O:10][CH2:9][CH2:8][O:7]2)=[CH:2]1.C([Li])CCC.[Br:16]C(C(Br)(F)F)(F)F>C1COCC1>[Br:16][C:2]1[S:1][CH:5]=[CH:4][C:3]=1[CH:6]1[O:10][CH2:9][CH2:8][O:7]1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: c1cc(C2OCCO2)cs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1sccc1C1OCCO1
Temperature: -78 °C
Reaction time: 0.58 h

Procedure:
A −78° C. solution of the dioxolane of Example 23(a) in dry THF (93 mL, Aldrich) was treated with n-butyllithium (34 mL, 50.7 mmol, 1.49 M/hexanes, Aldrich). The mixture was stirred at −78° C. for 35 minutes and then BrCF2CF2Br (6.1 mL, 51.1 mmol, Aldrich) was added. After 10 minutes, the mixture was allowed to warm to 0° C. and after 30 minutes at 0° C., the mixture was allowed to warm to room temperature. The solution was partitioned between H2O and ether (100 mL each). The layers were separated and the aqueous layer extracted with ether (100 mL). The combined ether solution was washed with 1 M sodium thiosulfate solution (2×100 mL) and brine (100 mL) and then was dried (MgSO4), filtered and evaporated to leave 11.15 g of 2-(2-Bromo-thiophen-3-yl)-[1,3]dioxolane as a yellow oil that was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([NH:22][O:23][CH2:24][CH2:25][O:26][C:27](=[O:40])[CH:28]([NH:32]C(OC(C)(C)C)=O)[CH:29]([CH3:31])[CH3:30])=[O:21])=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:41])[CH:3]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([NH:22][O:23][CH2:24][CH2:25][O:26][C:27](=[O:40])[CH:28]([NH2:32])[CH:29]([CH3:31])[CH3:30])=[O:21])=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[F:19])=[C:4]([Cl:41])[CH:3]=1
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)C(=O)OCCONC(=O)c1cc2c(ncn2C)c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
A mixture of 2-tert-butoxycarbonylamino-3-methylbutyric acid 2-{[6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbonyl]-aminooxy}-ethylester and its N-acylated isomer (0.6 g) were treated with 1.5 mL of trifluoroacetic acid for 0.5 hours. An HPLC trace of the reaction mixture showed the reaction was complete. The mixture was concentrated on a rotary evaporator and pumped on high vacuum to give yellow oil (0.9 g). The deprotected samples were submitted for HPLC purification to give purified product as a trifluoroacetic acid salt.