Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([C:21](O)=[O:22])[N:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29]>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:21]([C:17]1[N:18]([CH3:20])[N:19]=[C:15]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:24])[CH:16]=1)=[O:22]
Reactant: COCCN
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)O)n(C)n1
Product: COCCNC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Yield: 68 %

Procedure:
As described for example 55, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid (100 mg, 0.3 mmol) was converted, using 2-methoxyethylamine instead of 2-amino-2-methyl-1-propanol, to the title compound (80 mg, 68%) which was obtained as a colorless gum MS: m/e=389.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][NH2:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:39](Cl)(=[O:41])[CH3:40].Cl>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16](=[O:29])[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2)[CH2:14][CH2:13][C@@H:12]1[CH2:30][NH:31][C:39](=[O:41])[CH3:40])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CC[C@@H](C(=O)Nc2cccc(OC(F)(F)F)c2)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,5S)-2-aminomethyl-5-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (200 mg), and Et3N (77 μL, 0.55 mmol) in CH2Cl2 (3 mL) was added under nitrogen atmosphere at 0° C. acetyl chloride (39 μL, 0.55 mmol) and the mixture was stirred at 0° C. for 1 h. CH2Cl2 and 1N aqueous HCl were added, the layers were separated and the aqueous one back-extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc gradient 100:0 to 0:100) to give the title compound. MS (LC/MS): 480.1 [M+H]+; tR (HPLC conditions b): 4.69 min.
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[C:36]([C:37]([F:40])([F:39])[F:38])=[CH:35][C:7]([CH2:8][C@@H:9]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([OH:33])[CH:30]=4)[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)=[O:16])[C:10]([O:12]C)=[O:11])=[CH:6][C:5]=1[Cl:41].Cl>O.C1COCC1>[NH2:3][C:4]1[C:36]([C:37]([F:39])([F:38])[F:40])=[CH:35][C:7]([CH2:8][C@@H:9]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([OH:33])[CH:30]=4)[NH:25][C:24]3=[O:34])[CH2:19][CH2:18]2)=[O:16])[C:10]([OH:12])=[O:11])=[CH:6][C:5]=1[Cl:41]
Reactant: COC(=O)[C@H](CC(=O)N1CCC(N2Cc3cc(O)ccc3NC2=O)CC1)Cc1cc(Cl)c(N)c(C(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3Cc4cc(O)ccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 144 mg (6.00 mmol) LiOH in 15 mL water was added to a solution of 2.30 g (4.04 mmol) methyl(S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(6-hydroxy-2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-4-oxo-butanoate in 30 mL THF and the reaction mixture was stirred for 1 h at RT. The organic solvent was eliminated i.vac., the residue was diluted with 50 mL water and acidified with 1 M HCl. The precipitate formed was filtered, washed with 10 mL water and dried at 50° C.
Reaction SMILES: [I-].[CH2:2]([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([Zn+])=[CH:9][CH:8]=1)=[O:6])[CH3:3].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].Cl>C1COCC1.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>[CH3:14][C:15]([CH3:20])([CH3:19])[C:16]([C:10]1[CH:11]=[CH:12][C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=1)=[O:17]
Reactant: CCOC(=O)c1ccc([Zn+])cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(Ethoxycarbonyl)phenyl-zinc iodide (50.0 mL of a 0.5 M solution in THF, 25.0 mmol) was added slowly via cannula to a stirred solution of dichlorobis(triphenylphosphine)palladium(II) (484 mg, 0.690 mmol) in THF (50 mL) at 0° C. After 15 min, trimethylacetyl chloride (2.80 mL, 22.7 mmol) was added and the resulting mixture was stirred at 0° C. for 1.5 h. The reaction mixture was poured into 1 N HCl and extracted three times with EtOAc. The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0-10% EtOAc/hexanes as eluent) afforded the title compound i-1a. 1HNMR (500 MHz, CDCl3): δ 8.08 (d, 2H, J=8.5 Hz), 7.67 (d, 2H, J=8.5 Hz), 4.42 (q, 2H, J=7.2 Hz), 1.42 (t, 3H, J=7.2 Hz), 1.36 (s, 9H).
