Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH2:6].N1CCOCC1.[CH3:17][C:18]1([CH3:28])[O:22][C:21](=[CH:23][C:24](Cl)=[O:25])[C:20](=[O:27])[O:19]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][NH:6][C:24](=[O:25])[CH:23]=[C:21]1[C:20](=[O:27])[O:19][C:18]([CH3:17])([CH3:28])[O:22]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: NCc1ccc(F)c(F)c1
Solvent: ClCCl
Solvent: C1COCCN1
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)c(F)c2)O1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
To a stirred suspension of 3,4-difluorobenzylamine (0.43 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5–4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2Cl2 (3 mL) and the mixture stirred for 1 h. The mixture was filtered and the filtrate concentrated to give the title product as a white solid (81.8 mg, 92% yield). MS calcd for C14H13F2NO4Na (M+Na): 320.29. found: 320.27.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].Cl.[NH2:15]O.[OH-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]([NH2:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2cnccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])c2ccncc12

Procedure:
In Scheme 13, commercially available 5-nitroisoquinoline is aminated with hydroxylamine hydrochloride and sodium hydroxide in ethanol at 50° C. to yield the 5-nitro-isoquinolin-8-ylamine, which may be diazotized with a mixture of sodium nitrite in a strong acid such as hydrochloric, sulfuric or hydrofluoroboric acid. The diazonium salt may be heated with an appropriate copper salt such a copper chloride, copper bromide or copper cyanide to yield the 8-Cl, 8-Br or 8-CN nitro isoquinolines respectively. The diazonium salt may also be heated in with potassium iodide to yield the 8-iodo intermediate or heated in the presence of an aqueous acid such as sulfuric acid to yield the 8-OH nitroisoquinoline. The tetrafluoroborate diazonium salt may be heated to yield the 8-F nitroisoquinoline. In addition, the diazonium salt may be reacted with a sulfur nucleophile to yield the 8-thioalkyl nitroisoquinoline which may be further oxidized to the 8-sulfoxide or 8-sulfone. Any of the nitroisoquinolines described above may then be reduced by hydrogenation with a suitable catalyst or another suitable reducing agent such as tin(II) chloride and then further elaborated by the chemistry illustrated in Schemes 5 and 6 to the target ureas.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)=[O:13])=[CH:8][C:7]=1[Br:25]>O1CCCC1.CO.C(OCC)(=O)C>[Br:25][C:7]1[CH:8]=[C:9]([C:12]([NH:14][CH2:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)=[O:13])[CH:10]=[CH:11][C:6]=1[C:5]([OH:26])=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)O)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Sodium hydroxide (21.5 mg, 0.54 mmol) was added to a solution of 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid methyl ester (Example 83; 208 mg, 0.54 mmol) in tetrahydrofuran/methanol (2:1; 1.8 mL). The solution was allowed to stir at room temperature for 4 h and then more sodium hydroxide (21.5 mg, 0.54 mmol) was added. The solution was allowed to stir at room temperature overnight, then it was diluted with ethyl acetate and the solution was washed with 1N hydrochloric acid solution (10 mL), washed with brine, dried (MgSO4), filtered and concentrated to give crude 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid. This was mixed with a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (213.5 mg, 0.64 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (203.5 mg, 0.54 mmol), 1-hydroxybenzotriazole (72.6 mg, 0.54 mmol) and diisopropylethylamine (281 μL, 1.61 mmol) in N,N-dimethylformamide (1.5 mL). The solution was allowed to stir for 3 h, then ethyl acetate (20 mL) was added. The solution was washed with 1N hydrochloric acid solution (10 mL), saturated sodium bicarbonate solution (15 mL) and each aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, evaporated and chromatographed over silica gel (3-5% methanol/dichloromethane) to give rac.-N-[2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (206.8 mg, 69% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][C:20]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19]2)=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=O.[N-:30]=[N+:31]=[N-:32].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH:5]([C:6]1[N:8]([CH3:9])[N:32]=[N:31][N:30]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][C:20]3([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:19]2)=[CH:12][CH:11]=1
