Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:26][N:25]=[C:24]([C:27]([O:29]C)=[O:28])[CH:23]=4)[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[O:7][N:6]=1)=[O:4]>[OH-].[Na+].CO.O>[C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]4[O:26][N:25]=[C:24]([C:27]([OH:29])=[O:28])[CH:23]=4)[CH:17]=3)[CH:13]=[CH:14][CH:15]=2)[O:7][N:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1cc(-c2cccc(-c3cccc(-c4cc(C(=O)OC)no4)c3)c2)on1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2cccc(-c3cccc(-c4cc(C(=O)O)no4)c3)c2)on1
Reaction time: 2 h
Yield: 36.5 %

Procedure:
The ester from Example 10C (65 mg, 0.16 mmol) was dissolved in 4M NaOH (5 mL) in MeOH/H2O (5:3). After 2 hours no starting material was visible by TLC. When the reaction mixture was acidified to pH 1, the product precipitated out. The titled compound (22 mg, 36%) was obtained after reverse phase HPLC (0–70% acetonitrile in 0.1% aqueous TFA) as a white solid. MS (DEI) positive ion; m/z 376 (M)+: negative ion; m/z 751.1 (2M−H)−, 375.1 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 7.6 (s, 2H), 7.7 (t, J=7.8 Hz, 2H), 8.0 (dd, J=8.1, 1.5 Hz, 4H), 8.3 (s, 2H), 14.0 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17](=[O:20])[NH:18][CH3:19])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:25]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:18][CH3:19])=[O:20])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(C3CCN(C(=O)OC(C)(C)C)C3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c2cc(C3CC3)c(N(C3CCNC3)S(C)(=O)=O)cc2nn1-c1ccc(Br)cc1
Temperature: 40 °C
Reaction time: 0.67 h
Yield: 43.5 %

Procedure:
To a solution of tert-butyl 3-{[2-(4-bromophenyl)-5-cyclopropyl-3-(methylcarbamoyl)-2H-indazol-6-yl](methylsulfonyl)amino}pyrrolidine-1-carboxylate (12 mg, 0.019 mmol) in DCM (0.5 mL) was added trifluoroacetic acid (50 μL) and the mixture was stirred at 40° C. for 40 min. The mixture was cooled to RT, washed with saturated aqueous sodium bicarbonate (0.5 mL), dried (MgSO4) and concentrated to dryness. The residue was purified by preparative LCMS (5-100% ACN in 0.1% aqueous formic acid) to afford 2-(4-bromophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)(pyrrolidin-3-yl)amino]-2H-indazole-3-carboxamide as a white solid (4.4 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[NH:15]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][N:24]=1)[C:20]#[N:21])[NH2:16].CC(O)=O>CCO>[CH2:11]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:15]([C:17]2[CH:18]=[C:19]([C:20]#[N:21])[CH:22]=[CH:23][N:24]=2)[N:16]=1)[CH3:12]
Reactant: CCC(=O)CC(=O)c1ccc(C)cc1
Reactant: N#Cc1ccnc(NN)c1
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1cc(-c2ccc(C)cc2)n(-c2cc(C#N)ccn2)n1
Yield: 176.6 %

Procedure:
To a solution of 1-(4-methylphenyl)pentane-1,3-dione (370 mg, 1.9 mmol) and 2-hydrazinylisonicotinonitrile (150 mg, 1.1 mmol, PREPARATION 2) in 10 mL EtOH was added 2 mL AcOH. The reaction mixture was heated under reflux conditions overnight before being cooled and concentrated to dryness. The residue was adjusted to pH>8 with saturated aq. K2CO3, then extracted by EtOAc (10 mL×3). The combined organic layers were washed with 20 mL brine, dried over Na2SO4, concentrated, and purified by flash column chromatography (PE/EtOAc=10/1) to give the title compound (560 mg, 77%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.33 (3H, m), 2.38 (3H, s), 2.76 (2H, m), 6.33 (1H, s), 7.15 (4H, m), 7.31 (1H, m), 7.82 (1H, s), 8.42 (1H, m). [M+H] Calc'd for C18H16N4, 289; Found, 289.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][CH2:27][CH2:28][NH2:29]>>[NH2:26][CH2:27][CH2:28][NH:29][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=1
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Reactant: NCCN
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NCCN)nc21

