Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[Br:14]Br>C(O)(=O)C>[Br:14][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8])=[O:3]
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(C(=O)CBr)c1
Temperature: 80 °C

Procedure:
The compound obtained in Step A (32.2 mmol) is dissolved in glacial acetic acid (40 ml) and then 48.3 mmol of bromine are added. The mixture is heated at 80° C. for 2 hours and is then hydrolysed using ice-cold water. The precipitate obtained is filtered off, washed with water until a pH of 5-6 is obtained, and then dried and recrystallised.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C1COCC1>[Cl:17][C:12]1[CH:11]=[C:10]([CH:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][CH:3]2[CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CNS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 106.9 %

Procedure:
To a solution of tert-butyl (6RS,7RS)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (144 mg) in THF (1.5 mL) were added triethylamine (0.08 mL) and methanesulfonyl chloride (66 mg), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (186 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=O)=[O:11])[N:5]=[CH:4][C:3]=1[NH:19][C@@H:20]1[CH2:25][C@@H:24]2[CH2:26][C@@H:22]([C:23]2([CH3:28])[CH3:27])[C@H:21]1[CH3:29].[N:30]1(C(N2C=CN=C2)=O)C=CN=C1.N.O>CN(C)C=O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([NH2:30])=[O:16])=[O:11])[N:5]=[CH:4][C:3]=1[NH:19][C@@H:20]1[CH2:25][C@@H:24]2[CH2:26][C@@H:22]([C:23]2([CH3:27])[CH3:28])[C@H:21]1[CH3:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)C(=O)O
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CCC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)C(N)=O
Yield: 29.2 %

Procedure:
2-({[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)butyric acid (48 mg, 0.113 mmol) in N,N-dimethylformamide (2 mL) was stirred with di-1H-imidazolylmethanone (55 mg, 0.340 mmol) at room temperature for 2 days and then with 30% aqueous ammonia (0.2 mL) at room temperature for 5 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (14 mg, 29% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][N:43]5[CH3:47])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:57][S:58](Cl)(=[O:60])=[O:59]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:18][C:19]([NH:21][C@@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:25]([O:32][C:33]3[CH:34]=[CH:35][C:36]4[N:37]([C:39]([C@@H:42]5[CH2:46][CH2:45][CH2:44][N:43]5[CH3:47])=[N:40][N:41]=4)[CH:38]=3)[CH2:24][CH2:23]2)=[O:20])[N:8]([C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[CH2:16][O:17][S:58]([CH3:57])(=[O:60])=[O:59])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A solution of Intermediate 149a (200 mg, 0.32 mmol) and DIPEA (164 μL, 0.95 mmol) in DCM (4 mL) was treated with methanesulfonyl chloride (32 μL, 0.41 mmol) and the reaction mixture was stirred at RT for 0.5 h. The mixture was diluted with DCM (5 mL) and washed with water (10 mL) and brine (10 mL). The layers were separated and the organic layer was passed through a phase separator and concentrated in vacuo to afford the title compound as a pale yellow solid (208 mg, 92%). LCMS (Method 3): Rt 3.02 min, in/z 713 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=O.C[Si](C)(C)N[Si](C)(C)C.[Na].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1
Reactant: O=C1OCc2ccccc21
Reactant: O=C1Cc2cc(Cl)ccc2N1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C1=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 27.8 %