Reactant: CNC(=O)C(CC(=O)OC)c1ccc(OCC2CCCC3(CCCCC3)C2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CC(c1ccc(OCC2CCCC3(CCCCC3)C2)cc1)c1nnnn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.7 %

Procedure:
To a solution of N-methyl-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-succinamic acid methyl ester (178 mg) obtained in Step 7 in acetonitrile (5 mL) were added successively sodium azide (85 mg) and trifluoromethanesulfonic anhydride (0.29 mL), followed by stirring the reaction mixture at room temperature for 24 hours. Then, after addition of saturated aqueous sodium bicarbonate solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. The residue was purified by thin-layer column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:1) to give 3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid methyl ester (41 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:23]=[CH:22][C:10]([CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:18])([CH3:17])[C:13]2([OH:21])[CH2:19][OH:20])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH:12]2[CH2:16][CH2:15][C:14]([CH3:17])([CH3:18])[C:13]2([OH:21])[CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:22][CH:23]=1
Reactant: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCC(Cc2ccc(Cl)cc2)C1(O)COS(C)(=O)=O
Reaction time: 2 h
Yield: 79.8 %

Procedure:
2.76 g (1.05 equivalents)methylsulphonyl chloride were added to a solution of 6.42 g (24 mmols) 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-hydroxymethylcyclopentane prepared as described in (i) and 2.55 g (1.1 equivalents) triethylamine in 50 ml dichloromethane at 10°-15° C. The reaction mixture was kept at 10°-15° C. for further 2 hours and then washed with 20 ml water, then 20 ml aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulphate and flashed. Trituration with 60/80 petroleum gave 6.64 g 1-(4-chlorobenzyl)-3,3-dimethyl-2-hydroxy-2-methylsulphonyloxymethylcyclopentane (Isomer A) as a white solid, m.pt. 113°-114° C. Yield: 80%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]4)[CH:42]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (0.20 g, 0.40 mmol) in N,N-dimethylformamide (8 mL) and water (2 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.15 g, 0.40 mmol), potassium carbonate (0.22 g, 1.59 mmol), and tetrakis(triphenylphosphino)palladium(O) (0.021 g, 0.018 mmol). The mixture was heated to 100° C. After 1 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated, and the residue purified via silica gel chromatography (5% methanol/dichloromethane elute) to provide 0.15 g (60%) of tert-butyl 4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([NH:18][C:19](=[O:27])[C:20]([OH:26])([CH3:25])[C:21]([F:23])([F:24])[F:22])[CH:6]=[CH:7][C:8]=1[S:9]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)(=[O:10])=[O:11]
Reactant: COc1cc(NC(=O)C(C)(O)C(F)(F)F)ccc1S(=O)(=O)c1ccncc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ccncc2)c(O)c1)C(F)(F)F
Yield: 17.7 %

Procedure:
To a stirred suspension of N-[3-methoxy-4-(4-pyridylsulfonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (1.05 g, 2.6 mmol) in dry methylene chloride (30 mL) was added boron tribromide (10.4 mL of a 1.0M solution of boron tribromide in methylene chloride, 10.4 mmol). The resulting solution was stirred at reflux for 2 hours. An additional 5 mL of 1.0M boron tribromide solution in methylene chloride was added and the reaction stirred overnight at room temperature. The reaction mixture was diluted with methylene chloride (50 mL) and washed with water. The organic layer was dried (MgSO4) and concentrated in vacuo to yield an oil. Purification by flash column chromatography (20% v/v methanol in ethyl acetate) yielded the title propanamide as a white solid (0.18 g, 18%); mp 188°-189° C. 1H-NMR (250 MHz, d6-DMSO): 1.54 (s, 3H, CH3) 7.35 (d, 1H, J=9.0 Hz, aromatic) 7.51 (s, 1H, OH) 7.61 (s, 1H, aromatic) 7.77 (d, 2H, J=5.5 Hz, aromatic) 7.84 (d, 1H, J=8.9 Hz, aromatic) 8.83 (d, 2H, J=5.5 Hz, aromatic) 10.26 (s, 1H, NH) 11.04 (s, 1H, ArOH). MS (CI, CH4): 391 (M+1). Analysis for C15H13F3N2O5S.0.25 H2O: Calculated: C, 45.63; H, 3.44; N, 7.09. Found: C, 45.51; H, 3.58; N, 6.98.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[C:5]([N+:15]([O-])=O)[C:4]=1[NH:18][C:19](=O)[CH3:20]>CC(O)=O.[Fe]>[CH3:1][O:2][C:3]1[C:4]2[N:18]=[C:19]([CH3:20])[NH:15][C:5]=2[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1