Procedure:
The product of Example 44, and 1,2-diaminoethane were reacted by the procedure of Example 60 to afford 2-(2-amino-ethylamino)-4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=386 (MH+). Rt=1.54 min.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:8][C:7]=1[CH2:27][CH2:28][NH2:29].Cl[C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33]>C(Cl)Cl>[CH:35]([O:34][C:32]([NH:29][CH2:28][CH2:27][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:33])([CH3:37])[CH3:36]
Reactant: COC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CCN
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)c(CCNC(=O)OC(C)C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-{2-(2-amino-ethyl)-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid methyl ester (26 mg, 0.064 mmol) in CH2Cl2 (2 mL) at 0° C. was treated with TEA (0.2 mL) and isopropyl chloroformate (0.13 mL, 1.0 M in ether). The resulting mixture was allowed to warm gradually to ambient temperature. After 2 h, the mixture was concentrated to a residue, which was purified by silica gel chromatography (hexanes/EtOAc 7/3) to afford the isopropyl carbamate as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.19 (d, 6H, J=5.9 Hz), 2.42 (s, 3H), 2.54 (t, 2H, J=7.8 Hz), 2.79 (t, 2H, J=6.8 Hz), 2.89 (t, 2H, J=7.8 Hz), 3.05 (br s, 2H), 3.38 (br s, 2H), 3.60 (s, 3H), 4.26 (t, 2H, J=6.8 Hz), 4.68 (br s, 1H), 4.89 (q, 1H, J=6.4 Hz), 6.70 (br s, 1H), 6.71 (d, 1H, J=8.3 Hz), 7.05 (d, 1H, J=8.3 Hz), 7.47 (m, 3H), 8.10 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=1.C(=O)(O)[O-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:2]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cccnc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)c2cccnc2)cc1
Temperature: 0 °C
Yield: 77 %

Procedure:
A stirred solution of 4-nitrophenyl 3-pyridyl sulfone (1.60 g, 6.1 mmol) and stannous chloride dehydrate (6.83 g, 30.2 mmol) in absolute ethanol (20 mL) was heated at reflux for 45 min. The reaction mixture was poured into ice water, and the aqueous solution basified with sodium bicarbonate (pH=8-9) and extracted with ethyl acetate (2×200 mL). The organics were combined, dried (MgSO4), filtered, and the solvent distilled to yield the title benzenamine (1.10 g, 79%) as a pale yellow solid; mp 182°-184° C. 1H--NMR (300 MHz, d6 --DMSO): 6.29 (broad s, 2H, NH2), 6.64 (d, 2H, J=11.2 Hz, aromatic), 7.58 (m, 1H, aromatic), 7.61 (d, 2H, J=11.1 Hz, aromatic), 8.21 (dd, 1H, J=9.8, 2.4 Hz, aromatic), 8.78 (dd, 1H, J=9.9, 1.4 Hz, aromatic), 9.01 (d, 1H, J=2.4 Hz). MS (CI, CH4): 235(M+1).
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:28]([F:31])([F:30])[F:29])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=2[F:27])[C:21]([OH:23])=O)([CH2:16][F:17])[N:15]=1)(=O)C1C=CC=CC=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1O>>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]2[N:32]=[C:21]([C:20]3[CH:24]=[CH:25][C:26]([F:27])=[C:18]([C@:14]4([CH2:16][F:17])[CH2:13][C@@H:12]([C:28]([F:29])([F:30])[F:31])[O:11][C:10]([NH2:9])=[N:15]4)[CH:19]=3)[O:23][C:34]=2[CH:35]=1
Reactant: Nc1ccc(Cl)cc1O
Reactant: O=C(O)c1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Product: NC1=N[C@](CF)(c2cc(-c3nc4ccc(Cl)cc4o3)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 160 °C
Reaction time: 0.43 h
Yield: 3.4 %