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[C:19]([OH:30])=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[N:23]([CH3:28])[C:22]=4[CH:29]=3)(O)[C:9]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C2C(=CC=CC=2)C(C2C(O)=CC3N(C)C(=O)COC=3C=2)(O)C1=O)(C1C=CC=CC=1)C1C=CC=CC=1>>[C:32]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:19]([OH:30])=[CH:20][C:21]4[O:26][CH2:25][C:24](=[O:27])[N:23]([CH3:28])[C:22]=4[CH:29]=3)[C:9]2=[O:31])[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CN1C(=O)COc2cc(O)c(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Agent: CN1C(=O)COc2cc(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Product: CN1C(=O)COc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 17B, and making non-critical variations using 6-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one to replace 7-(1-benzhydryl-3-hydroxy-2-oxoindolin-3-yl)-6-hydroxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 6-[1-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-7-hydroxy-4-methyl-2H-1,4-benzoxazin-3(4H)-one was obtained (65%) as an amorphous solid: MS (ES+) m/z 477.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][S:6][C:7]1[NH:12][C:11](=O)[CH:10]=[C:9]([CH:14]=[C:15]2[S:19][C:18](=[S:20])[NH:17][C:16]2=[O:21])[N:8]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[Cl:25])[CH2:5][S:6][C:7]1[N:8]=[C:9]([CH:14]=[C:15]2[S:19][C:18](=[S:20])[NH:17][C:16]2=[O:21])[CH:10]=[CH:11][N:12]=1
Reactant: O=C1NC(=S)SC1=Cc1cc(=O)[nH]c(SCc2ccc(Cl)c(Cl)c2)n1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: Cc1ccccc1
Product: O=C1NC(=S)SC1=Cc1ccnc(SCc2ccc(Cl)c(Cl)c2)n1
Temperature: 80 °C
Yield: 8.8 %

Procedure:
To a stirred suspension of 5-(2-(3,4-dichlorobenzylthio)pyrimidin-4-ylmethylidene)rhodanine (Example 25, 0.3 mmol) in toluene (5 mL) was added diethyl 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylate (109 mg, 0.39 mmol) and 0.3 g of activated silica gel. The mixture was heated to 80° C. for 20 h then filtered while warm. The filter cake was rinsed with ethyl acetate and the combined filtrates were evaporated to dryness. The residue was redissolved in ethyl acetate and extracted with 1 N aqueous hydrochloric acid. The organic layer was dried (sodium sulfate) and concentrated to give 11 mg of pure product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[N:33]=[C:32](Cl)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:35])[CH:30]=2)[N:25]=1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:24]1[N:33]=[C:32]([C:16]2[CH:15]=[C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:19]=[CH:18][CH:17]=2)[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:35])[CH:30]=2)[N:25]=1
Reactant: Clc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(B(O)O)c2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-c3nc(Cl)nc4ccc(Cl)cc34)c2)CC1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid (intermediate 60.2) (960 mg, 3.14 mmol, 1.00 equiv), 2,4,6-trichloroquinazoline (800 mg, 3.43 mmol, 1.09 equiv), PdCl2(dppf).CH2Cl2 (130 mg, 0.16 mmol, 0.05 equiv), Potassium Carbonate (860 mg, 6.23 mmol, 1.99 equiv) in N,N-dimethylformamide (30 mL). The resulting solution was stirred for 3 h at 85° C. The reaction was then quenched by the addition of 50 mL of saturated brine. The resulting solution was extracted with 2×30 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 0.45 g (31%) of tert-butyl 4-(3-(2,6-dichloroquinazolin-4-yl)phenyl)piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:35][CH:34]=2)[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH4-].[Na+].O>C(O)C>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[CH:37][CH:38]=2)[C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH2:27][NH:9][CH:1]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:20][CH:19]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC1CCCCCCC1
Reactant: O=Cc1ccccc1C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc(COc2ccc(C(c3ccc(OCc4ccccc4)cc3)c3ccccc3CNC3CCCCCCC3)cc2)cc1
Yield: 65.5 %

Procedure:
In 50 ml of ethanol was dissolved 3 g of cyclooctylamine. To the solution was added 11.41 g of 2-[bis-(4-benzyloxyphenyl)methyl]benzaldehyde obtained by Reference Example 8, and the mixture was heated under reflux for 2 hours. Thereafter, 1.78 g of sodium borohydride was added thereto, and the mixture was heated under reflux for 2 hours. The solvent was evaporated-under reduced pressure, and water was added to the residue. The aqueous mixture was extracted with ether, and the organic layer was separated. The aqueous layer was extracted with ether, and then the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized to afford 9.19 g of the desired product (Compound 82).