Reactant: COc1cc(N2CCOCC2)cc([N+](=O)[O-])c1NC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(N2CCOCC2)cc2[nH]c(C)nc12
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a refluxing solution of combined batches of N-(2-methoxy-4-morpholino-6-nitrophenyl)acetamide (2.06 g) in HOAc (60 mL) was added iron powder (1.18 g) and the mixture was stirred at reflux temperature overnight. It was cooled to room temperature and filtered. The filtrate was concentrated in-vacuo and the residue was washed with EtOAc: petroleum ether=1:1 to afford crude product as a solid (1.73 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.56 (s, 3H), 3.12 (t, 4H, J=4.8 Hz), 3.88 (t, 4H, J=4.8 Hz), 3.94 (s, 3H), 6.39 (s, 1H), 6.62 (s, 1H); LC-MS: m/e=248 [M+1]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:22][C@@H:23]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:37][C:34]1[CH:33]=[CH:32][C:31]([C@H:23]([NH:22][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)[C@@H](N)c1ccc(O)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N[C@H](C(=O)OC(C)(C)C)c3ccc(O)cc3)cc2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-(2-(4-methoxyphenyl)acetamido)benzoic acid INT-12 (500 mg, 1.75 mmol) and (S)-tert-butyl 2-amino-2-(4-hydroxyphenyl)acetate (391 mg, 1.75 mmol) in DMF (10 mL) was added TEA (611 μL, 4.38 mmol) and HATU (700 mg, 1.84 mmol). After stirring for 2 h the reaction was diluted with EA (10 mL) and washed with brine (2×100 mL). The crude material was purified by chromatography (EA/hexanes) to give 860 mg (100%) of (S)-tert-butyl 2-(4-hydroxyphenyl)-2-(4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-13. LCMS-ESI (m/z) calculated for C28H30N2O6: 490; found 489, [M−H]−, tR=2.14 min (Method 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Cl-].[CH3:14][O:15][C:16]1[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=1[CH:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:18]([C:17]1[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=1[O:15][CH3:14])[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: COc1ccccc1C=[N+]1CCOCC1
Reactant: Fc1ccccc1-n1cccc1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1-c1ccccc1F)N1CCOCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-(2-fluoro-phenyl)-1H-pyrrole and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.[NH2:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:30][C:31]2[N:35]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)[N:34]=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:43]([C:33]1[CH:32]=[C:31]([NH:30][C:28]([NH:27][C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([NH:19][C:16]([C:11]3[CH:12]=[CH:13][C:14](=[O:15])[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:10]=3)=[O:18])[CH:21]=2)=[O:29])[N:35]([C:36]2[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[N:34]=1)([CH3:46])([CH3:45])[CH3:44]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c(N)c2)cc1
Reactant: O=C(O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c(NC(=O)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (35 mg) and 1-(3-amino-4-methylphenyl)-3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (70 mg) in DMF (1 mL) were added HATU (71 mg) and iPr2NEt (96 mg) successively under a nitrogen atmosphere, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with EtOAc (5 mL) and the resulted mixture was successively washed with 1M HCl (5 mL×2), saturated aqueous NaHCO3 (5 mL×2) and brine, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with 5% MeOH in CH2Cl2. The isolated material was triturated with CH2Cl2, and the precipitates were collected by filtration to give