Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([C:26]3([OH:36])[CH2:35][CH2:34][C:29]4(OCC[O:30]4)[CH2:28][CH2:27]3)[CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[OH:36][C:26]1([C:22]2[CH:21]=[C:20]([C:5]3[CH:6]=[C:7]([NH:9][C:10]4[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=4)[CH:8]=[C:3]([CH3:2])[CH:4]=3)[CH:25]=[CH:24][N:23]=2)[CH2:35][CH2:34][C:29](=[O:30])[CH2:28][CH2:27]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccnc(C3(O)CCC4(CC3)OCCO4)c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccnc(C3(O)CCC(=O)CC3)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrochloric acid (1.75 mL, 10.5 mmol, 6.0 M in dioxane) was added to a solution of 8-[4-(3-Methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (255 mg, 0.524 mmol) in THF (3 mL). The reaction mixture was stirred for 1 hour at room temperature, then brought to pH 8 with saturated aqueous sodium bicarbonate. The reaction mixture was extracted with EtOAc (3×), and the combined organic layers were washed with saturated aqueous sodium bicarbonate. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 4-hydroxy-4-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]cyclohexanone as a white foam. MS ESI calc'd for C23H22F3N4O2 [M+H]+ 443. found 443. 1H NMR (500 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.83 (d, J=4.9 Hz, 1H), 8.56 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 8.00 (d, J=1.1 Hz, 1H), 7.62 (s, 1H), 7.49 (dd, J=5.1, 1.8 Hz, 1H), 7.29-7.26 (m, 2H), 5.68 (s, 1H), 2.77 (td, J=14.1, 6.2 Hz, 2H), 2.46-2.36 (m, 2H), 2.37 (s, 3H), 2.18 (d, J=14.5 Hz, 2H), 2.02-1.91 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[Cl:34][CH2:35][CH2:36][N:37]=[C:38]=[S:39].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:38](=[S:39])[NH:37][CH2:36][CH2:35][Cl:34])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: S=C=NCCCl
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=S)NCCCl)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (18.18 mg, 0.18 mmol) in dichloromethane (6 ml) was added 1-chloro-2-isothiocyanatoethane (21.87 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 10 mg (15%); 1H NMR (CDCl3, 300 MHz): δ 9.945 (s, 1H), 7.966-7.996 (d, 1H, J=9 Hz), 7.745-7.773 (d, 2H, J=8.4 Hz), 7.615-7.645 (dd, 1H, J=9, 2.1 Hz), 7.516-7.544 (d, 2H, J=8.4 Hz), 7.082-7.089 (d, 1H, J=2.1 Hz), 4.289-4.344 (t, 2H), 3.411-3.467 (t, 2H), 1.82 (s, 6H); MS: m/z 491 (M−HCl).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=O.C([O-])(=O)C.[NH4+:29]>C(O)C>[CH3:17][C:4]1[C:3](=[CH:23][C:19]2[S:18][CH:22]=[CH:21][CH:20]=2)[C:2](=[O:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([S:13]([O-:16])(=[O:15])=[O:14])=[CH:11][CH:12]=2)[N:5]=1.[NH4+:29]
Reactant: O=Cc1cccs1
Reactant: Cc1cc(O)n(-c2ccc(S(=O)(=O)O)cc2)n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC1=NN(c2ccc(S(=O)(=O)[O-])cc2)C(=O)C1=Cc1cccs1
Reaction time: 4 h

Procedure:
12.75 g of 5-hydroxy-3-methyl-1-(4-sulfophenyl)-1H-pyrazole, 6.2 g of thiophene-2-carboxaldehyde and 3.85 g of ammonium acetate in 100 mL of ethanol were heated at 80° C. After 4 hours, the mixture was cooled and filtered. The crude product was allowed to reflux in 250 mL of methanol for 30 min and the mixture was then cooled and filtered.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>C(Cl)Cl.O>[F:33][C:34]1[CH:39]=[C:38]([C:2]2[N:7]=[C:6]([C:8]([N:10]([CH3:32])[C:11]3[CH:12]=[CH:13][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:15][CH:16]=3)=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(Cl)n3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3cccc(-c4cccc(F)c4)n3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 84.1 %