Procedure:
To a solution containing 5-chlorooxindole (0.30 g, 1.79 mmol) and phthalide (0.312 g, 2.33 mmol) in 6.0 mL of dimethylformamide (DMF) was added 3.76 mL of sodium hexamethyldisilazane (1.0 M in tetrahydrofuran (THF)) over 1 min. The solution was stirred at room temperature for 25 min and then 85 mg (0.634 mmol) phthalide was added. After an additional 20 min at room temperature the mixture was poured into 70 mL of 4% aqueous HCl solution to give a yellow solid. The aqueous mixture was extracted with EtOAc and the organic phase washed with saturated NaHCO3, brine and then dried with Na2SO4. After removal of the solvent in vacuo, the solid residue was recrystallized from MeOH/EtOAc to afford the title (141 mg, 28%) compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10](C=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([OH:25])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(Oc2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-(4'-methylphenoxy)benzaldehyde (9.00 g, 41.63 mmol) in CHCl3 (75 mL) was treated with m-chloroperbenzoic acid (46-85%, 15.80 g, 52.00 mmol) and stirred for 3 h at room temperature. The reaction was washed with sat. aq. NaHSO3, sat. aq. NaHCO3, and water. The organic layer is concentrated and the residual oil taken up in MeOH (10 mL) containing a few drops of conc. HCL and stirred for 1 h at room temperature. The solvent is removed in vacuo and the resulting oil was chromatographed on silica gel (20% ethyl acetate/hexane) to afford 4-(4'-methylphenoxy)phenol.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[CH3:2].[OH-].[Na+].[C:26]1([CH2:32][C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>ClCCl>[CH2:1]([N:3]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:13]1)[C:33](=[O:34])[CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCN(C(=O)Cc1ccccc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (100 mg) in dichloromethane (3 ml) were sequentially added an aqueous solution of 1N sodium hydroxide (1 ml) and phenylacetyl chloride (0.06 ml) on an ice bath, and the solution was stirred overnight while warming to room temperature. To the reaction solution was added water, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo to provide the title compound (140 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([F:40])=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:38][CH3:39])=[C:23]([CH2:26][N:27]([CH3:37])[C:28]4([C:34]([NH2:36])=[O:35])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1.[C:41]([O:44][CH2:45][C:46](Cl)=[O:47])(=[O:43])[CH3:42]>CN1C(=O)CCC1>[C:41]([O:44][CH2:45][C:46]([N:31]1[CH2:32][CH2:33][C:28]([C:34]([NH2:36])=[O:35])([N:27]([CH2:26][C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][C:22]=2[O:38][CH3:39])[N:19]=[CH:18][N:17]=[C:16]3[NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:40])[CH3:37])[CH2:29][CH2:30]1)=[O:47])(=[O:43])[CH3:42]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CCN(C(=O)COC(C)=O)CC1
Temperature: 25 °C

Procedure:
Triethylamine (360 μl, 2.58 mmol) was added to a stirred, cooled (0° C.) suspension of 4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidine-4-carboxamide (300 mg, 0.63 mmol) (Example 16) in NMP (5 ml). Acetoxyacetyl chloride (100 μl 0.93 mmol) was then added drop wise and the reaction mixture left to warm to room temperature over a period of 2 hours. This was then partitioned between saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase was washed with saturated aqueous ammonium chloride solution followed by brine, dried over magnesium sulfate, filtered and evaporated to give 2-{4-(aminocarbonyl)-4-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]piperidin-1-yl}-2-oxoethyl acetate as a dry film (250 mg). Mass spectrum: (M+H)+ 573.
Reaction SMILES: [CH3:1][S:2]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)(=[N:4]C(=O)C(F)(F)F)=[O:3].C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][S:2]([C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)(=[NH:4])=[O:3]
Reactant: COC(=O)CCc1ccc(S(C)(=O)=NC(=O)C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)CCc1ccc(S(C)(=N)=O)cc1
Reaction time: 0.08 h
Yield: 93.3 %

Procedure:
Methyl 3-{4-[S-methyl-N-(trifluoroacetyl)sulfonimidoyl]phenyl}propanoate (0.200 g, 0.653 mmol) was dissolved in MeOH (3 mL). K2CO3 (0.450 g, 3.27 mmol) was added to the solution, and the resulting suspension was allowed to stir for 5 minutes. The suspension was filtered and the filtrate was concentrated. The residue was dissolved in EtOAc and dried over anhydrous anhydrous Na2SO4(s) to give the title compound (0.147 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][CH3:16].[N+:17]([O-])([OH:19])=[O:18]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[O:10][C:6]=2[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[C:3]=1[O:15][CH3:16]
Reactant: COC(=O)c1cc2c(Cl)c(OC)ccc2o1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc2c(Cl)c(OC)c([N+](=O)[O-])cc2o1
Temperature: 0 °C
Yield: 91 %