Procedure:
To a 3 mL microwave vial was added 3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorobenzoic acid (76.5 mg, 0.17 mmol). 2-amino-5-chlorophenol (74.0 mg, 0.52 mmol) and polyphosphoric acid (0.50 mL). The mixture was purged with Ar for 1 min, then the tube was sealed and heated to 160° C. for 1 h. The mixture was then diluted with Na2CO3 in water and extracted with DCM three times. The organic layer was dried over Na2SO4, and concentrated in vacuo. The crude was purified by reverse phase HPLC: 10-100% in 26 min, MeCN in water with 0.1% TFA. The combined fractions were neutralized with solid Na2CO3, and extracted with DCM three times. The organic phase was dried over Na2SO4 and concentrated in vacuo. The product was obtained as an off-white solid (2.6 mg, 3.6% yield). MS m/z=446 [M+H]+. Calculated for C19H13ClF5N3O2: 445.8.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:15]4[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]4[CH:13]([CH2:21][N:22]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[NH:34][C:33]5[CH:35]=[CH:36][C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:38][C:32]=5[N:31]=4)[CH:23]([CH3:25])[CH3:24])[CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:43]>>[C:39]([C:37]1[CH:36]=[CH:35][C:33]2[NH:34][C:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:22]([CH2:21][CH:13]3[C@H:14]4[O:18][C:17]([CH3:20])([CH3:19])[O:16][C@H:15]4[C@H:11]([N:8]4[C:4]5[N:5]=[CH:6][N:7]=[C:2]([NH2:43])[C:3]=5[CH:10]=[CH:9]4)[CH2:12]3)[CH:23]([CH3:25])[CH3:24])=[N:31][C:32]=2[CH:38]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(C)N(CCCCc1nc2cc(C(C)(C)C)ccc2[nH]1)CC1C[C@@H](n2ccc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reactant: N
Product: CC(C)N(CCCCc1nc2cc(C(C)(C)C)ccc2[nH]1)CC1C[C@@H](n2ccc3c(N)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 8 h
Yield: 67 %

Procedure:
A solution of {[(3aR,6R,6aS)-6-{4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]methyl}[4-(5-tert-butyl-1H-1,3-benzodiazol-2-yl)butyl]propan-2-ylamine, (120 mg, 0.2 mmol) in methanolic ammonia (7N, 10 ml) was heated to 80° C. in a glass walled sealed tube with stirring overnight. The reaction mixture was then concentrated in vacuo, re-treated with methanolic ammonia (7N, 10 ml) and the reaction was continued for a further 48 hrs. This was then absorbed onto silica gel and purified by silica gel column chromatography, eluting with 7N NH3 in MeOH:DCM (4:96). The product was purified further on a preparative TLC plate, eluting with 7N NH3 in MeOH:DCM (1:9) to give an off-white solid product (75 mg, 67%): MS (ESI+) for C33H47N7O2 m/z 573.79 [M+H]+; HPLC purity 98% (ret. time, 1.23 min); 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.92-8.29 (1H, m), 7.22-7.58 (2H, m), 6.58-7.08 (1H, m), 6.24-6.58 (1H, m), 4.68-5.00 (2H, m), 4.28-4.46 (2H, m), 3.21-3.33 (2H, m), 2.50-3.03 (4H, m), 2.36 (5H, d, J=5.34 Hz), 1.54-2.09 (3H, m), 1.32-1.49 (6H, m), 1.14-1.34 (9H, m), 0.71-1.01 (6H, m)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH:33]=[C:32](B(O)O)[CH:31]=[N:30]2)[CH:26]=[CH:27][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH:33]=[C:32]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]5[CH:21]=[CH:20][N:19]=[CH:18][N:17]=5)(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH:31]=[N:30]2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(Cl)nccc2c1
Reactant: OB(O)c1cnn(-c2cccc(Cl)c2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3cnn(-c4cccc(Cl)c4)c3)nccc2c1
Temperature: 100 °C