Reaction SMILES: [K].[S:2]([C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])(O)(=[O:4])=[O:3].C[N:16](C)C=O.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[S:2]1(=[O:4])(=[O:3])[C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8](=[O:9])[NH:16]1
Reactant: O=C(O)c1ccccc1S(=O)(=O)O
Reactant: CN(C)C=O
Agent: O=C(Cl)Cl
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C1NS(=O)(=O)c2ccccc21
Temperature: 80 °C

Procedure:
Into a four necked flask equipped with a stirrer, a thermometer, a condenser and a phosgene inlet, were charged 24.0 g (0.1 mole) of the monopotassium salt of o-sulfobenzoic acid ##STR10## 150 ml of toluene and 0.22 g (0.003 mole) of dimethylformamide. The mixture was stirred at 80° C and 23 g of phosgene were introduced into the mixture over 4 hours. The reaction was continued by maintaining the temperature at 80° - 90° C under refluxing with stirring for 3 hours. After the reaction, nitrogen gas was injected into the mixture to remove excess phosgene. The reaction mixture was filtered to remove potassium chloride and the filtrate was condensed and a colorless condensate was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1ccc(O)cc1
Reactant: CS(=O)(=O)c1ccc(Br)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: [Na+]
Solvent: COCCOC
Product: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1

Procedure:
[4-(Methylsulfonyl)phenyl]boronic acid (0.69 g, 3.40 mmol) was added to a solution of 4-bromophenol (0.5 g, 2.83 mmol) in DME (25 mL), followed by addition of 2M Na2CO3 (25 mL) and Pd(PPh3)4 (0.17 g, 0.14 mmol). The reaction mixture was heated at 90° C. for 3 h, then cooled to ambient temperature, and extracted with ether. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as an off-white solid. The crude product was purified by chromatography on a silica gel column eluted with 50% EtOAc/hexane to give 0.45 g (64%) of 4′-(methylsulfonyl)-4-biphenylol as a white solid. Alternatively, 4′-(methylsulfonyl)-4-biphenylol was prepared from 4-bromophenyl methyl sulfone (2 g, 8.5 mmol), (4-hydroxyphenyl)boronic acid (1.76 g, 12.75 mmol), 2M Na2CO3 (100 mL) and Pd(PPh3)4 (0.1 g, 0.08 mmol) in DME (100 mL) in a manner similar to the conditions above. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.6 Hz), 7.71 (d, 2H, J=8.3 Hz), 7.51 (d, 2H, J=8.6 Hz), 6.94 (d, 2H, J=8.5 Hz), 4.92 (s, 1H), 3.08 (s, 3H); LRMS (ESI), m/z 249 (M+H).