Procedure:
Methyl 4-chloro-5-methoxybenzofuran-2-carboxylate was dissolved in conc. sulphuric acid (58 mL) with stirring in an ice bath then conc. nitric acid was added dropwise, maintaining the temperature below 5° C. The reaction was then stirred at room temperature for 2.5 h. The reaction was added to ice water (500 mL) over 2 h. The resulting solid was filtered and washed with water until neutral. The solid was dried to afford methyl 4-chloro-5-methoxy-6-nitrobenzofuran-2-carboxylate (6.3 g, 91%), which was taken through to the next step with no further purification.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH3:16][N:17]([CH3:35])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:34])[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][CH2:33][C:28]3=[CH:27][C:25]=2[N:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[O-:34][N+:23]1[C:24]2[CH:30]=[C:29]3[O:31][CH2:32][CH2:33][C:28]3=[CH:27][C:25]=2[N+:26]([O-:4])=[C:21]([NH:20][CH2:19][CH2:18][N:17]([CH3:35])[CH3:16])[N:22]=1
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)OCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCO3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
H2O2 (70%, 0.66 mL, ca. 13.2 mmol) was added dropwise to a stirred solution of TFAA (1.9 mL, 13.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 197 (363 mg, 1.3 mmol) and TFA (0.51 mL, 6.6 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 198 (98 mg, 25%) as a red solid: mp (MeOH/EtOAc) 149-151° C.; 1H NMR δ 8.12 (s, 1H, H-5), 7.54 (s, 1H, H-9), 7.27 (br s, 1H, NH), 4.75 (t, J=8.3 Hz, 2H, H-7), 3.58-3.64 (m, 2H, CH2N), 3.43 (t, J=8.2 Hz, 2H, H-6), 2.62 (t, J=6.0 Hz, 2H, CH2N), 2.31 [s, 6H, N(CH3)2]; 13C NMR δ 159.9, 148.9, 141.6, 135.2, 130.9, 113.1, 97.4, 72.4, 57.5, 45.1 (2), 38.8, 29.7. Anal. calcd for C13H17N5O3.¼H2O: C, 52.8; H, 6.0; N, 23.7. Found: C, 52.8; H, 5.7; N, 23.5%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CNS(C)(=O)=O)c1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.9 %

Procedure:
To a degassed solution of 1.5 g (5.1 mmol) of material from Example 1, 1.2 g (8.1 mmol) of 4-formylbenzeneboronic acid and 1.1 g (8.1 mmol) of potassium carbonate in 30 mL of toluene was added 0.3 g (0.3 mmol) of tetrakis(triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 4 hours whereupon 0.3 g (2.0 mmol) of 4-formylbenzeneboronic acid and 0.1 g (0.09 mmol) of tetrakis(triphenylphosphine)palladium(0) was added and heating continued for 16 hours. To this solution was added 5 mL of water and heating continued for 1 hour. The mixture was then cooled to ambient temperature and 10 mL of water was added. The organic portion was separated and the aqueous portion was extracted twice with ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography on 50 g silica gel (50% ethyl acetate/hexane) afforded a solid which was recrystallized from bromobutane/ethyl acetate, filtered and dried in vacuo at 60° C. to afford 0.5 g (32%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]2[N:33]3[C:29]([S:30][CH:31]=[CH:32]3)=[N:28][C:27]=2[CH3:34])=[O:25])[CH2:18]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24]([C:26]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[CH3:34])=[O:25])[CH2:18]2)=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: Cc1nc(C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c(-c2ccc(F)cc2)s1

Procedure:
prepared by reaction of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:9](=[O:31])[N:10]([CH3:30])[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][CH:21]3[CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1(C)C(C)=CC=C[CH:37]=1.CN(C=O)C.[F-].[K+]>ClCCl>[CH:27]([NH:26][CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:11]1[N:10]([CH3:30])[C:9](=[O:31])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH:32]=[CH2:37])[CH:3]=2)=[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:12]=1)([CH3:29])[CH3:28]
Reactant: CC(C)NCC1CCCN1c1nc(-c2ccncc2)c(-c2cccc(Br)c2)c(=O)n1C
Reactant: Cc1ccccc1C
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C=Cc1cccc(-c2c(-c3ccncc3)nc(N3CCCC3CNC(C)C)n(C)c2=O)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a 250 mL RBF, was added 5-(3-bromo-phenyl)-2-[2-(isopropylamino-methyl)-pyrrolidin-1-yl]-3-methyl-6-pyridin-4-yl-3H-pyrimidin-4-one (0.48 g, 1.0 mmol), 50 mL xylene, 5 mL DMF and 0.58 mL tributhyl(vinyl)tin. The mixture was degassed by nitrogen bubbled through for 1 h. After added Pd(PPh)4 (58 mg, 0.05 mmol), the mixture was warmed up to 140° C. and stirred for 1 h under nitrogen. The mixture was cooled down to rt, 20 mL 10% KF solution was added and stirred for 30 min. The mixture was diluted with 200 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.28 g as pale yellow solid. MS (ES+): 430 (M+H)+; (ES−): 428 (M−H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=2)=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([NH:21][NH:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]2)=[O:32])=[CH:28][CH:27]=1
Reactant: O=C(CCCCN1CCC(Cc2ccccc2)CC1)NNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)NNC(=O)CCCCN2CCC(Cc3ccccc3)CC2)cc1
Yield: 32.2 %