N-[5-[({[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]amino]carbonyl)amino]-2-methylphenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (34 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([OH:22])[CH:20]=[CH2:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH:19]([O:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH2:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC(O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C=CC(OC(=O)c1ccccc1)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 10.0 g of 1-(1-benzenesulfonyl-1H-indol-2-yl)-allyl alcohol (32 mmol) in 100 ml of pyridine were added dropwise 5.6 ml benzoyl chloride (48 mmol) at 10° C. The mixture was stirred for an additional 1 h at 20° C. Most of the pyridine was distilled off, the residue was given in portions to 300 ml of ice water. The pH was adjusted to 2–3 with conc. HCl. The water was distilled off and the residue was dissolved in 100 ml of diethyl ether. After about 1 h the product crystallized. The suspension was stirred in an ice bath for 2 h, the solid was filtered off. The crude material was recrystallized from 90 ml methanol and dried 12 h at 35° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:8].[CH3:29][N:30]1[CH:34]([CH2:35][CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][N:32]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[C:31]1=[O:59]>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:28])[C:11]([CH3:27])([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:36][CH2:35][CH:34]2[CH2:33][N:32]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:56])[F:58])=[CH:51][CH:50]=3)[C:31](=[O:59])[N:30]2[CH2:29][C:13]2[CH:18]=[CH:17][C:16]([O:4][CH3:1])=[CH:15][CH:14]=2)=[CH:15][CH:14]=1)[CH3:8]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2Cc2ccc(OC)cc2)cc1)Oc1ccccc1
Yield: 194.3 %

Procedure:
Cesium carbonate (2.18 g, 6.702 mmol) is added to a solution of 3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.55 g, 5.155 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (3.19 g, 5.67 mmol) in DMF (30 mL). The resultant mixture is stirred at 55° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed, then dried, concentrated, and purified by flash chromatography (17% acetone in hexanes) to provide the title compound (3.46 g, 97%). 1H NMR (400 MHz, CDCl3): δ 7.57 (d, 2H, J=7.01 Hz), 7.37 (d, 2H, J=7.1 Hz), 7.23-7.19 (m, 4H), 7.13 (d, 2H, J=8.7 Hz), 6.97 (t, 1H, J=7.1 Hz), 6.87-6.80 (m, 4H), 6.67 (d, 2H, J=8.7 Hz), 4.79, 4.07 (ABq, 2H, J=15.0 Hz), 4.47, 4.43 (ABq, 2H, J=15.0 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.92-3.87 (m, 2H), 3.80 (s, 3H), 3.61-3.55 (m, 1H), 3.31 (t, 2H, J=8.7 Hz), 3.24, 3.10 (ABq, 2H, J=14.2 Hz), 3.00 (t, 1H, J=7.9 Hz), 2.21-2.14 (m, 1H), 1.87-1.78 (m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+] 691 (M+H)+. Rf=0.49 in 50% acetone in hexanes.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@@H:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]2)[CH:20]=[N:19][CH:18]=1.[CH3:37][O:38][C:39]1[CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:43][CH:44]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[C:5]3[C:17]2[N:22]=[C:21]([O:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:25]3)[CH:20]=[N:19][CH:18]=2)[CH:42]=[N:43][CH:44]=1
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(-c3nn(C4CCCCO4)c4ccc(Br)cc34)n2)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cncc(-c2ccc3c(c2)c(-c2cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n2)nn3C2CCCCO2)c1
Temperature: 120 °C
Yield: 59.2 %

Procedure:
A glass microwave reaction vessel was charged with tert-butyl (3R)-3-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.100 g, 0.179 mmol), 5-methoxy-3-pyridineboronic acid pinacol ester (0.084 g, 0.358 mmol, Sigma-Aldrich), trans-dichlorobis(triphenyl-phosphine)palladium (II) (10.05 mg, 0.014 mmol) and Na2CO3 (0.095 g, 0.895 mmol) in dioxane (0.7 mL) and Water (0.175 mL). The reaction mixture was stirred and heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 120° C. for 20 min. The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide tert-butyl (3R)-3-((6-(5-(5-methoxy-3-pyridinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.062 g, 0.106 mmol, 59.0% yield) as a brown oil. MS (ESI, pos. ion) m/z: 587.2 (M+1).