Reaction SMILES: CC1C=CC=C(C)N=1.[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18](Br)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1.[Br:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2>CN(C)C=O>[O:9]1[C:13]2[CH:14]=[CH:15][C:16]([CH:18]([C:28]3[C:27]4[C:31](=[CH:32][CH:33]=[C:25]([Br:24])[CH:26]=4)[N:30]([CH3:34])[CH:29]=3)[C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:12]=2[O:11][CH2:10]1
Reactant: Cn1ccc2cc(Br)ccc21
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc2c(c1)OCO2)c1cn(C)c2ccc(Br)cc12
Temperature: 80 °C
Yield: 76.6 %

Procedure:
2,6-Dimethylpyridine (0.75 ml) was added to a stirred solution of methyl 2-(1,3-benzodioxol-5-yl)-2-bromoacetate (from Example 61(c), 1.75 g, 6.43 mmol) and 5-bromo-1-methylindole (from step (a), 1.35 g) in anhydrous dimethylformamide (10 ml) at ambient temperature, under a nitrogen atmosphere. The solution was heated at 80° C. for 8 hours. The reaction mixture was partitioned between diethylether and water, separated and the organic layer dried (magnesium sulphate) and evaporated in vacuo. The residue was flash chromatographed (using 50% dichloromethane and 50% hexane as eluant) to give the subtitle compound as a colourless oil (1.98 g).
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([CH:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:26])=O.C(N(C(C)C)CC)(C)C>>[C:1]([C:5]1[CH:23]=[CH:22][C:8]([C:9]([Cl:26])=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(C(C)(C)C)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C(=O)OCC)=C(Cl)c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a mixture of 72.5 g of diethyl 4-t-butyl-benzoylmalonate and 337.7 g of phosphorus oxychloride, 48.9 g of diisopropylethylamine was added, and the resulting mixture was stirred at 100° C. for 3 hours. The reaction mixture was evaporated under reduced pressure, and the resulting solid residue was extracted with diethyl ether, and the still remaining solid was mixed with water and then extracted diethyl ether. The extracts were combined, concentrated under reduced pressure, washed with 1N hydrochloric acid, 1N aqueous sodium hydroxide and water successively and dried over anhydrous sodium sulfate. The insoluble were filtered off, and the solvent was removed by evaporation. The resulting residue was purified by silica gel chromatography (eluent; n-hexane/ethyl acetate=7:1) to give 73.19 g of the title compound as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)(=[O:19])=[O:18].C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCO>[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:1][C:2]2[C:6]([C:7]([NH2:9])=[O:8])=[CH:5][N:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:3]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: NC(=O)c1cn(-c2ccccc2)nc1N
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Nc2nn(-c3ccccc3)cc2C(N)=O)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
3-amino-1-phenyl-1H-pyrazole-4-carboxamide (50 mg, 0.247 mmol), 4-bromophenyl methyl sulfone (58.1 mg, 0.247 mmol), Pd2 dba3 (22.64 mg, 0.025 mmol), K2CO3 (37.6 mg, 0.272 mmol) and X-Phos (58.9 mg, 0.124 mmol) were added to a 5 mL microwave vial. Degassed EtOH (0.75 mL) was added and the vial evacuated and back-filled with N2 (×3). The resulting mixture was stirred at 100° C. for 4 hours. Room temperature was attained, MeOH was added and the solvent removed in vacuo while loading onto silica. Purification of the residue by MPLC (0-6% MeOH—CHCl3) gave 3-{[4-(methylsulfonyl)phenyl]amino}-1-phenyl-1H-pyrazole-4-carboxamide as a pale yellow solid after triturating in DCM.