Procedure:
To a solution of N-(5-(4-benzylpiperidin-1-yl)valeroyl)-N′-(4-nitrobenzoyl)hydrazine (200 mg, 0.456 mmol) in 20 mL of methanol was added 50 mg of 5% Pd/C. The resulting mixture was hydrogenated at 30 psi of hydrogen for 3 hr. The catalyst was removed through a short column of Celite and was washed with methanol (15 mL). The extracts were evaporated in vacuo to give an oil, which was purified by flash chromatography to give the title product as a solid (60 mg, 32%):. mp 163-165° C.; 1H NMR (CDCl3) 1.26 (m, 2 H), 1.59 (m, 9 H), 1.92 (m, 2 H), 2.28 (m, 4 H), 2.52 (m, 2 H), 2.90 (m, 2 H), 3.29 (s, 2 H), 6.83 (d, J=8.1 Hz, 2 H), 7.10 (m, 3 H), 7.20 (m, 2 H), 7.63 (d, J=7.8 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10](Cl)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)(C)N
Reactant: COc1ccc(S(=O)(=O)Cl)cc1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)NC(C)(C)C)cc1Br
Reaction time: 2 h
Yield: 77 %

Procedure:
3-Bromo4-methoxyphenylsulfonyl chloride (2.80 g, 9.8 mmol) was dissolved in dichloromethane (30 mL) and the solution was treated with triethylamine (1.76 mL, 12.6 mmol), followed by the dropwise addition of t-butylamine (1.33 mL, 12.6 mmol). The mixture was allowed to stand for 2 hours and then was poured onto a mixture of 5% citric acid solution and dichloromethane. The organic layer was separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were dried and concentrated. Crystallization of the crude solid from ethyl acetate/hexane gave 3-bromo-N-tert-butyl-4-methoxybenzenesulfonamide (2.43 g, 77%).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[C:8]([CH2:10][C:11]1([N:32]2[CH:36]=[C:35](B3OC(C)(C)C(C)(C)O3)[CH:34]=[N:33]2)[CH2:14][N:13]([C:15]2[C:29]([F:30])=[CH:28][C:18]([C:19]([NH:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:25])[F:24])=[O:20])=[C:17]([F:31])[CH:16]=2)[CH2:12]1)#[N:9].Br[C:47]1[C:48]([CH2:52][OH:53])=[N:49][NH:50][CH:51]=1>>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[C:8]([CH2:10][C:11]1([N:32]2[CH:36]=[C:35]([C:47]3[C:48]([CH2:52][OH:53])=[N:49][NH:50][CH:51]=3)[CH:34]=[N:33]2)[CH2:12][N:13]([C:15]2[C:29]([F:30])=[CH:28][C:18]([C:19]([NH:21][C@@H:22]([CH3:27])[C:23]([F:26])([F:24])[F:25])=[O:20])=[C:17]([F:31])[CH:16]=2)[CH2:14]1)#[N:9]
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(B4OC(C)(C)C(C)(C)O4)cn3)C2)cc1F)C(F)(F)F
Reactant: OCc1n[nH]cc1Br
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(CC#N)(n3cc(-c4c[nH]nc4CO)cn3)C2)cc1F)C(F)(F)F

Procedure:
This compound was prepared as TFA salt by using procedures analogous to those described for the synthesis of Example 4, Step 6 starting from 4-{3-(cyanomethyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide and (4-bromo-1H-pyrazol-3-yl)methanol. LCMS calculated for C22H21F5N7O2 (M+1)+: m/z=510.2. Found: 510.0.
Reaction SMILES: [CH2:1]([C:8]1([CH2:11]O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:20][CH2:11][C:8]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:9]1
Reactant: OCC1(Cc2ccccc2)CC1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: BrCC1(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
To a solution of the title C compound, (1-benzyl-cyclopropyl)-methanol (0.8 g, 4.93 mmol), pyridine (994 uL, 12.3 mmol) and CBr4 (1.8 g, 5.42 mmol) in methylene chloride (25 mL) is added triphenylphosphine (1.8 g, 6.9 mmol), with stirring at 0° C. After completion of the reaction, the mixture is poured into a saturated aqueous solution of NaHCO3. The aqueous layer is extracted twice with methylene chloride and the combined organic extracts are dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is taken up into ether and the triphenylphosphine oxide precipitate is filtered off. The filtrate is concentrated under reduced pressure and purified by flash column chromatography on silica gel (hexane/EtOAc 9/1) to afford the title compound: TLC, Rf (hexane/AcOEt 99/1)=0.54. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 6.41 min.