Procedure:
A mixture of 1,1-dimethylethyl (2S)-4-({4-[[(6-chloro-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D107) (0.0825 g, 0.179 mmol), 3-fluorobenzeneboronic acid (0.0302 g, 0.216 mmol), tetrakis-(triphenylphosphine)palladium (0) (0.0104 g, 0.009 mmol) and sodium carbonate (0.0762 g, 0.719 mmol) in a DME/water (4 mL, 1:1) was heated at 140° C. in a microwave for 10 minutes. The reaction mixture was diluted with DCM/water and the aqueous layer was further extracted with DCM (×3). The combined organics were dried and concentrated to give the crude product which was purified by column chromatography. Elution with 0-100% EtOAc/hexane gave the title compound as a colourless oil (0.0781 g). MS (ES): MH+ 519.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[C:23](=[O:26])([O-])[O-:24].[Na+].[Na+]>O1CCCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[C:5]2[C:14]([CH3:21])=[C:15]([N:20]3[CH:21]=[C:14]4[C:5]([CH:4]=[C:17]5[O:26][CH2:23][O:24][C:16]5=[CH:15]4)=[CH:6]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C2c3c(C)c(-n4cc5cc6c(cc5c4)OCO6)c(C)c(C)c3OC2(C)C)cc1
Temperature: 25 °C
Yield: 22.8 %

Procedure:
To a solution of 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine (799.8 mg, 2.73 mmol) in tetrahydrofuran (30 ml) were added 5,6-bis(chloromethyl)-1,3-benzodioxazole (603.8 mg, 2.76 mmol), sodium carbonate (877.8 mg, 8.28 mmol), and tetrabutylammonium iodide (506.8 mg, 1.37 mmol) and the mixture was refluxed with heating for 23 hours. The reaction mixture was cooled down to room temperature and then poured into ice water. The product was extracted twice with isopropyl ether. The combined extracts were washed with an aqueous saturated solution of sodium chloride, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 10:1) to obtain 136.8 mg (11% yield) of the title compound. Melting point: 236-242° C. (Ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27](OC)=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O.[NH2:32][NH2:33]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:11](=[O:25])[C@@H:10]([CH2:26][C:27]([NH:32][NH2:33])=[O:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CC2)C1=O

Procedure:
To a solution of 120 mg (0.27 mmol) of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate (Example 47) in EtOH was added hydrazine, monohydrate (135 μl, 2688 μmol). After being refluxed for 14 h, the reaction was concentrated, diluted (H2O) and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (5% MeOH/CH2Cl2, gradient elution) provided the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[CH2:21]([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23].C([BH3-])#N.[Na+].C(O)(=O)C>CO.O>[CH2:21]([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][CH2:17][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:3]3[C:4](=[O:11])[C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C:2]3=[O:1])=[CH:20][CH:19]=2)=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27])[CH2:22][CH3:23]
Reactant: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: CCCN(CCC)Cc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCCN(CCC)Cc1ccc(NCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 250.1 %

Procedure:
The compound (17.6 mg) obtained in Example 25-1, the compound (13.2 mg) obtained in Example 19-2, and sodium cyanoborohydride (8.7 mg) were dissolved in anhydrous methanol (1.0 ml). The solution was then adjusted to pH 5 with the addition of acetic acid, followed by stirring at room temperature for 4 hours. The reaction solution was added with distilled water and then subjected to extraction with chloroform. After that, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then purified through silica gel preparative thin-layer chromatography (chloroform/methanol), thereby obtaining the subject compound (72.9 mg) as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[CH:9][CH:10]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH:19]=1)[CH:17]=O>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:20])=[C:16]([CH2:17][C:5]2[S:1][C:2]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)=[CH:3][CH:4]=2)[CH:19]=1
Reactant: c1csc(-c2cccs2)c1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: Clc1ccc(Br)cc1Cc1ccc(-c2cccs2)s1

Procedure:
2,2′-Bithiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were used and treated in a manner similar to Reference Example 9 to give the target compound. APCI-Mass m/Z 369/371 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[C:22]([O:26][C:27]([C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])[C:30](O)=[O:31])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:22]([O:26][C:27]([C@@H:29]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41])[C:30]([NH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:31])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)[C@@H](Cc1ccc(Cl)cc1Cl)C(=O)O
Reactant: Cc1cc(-c2cc(N)cc(C(=O)OC(C)(C)C)c2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2cc(NC(=O)[C@H](Cc3ccc(Cl)cc3Cl)C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c2)ccn1
Temperature: 80 °C
Reaction time: 4 h
Yield: 100.5 %