Procedure:
A vial was charged with 1-chloro-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide (Intermediate GG) (53 mg, 0.17 mmol), (1-(3-chlorophenyl)-1H-pyrazol-4-yl)boronic acid (44 mg, 0.200 mmol), Pd(AmPhos)2Cl2 (12 mg, 0.017 mmol), potassium phosphate (106 mg, 0.500 mmol), dioxane (1.042 μl), and water (0.347 μl). The vial was sealed and heated in an oil bath overnight at 100° C. The crude reaction mixture was purified using reverse-phase HPLC with a Waters-Xbridge C18, 19×100 mm, 10 μm column with a gradient 5-95% acetonitrile and water with 0.1% ammonium hydroxide modifier to yield 1-(1-(3-chlorophenyl)-1H-pyrazol-4-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide. m/z (ESI) 463.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][C:14]([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][C:14]([OH:16])=[O:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A mixture of 4-fluoro-benzenesulfonyl chloride (9.68 g, 0.497 mol), glycine (4.48 g, 0.0598 mol), and sodium carbonate (16.99 g, 0.160 mol) in water (60 mL) was stirred at room temperature for 42 hours. The mixture was carefully acidified to pH 8 to 9 with concentrated hydrochloric acid, and washed 2 times with dichloromethane. The aqueous layer was acidified further to pH 2, and the resulting white suspension was extracted two times with ethyl acetate. The extracts were combined, washed with saturated sodium chloride solution, and dried over magnesium sulfate. The dried solution was rotary evaporated to give a white solid, which was dried in vacuo; yield 4.7 g (41%), mp=154.0-155.5° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:16])[C@@H:6]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:7])[CH:2]=[CH2:3].C(N(CC)CC)C.[C:24]([NH:34][C:35]([CH3:40])([C:37](O)=[O:38])[CH3:36])([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:16])[C@H:6]([NH:7][C:37](=[O:38])[C:35]([NH:34][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])([CH3:40])[CH3:36])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH:2]=[CH2:3]
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: C=CCOC(=O)[C@H](N)CCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)[C@@H](CCc1ccccc1)NC(=O)C(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
The amine obtained in Step B of this Example (300 mg; 1.37 mmol) triethylamine (380 ml; 2.73 mmol) and N-carbobenzyloxy-2-methylalanine (278 mg; 1.37 mmol) were dissolved in dry methylene chloride (3 ml) and BOP (605 mg; 1.37 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and the resultant homogenous yellow solution quenched by addition of brine. The two phase system was extracted with methylene chloride (2×25 ml) and the combined methylene chloride layers dried over powdered anhydrous magnesium sulfate. Filtration of the methylene chloride solution to remove the spent drying agent followed by evaporation of solvent afforded an oil which was purified by column chromatography on silica gel using a solvent mixture of ethyl acetate and hexanes (1:1 v/v) as eluant. The desired product (419 mg; 69.7%) was isolated as a white amorphous solid. FAB-MS:- calculated for C25 H30N2O5 438.2; found 439.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]3[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=3[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=1)[N:7]([CH3:26])[CH:6]=[C:5]2[CH:27]([CH3:29])[CH3:28].Cl.[CH3:31][N:32]([CH2:34][C:35]1[CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:39][CH:40]=1)[CH3:33]>>[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH:13][CH2:14][C:15]4[C:16](=[O:25])[NH:17][C:18]([CH3:24])=[CH:19][C:20]=4[CH2:21][CH2:22][CH3:23])=[O:12])[CH:10]=2)[N:7]([CH3:26])[CH:6]=[C:5]3[CH:27]([CH3:28])[CH3:29])[CH:38]=[CH:37][CH:36]=1)[CH3:33]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2cccc(CN(C)C)c2)cc2c(C(C)C)cn(C)c12
Yield: 63 %