Reaction SMILES: [H-].[Na+].[C:3]1(/[CH:9]=[CH:10]/[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:16][CH:15]=2)=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>C1COCC1.C(OCC)(=O)C>[CH3:36][O:35][C:33]([CH2:32][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:30])/[CH:22]=[CH:23]/[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:15]=1)=[O:34]
Reactant: COC(=O)CBr
Reactant: O=C(/C=C/c1ccccc1)Nc1ccc(OC(=O)/C=C/c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CN(C(=O)/C=C/c1ccccc1)c1ccc(OC(=O)/C=C/c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.4 %

Procedure:
Sodium hydride (60%, 162 mg, 4.06 mmol) was washed with anhydrous THF (×2) and then suspended in anhydrous THF (20 mL). To this was added (E)-3-phenylacrylic acid 4-[(E)-(3-phenylacryloyl)amino]phenyl ester 11 (1.00 g, 2.71 mmol) followed by methyl bromoacetate (0.51 mL, 5.41 mmol). The reaction mixture was stirred at room temperature for 3 days. It was then diluted with ethyl acetate and washed with brine (×3), dried (Na2SO4) and evaporated. The resultant residue was purified by flash column chromatography on silica gel, eluting with petrol/ethyl acetate (2:1→1:1) and then ethyl acetate, to afford the title compound (0.734 g, 61%). 1HNMR (300 MHz) (CDCl3) δ 3.77 (3H, s), 4.52 (2H, s), 6.43 (1H, d, J=16 Hz), 6.65 (1H, d, J=16 Hz), 7.25-7.40 (7H, m), 7.45 (4H, m), 7.61 (3H, m), 7.75 (1H, d, J=16 Hz) and 7.91 (1H, d, J=16 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6](=[O:20])[CH2:7][C@@H:8]([CH2:9][OH:10])[CH2:12][C@H:13]([CH3:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Product: CCCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Compound 157 (3.52 g, 12.3 mmol) was dissolved in anhydrous THF (123 mL) and cooled to 0° C. Borane dimethylsulfide complex (10 M, 3.69 mL) was added dropwise, and the reaction then warmed to room temperature and stirred for 1 hour. the reaction was cooled to 0° C., and quenched with MeOH (20 mL) added dropwise. The reaction was stirred for 18 hours, and the solvent rotovapped off. The crude material was chromatographed on silica eluting with 20% EtOAc/hexanes to give 158 (2.28 g, 68%) as an oil. 1H NMR (400 MHz, CDCl3) δ3.65-3.59 (m, 1H), 3.43 (dd, J=11.1, 6.96 Hz, 1H), 2.31 (dd, J=14.9, 7.57 Hz, 1H), 2.21 (dd, J=15.1, 5.62 Hz, 1 H), 2.06-2.02 (m, 1H), 1.43 (s, 9H), 1.40-1.25 (m, 4H), 1.07-1.13 (m, 1H), 1.03-0.96 (m, 1H), 0.86-0.84 (m, 6H); MS (APCI) m/z 216 (M+−56, 100%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[CH:12]=[C:13]([O:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@@H]3CCC[C@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@@H]1CCC[C@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1F
Yield: 74.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1R,2S)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (436 mg, 0.74 mmol) prepared in Example 78a, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (239 mg, 74%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])=[CH:21][CH:20]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:2]3[CH:11]=[CH:10][N:9]=[C:8]4[C:3]=3[C:4]3[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:5]=3[C:6](=[O:12])[NH:7]4)=[CH:24][CH:23]=2)=[O:38])=[C:28]([C:34]([F:35])([F:36])[F:37])[CH:29]=1
Reactant: Nc1ccc(NC(=O)c2ccc(F)cc2C(F)(F)F)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2cccc(O)c12
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c(=O)c4c(O)cccc4c23)cc1)c1ccc(F)cc1C(F)(F)F

Procedure:
The intermediate ethyl ester was synthesized according to the procedure described for the preparation of Example 378, method 2 using 1-chloro-7-hydroxy-5H-benzo[c][1,8]naphthyridin-6-one and N-(4-amino-phenyl)-4-fluoro-2-trifluoromethyl-benzamide to provide 445. LC-MS (M+H=509, obsd.=509). 1H NMR (400 MHz, DMSO-d6): δ, 6.95 (m, 2H), 7.18 (m, 2H), 7.67 (m, 4H), 7.81 (m, 3H), 8.11 (d, 1H), 8.24 (s, 1H), 8.79 (d, 1H), 10.53 (s, 1H).