Procedure:
A mixture of tert-butyl 3-amino-5-(2-methylpyridin-4-yl)benzoate (100 mg, 0.35 mmol), (S)-2-(tert-butoxycarbonyl)-3-(2,4-dichlorophenyl)-propanoic acid (152 mg, 0.45 mmol), HBTU (174 mg, 0.45 mmol) and N-ethyl-N-isopropylpropan-2-amine (92 μl, 0.53 mmol) in N,N-dimethylformamide (0.70 mL) was allowed to stir at 80° C. for 4 hours. Upon completion, the mixture was directly purified by HPLC to give 206 mg of tert-butyl 3-((S)-2-(tert-butoxycarbonyl)-3-(2,4-dichlorophenyl)propanamido)-5-(2-methylpyridin-4-yl)benzoate 49.1C. LCMS (ES+) m/z 601.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH3:21])[C:5]([B:10]2[O:14][C:13]([CH3:16])(C)C(C)(C)[O:11]2)=[C:6]([CH:9]=1)C=O.[OH-].[Na+].[N+:24](C)([O-:26])=[O:25].Cl>CCCCCCCCCCCCCCCC[N+](C)(C)C.[Br-].O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:19][CH2:20][CH3:21])[C:5]2[B:10]([OH:11])[O:14][CH:13]([CH2:16][N+:24]([O-:26])=[O:25])[C:6]=2[CH:9]=1
Reactant: CCOc1cc(Cl)cc(C=O)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[N+](=O)[O-]
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(Cl)cc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
The mixture of 5-chloro-3-ethoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (310 mg, 1 mmol), NaOH (40 mg, 1 mmol) and CTAB (5 mg, 0.05 mmol) in H2O (2 mL) and THF (10 mL) was stirred for 0.5 h at room temperature. After dropwise addition of nitromethane (0.2 mL, 2 mmol), the reaction mixture was stirred at room temperature for 3 h. Then the cyclization was afforded by adding the diluted aqueous HCl solution (2 N) to pH=2 and then extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4 and concentrated to dryness. The residue was purified by prep-HPLC to give the compound (100 mg, yield: 56%). 1H NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 7.22 (s, 1H), 6.96 (s, 1H), 5.69-5.72 (m, 1H), 5.30-5.34 (m, 1H), 4.61-4.67 (m, 1H), 4.10-4.15 (m, 2H), 1.31-1.34 (m, 3H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1)[NH2:6].Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])[CH:20]=[C:19]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:34])[F:33])[N:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:17]2[N:22]=[C:21]([NH:23][CH2:24][C:25]([CH3:26])([OH:27])[CH3:28])[CH:20]=[C:19]([CH2:29][O:30][CH2:31][C:32]([F:35])([F:33])[F:34])[N:18]=2)[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]1
Reactant: CC(C)(O)CNc1cc(COCC(F)(F)F)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(NCC(C)(C)O)n2)ccc1-n1cnc(C)c1
Temperature: 120 °C
Yield: 30.3 %

Procedure:
A mixture of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (45 mg, 0.22 mmol), 1-(2-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidin-4-ylamino)-2-methylpropan-2-ol (35 mg, 0.11 mmol), cesium carbonate (73 mg, 0.22 mmol), palladium(II) acetate (4 mg, 0.02 mmol) and 2-(dicyclohexylphosphino)biphenyl (6 mg, 0.02 mmol) in dioxane (1 mL) was heated at 120° C. by microwave irradiation under nitrogen atmosphere for 90 minutes. An additional equivalent of each: 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline, cesium carbonate, palladium(II) acetate and 2-(dicyclohexylphosphino)biphenyl was added and the reaction mixture was heated by microwave irradiation at 120° C. for additional 90 minutes. The mixture was filtered and purified by preparative HPLC to give the title compound as a solid 16 mg (29%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH3:26])[NH:20][CH2:19][CH2:18]2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CCC1NCCc2cc(F)ccc21
Product: CCC1c2ccc(F)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: N1[CH:6]=[CH:5][C:4]([C:7]2[C:11]3([CH2:13][CH2:12]3)[O:10][C:9](=[O:14])[C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:17][CH:16]=2)=[CH:3][CH:2]=1.[CH3:33][O:34][C:35]1C=CC(B(O)O)=CC=1>>[CH3:33][O:34][C:35]1[CH:2]=[CH:3][C:4]([C:7]2[C:11]3([CH2:13][CH2:12]3)[O:10][C:9](=[O:14])[C:8]=2[C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:19][CH:20]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C1OC2(CC2)C(c2ccncc2)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC23CC3)cc1
Yield: 18 %

Procedure:
Following the procedure for the preparation of 7-(pyridin-4-yl)-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (Example 26) using 4-methoxyphenylboronic acid provided the title compound.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[Li+].[OH-]>C1COCC1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:16])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.7 %