Procedure:
The title compound was prepared in the same manner as described for Example 2 using 5-bromo-1-methyl-3-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indole-7-carboxamide (300 mg, 0.65 mmol) and 3-(N,N-dimethylaminomethyl)phenylboronic acid pinacol ester hydrochloride (250 mg, 0.84 mmol). Obtained 210 mg of the title compound (63% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 8.49 (t, J=4.80 Hz, 1H), 7.82 (d, J=1.77 Hz, 1H), 7.56-7.64 (m, 2H), 7.41 (t, J=7.58 Hz, 1H), 7.31 (d, J=1.52 Hz, 1H), 7.25 (d, J=7.58 Hz, 1H), 7.11 (s, 1H), 5.91 (s, 1H), 4.38 (d, J=5.05 Hz, 2H), 3.70 (s, 3H), 3.33 (s, 2H), 3.22 (quin, J=6.76 Hz, 1H), 2.52-2.59 (m, J=6.82, 8.59 Hz, 2H), 2.26 (br. s., 6H), 2.13 (s, 3H), 1.58 (sxt, J=7.53 Hz, 2H), 1.31 (d, J=6.82 Hz, 6H), 0.94 (t, J=7.33 Hz, 3H). MS (ES) [M+H]+ 513.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(OCCO)C>[CH2:12]([N:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCOCCO
Product: O=[N+]([O-])c1ccc(Cl)cc1NC1CCN(Cc2ccccc2)CC1
Yield: 35.3 %

Procedure:
A solution of 38.4 g of 2,4-dichloro-1-nitrobenzene in 160 ml of 2-ethoxyethanol is heated to 100° C. A solution of 152.23 g of N-benzyl-4-aminopiperidine in 40 ml of 2-ethoxyethanol is then added slowly. The mixture is refluxed for 5 hours. The solvent is evaporated off under vacuum, the residue is taken up with H2O, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using isopropyl ether as the eluent to give 24.4 g of the expected product after crystallization from isopropyl ether. M.p.=84° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1cccc(Cl)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(3-chlorophenyl)acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.41-8.43 (m, 1H), 7.93-8.04 (m, 2H), 7.72-7.75 (m, 1H), 7.62-7.66 (m, 4H), 7.47 (t, J=1.8 Hz, 1H), 7.31-7.42 (m, 3H), 3.74 (s, 2H); MS (ESI−) M/Z 422 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O>[Cl:9][C:6]1[CH:5]=[C:3]([NH2:4])[C:2]([C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:8][CH:7]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(Cl)ccc1-c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
2-Bromo-5-chloroaniline (CAS#823-57-4; 5 g), 4-fluorophenylboronic acid (3.56 g) and cesium carbonate (31.6 g) were combined in THF (70 ml) and water (35 ml). The mixture was degassed by bubbling argon through the solution. After addition of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (886 mg) the reaction mixture was stirred 1 h at 80° C. in a sealed tube. The reaction mixture was diluted with EtOAc, washed with water, dried over Na2SO4, evaporated and purified by chromatography (silica gel, 0% to 30% EtOAc in heptane). The product was finally bulb-to-bulb distilled at 0.3 mbar and 120-130° C. oven temperature to give the title compound (5.07 g) as a light yellow liquid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Br:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1>[Br:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]([OH:23])=[O:2])[C:10](=[O:22])[CH:11]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccccc2Br)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2ccccc2Br)=CC1=O
Temperature: 20 °C
Yield: 103.2 %

Procedure:
To a solution containing (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (2.00 g, 0.005 mol) in tetrahydrofuran (40 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 21 mL, 0.011 mol). The mixture was stirred at 20° C. for 2H, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2-bromo-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1.90 g, 99%) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:23])([CH3:22])[CH:10]2O)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([F:25])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[CH:16]=1)[C:11]([CH3:22])([CH3:23])[CH2:10]2)=[O:4]
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(F)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-6-fluoro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (24.3 g, 59.5 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (20 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×100 mL), washed with saturated aqueous sodium bicarbonate solution (2×50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(5% ethyl acetate/hexanes) to afford 2-(3-bromo-phenyl)-6-fluoro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (10 g, 43%) as a white solid: LC/MS m/e calcd for C19H19BrFNO2 M+: 392.3, observed: 391.9, 393.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[CH2:9](Br)[CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+]>O>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Sc1ccc(Br)cc1
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCSc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromothiophenol (30 g), pentyl bromide (26.4 g), sodium hydroxide (6.67 g) and water (30 ml) was heated at 90° C. and stirred for 48 hrs. The mixture was then poured into water, extracted with petroleum spirit, dried and distilled (bp 96° C. at 0.11 mmHG). Yield 27.3 g.