Procedure:
To a solution of 2-(4-Chloro-phenoxy)-2-methyl-propionic acid ethyl ester (6 g, 24.79 mmol) in THF (20 ml) was added a solution of LiOH (3 g, 74.38 mmol) in H20 (4 ml). The resulting solution was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was diluted with ethyl acetate (100 ml); cool to 0° C., acidified with 1N HCl (PH˜3-4). The organic phase were washed with, brine (20 ml) and dried over Na2SO4. After evaporation, the residue was purified by flash chromatography (1:1 hexanes/EtOAc) to give 2-(4-Chloro-phenoxy)-2-methyl-propionic acid (1.1 g, 20%). 1H NMR (400 MHz, CDCl3): δ 1.60 (s, 6H), 6.85 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.7 Hz, 2H). MS (EI) m/z: 215.5 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21]>>[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH:25][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:21]
Reactant: CCOC(=O)CN
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Product: CCOC(=O)CNC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (prepared from 3-nitrophenylacetic acid (Aldrich) and L-alanine ethyl ester hydrochloride (Sigma) using General Procedure C, followed by hydrolysis using General Procedure AF) and glycine ethyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=164-165° C.). The product was purified by silica gel chromatography using EtOAc as the eluent, followed by recrystallization from EtOAc.
Reaction SMILES: Cl.CC(C1C=[C:8](C=C(C(C)(C)C)C=1O)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)=[NH:20])=[CH:14][CH:13]=1)=O)(C)C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[C:39]2[CH2:45][C:46]([N:48]1CCN(C2C=CC(N)=CC=2)[CH2:50][CH2:49]1)=[O:47].CC(C1C=C(C=C(C(C)(C)C)C=1O)C(NC1C=CC(N)=CC=1)=O)(C)C>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:42](=[CH:43][CH:44]=1)[NH:41][CH:40]=[C:39]2[CH2:45][C:46]([N:48]1[CH2:8][CH2:9][N:11]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)=[NH:20])=[CH:16][CH:17]=2)[CH2:50][CH2:49]1)=[O:47]
Reactant: COc1ccc2[nH]cc(CC(=O)N3CCN(c4ccc(N)cc4)CC3)c2c1
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc(NC(=N)c3cccs3)cc2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C(=O)Nc2ccc(N)cc2)cc(C(C)(C)C)c1O
Agent: Cl
Product: COc1ccc2[nH]cc(CC(=O)N3CCN(c4ccc(NC(=N)c5cccs5)cc4)CC3)c2c1
Yield: 20 %

Procedure:
The experimental protocol used is the same as that described for the compound 1, with 1-[(5 methoxy-1H-indole-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine replacing the 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. The expected product is isolated in the form of the free base with a yield of 20% (pale yellow powder). Melting point: 221-222° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Br)cc4)nc23)CC1
Yield: 32.9 %

Procedure:
Beginning with 0.090 gm (0.39 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.128 gm (0.59 mMol) 4-bromobenzoyl chloride, 0.053 gm (23%) of the title compound was recovered as a crystalline solid by the procedure described in Example 4.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12](C(OC(C)(C)C)=O)[CH3:13])=[CH:8][C:7]=1[CH2:21][CH3:22].C(O)(C(F)(F)F)=O>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][C:7]=1[CH2:21][CH3:22]
Reactant: CCc1cc(N(C)C(=O)OC(C)(C)C)ccc1OCC(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(NC)ccc1OCC(=O)OC

Procedure:
Analogously, to example 1.4, [4-(tert-butoxycarbonyl-methyl-amino)-2-ethyl-phenoxy]-acetic acid methyl ester was deprotected with TFA to give (2-ethyl-4-methylamino-phenoxy)-acetic acid methyl ester as a light brown oil, MS: 224 (MH+).
Reaction SMILES: [S:1]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[C:5](=[O:11])[NH:4][CH2:3][CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:12][CH2:13][CH2:14][CH2:15][C:16]([C:9]1[S:8][C:7]2[S:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[C:6]=2[CH:10]=1)=[O:17]
Reactant: O=C1NCCSc2sccc21
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(CCCCl)c1cc2c(s1)SCCNC2=O
Reaction time: 3 h
Yield: 59 %

Procedure:
To a mixture of 13 g of 2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one and 21.5 g of 4-chlorobutyryl chloride in 200 ml of dichloroethane was added 21.5 g of aluminum chloride under cooling and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 12 g of 7-(4-chlorobutyryl)-2,3-dihydrothieno[3,2-f][1,4]thiazepin-5(4H)-one as white crystals, m.p. 124°-125° C.