Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[C:11]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[N:12][CH:13]=[CH:14][CH:15]=2)[C:5]([C:22]([F:25])([F:24])[F:23])=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([OH:35])[CH3:34])=[CH:29][CH:28]=1.OP([O-])([O-])=O.[K+].[K+]>CS(C)=O>[OH:35][CH:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:2]2[N:7]=[C:6]([NH:8][CH2:9][C:10]3[C:11]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])=[N:12][CH:13]=[CH:14][CH:15]=3)[C:5]([C:22]([F:25])([F:24])[F:23])=[CH:4][N:3]=2)=[CH:28][CH:29]=1)[CH3:34]
Reactant: CN(c1ncccc1CNc1nc(Cl)ncc1C(F)(F)F)S(C)(=O)=O
Reactant: CC(O)c1ccc(N)cc1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CS(C)=O
Product: CC(O)c1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1
Temperature: 100 °C
Reaction time: 36 h

Procedure:
A solution of C9 (0.253 mmol) and anhydrous DMSO (0.5 ml) was treated with 1-(4-aminophenyl)ethanol (0.277 mmol) followed by potassium phosphate dibasic (0.746 mmol). The mixture was stirred at 100° C. for 1.5 days, and treated with additional 1-(4-aminophenyl)ethanol (0.583 mmol). The mixture was stirred at 100° C. for 15 hours and concentrated. The resultant residue was purified first by column chromatography (silica gel; 10% (NH4OH/MeOH)/CH2Cl2) followed by preparatory thin layer chromatography developed in 5% MeOH/CH2C12 to provide 12. Yield: 13.6 mg, 10.8%. 1H NMR (CD3OD) δ: 8.39 (d, 1H), 8.13 (s, 1H), 7.73 (d, 1H), 7.33 (m, 3H), 7.14 (d, 2H), 4.87 (s, 2H), 4.72 (q, 1H), 3.17 (s, 3H), 3.10 (s, 3H), 1.37 (d, 3H). MS: m/z 497 (MH+).
Reaction SMILES: C(C1C=C(NC(=O)C[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([B:25]([OH:27])[OH:26])=[CH:21][CH:20]=2)C=CC=1S(CC)(=O)=O)#N.BrC1C=CC(C[CH2:35][N:36](C)[C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=CC=1>>[CH2:39]([O:38][C:37]([N:36]([CH3:35])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([B:25]([OH:26])[OH:27])=[CH:23][CH:24]=1)=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCS(=O)(=O)c1ccc(NC(=O)CCCc2ccc(B(O)O)cc2)cc1C#N
Reactant: CN(CCc1ccc(Br)cc1)C(=O)OCc1ccccc1
Product: CN(CCc1ccc(B(O)O)cc1)C(=O)OCc1ccccc1
Yield: 74 %

Procedure:
Using a procedure analogous to that used to prepare 6D, 28C (1.14 g, 3.3 mmol) was 5′,5′-tetramethyl-[2,2′]bi[[1,3,2]dioxaborinanyl] to give 28D (760 mg, 74%) as a white solid. MS (ESI) m/z 313.97 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:35])[F:34])=[CH:18][N:17]=1.C=O.[C:39](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH3:39])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[NH:15][C:16]1[N:21]=[C:20]([CH2:22][CH2:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:34])([F:35])[F:36])=[CH:18][N:17]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C2CCN(C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
To a solution of 3-(2-(2-((2-methoxy-4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzamide (5) (0.021 g, 0.042 mmol) in anhydrous methanol (2.00 mL) was added 37% aqueous formaldehyde (0.012 mL, 0.16 mmol) and sodium triacetoxyborohydride (0.044 g, 0.21 mmol) under a N2 atmosphere. The mixture was then stirred for 1.5 hours. The resulting mixture was concentrated under reduced pressure and diluted with EtOAc (10 mL) and washed with sat. aqueous NaHCO3 (10 mL). The Aqueous was further extracted with EtOAc (10 mL) and the combined organic layers were washed with brine (10 mL) and water (10 mL) then dried using a phase separation cartridge. The organics were concentrated under reduced pressure and purified using silica gel column chromatography (0-30% MeOH/EtOAc+1% 2 M ethanolic NH3). The product was then taken up in minimal hot acetonitrile and water and freeze dried to give the title compound (6) (0.016 g, 74%) as a white solid; 1H NMR (400 MHz, d6-Acetone) δ 8.62 (s, 1H), 8.27 (dd, J=8.3, 4.1 Hz, 1H), 8:15 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.41 (m, 3H), 6.99 (d, J=1.7 Hz, 1H), 6.89 (dd, J=8.2, 1.6 Hz, 1H), 6.55 (s, 1H), 3.98 (s, 3H), 3.20 (m, 4H), 2.90 (m, 2H), 2.57 (m, 1H), 2.22 (s, 3H), 1.98 (td, J=11.2, 3.8 Hz, 2H), 1.78 (m, 4H). LCMS Method C: rt 4.97 min; m/z 514.2 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[NH2:21][OH:22].[CH2:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl[O-].[Na+]>C(O)C.O1CCCC1>[C:25]1([CH:24]2[O:22][N:21]=[C:1]([C:3]3[N:4]=[C:5]([CH:8]4[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]4)[S:6][CH:7]=3)[CH2:23]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: C=Cc1ccccc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a suspension of 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (1.0 g, 3.4 mmol) in ethanol (5 mL) was added an aqueous solution of hydroxylamine (50 wt. %, 0.25 mL, 4.0 mmol). The reaction mixture was heated at 60° C. for 1 h, during which time the reaction mixture became homogeneous. The resulting solution was cooled to room temperature and diluted with tetrahydrofuran (10 mL). To the reaction mixture was added styrene (0.57 mL, 5 mmol), followed by portionwise addition of Clorox® aqueous sodium hypochlorite solution (10.5 mL) over 3 h. The reaction mixture was stirred overnight at room temperature, and the resulting solid was filtered, washed with water and diethyl ether, and air dried to give the title compound as a white powder (610 mg). The filtrate was diluted with saturated aqueous sodium bicarbonate solution and extracted with diethyl ether. The extract was dried (MgSO4) and concentrated under reduced pressure to give 850 mg of the title compound as a yellow oil. The oil was diluted with diethyl ether (4 mL) and allowed to stand to give additional 233 mg of the product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:56]=[CH:55][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C@@H:16]4[O:45][C@H:44]([CH2:46][O:47]CC5C=CC=CC=5)[C@@H:35]([O:36]CC5C=CC=CC=5)[C@H:26]([O:27]CC5C=CC=CC=5)[C@H:17]4[O:18]CC4C=CC=CC=4)[CH:14]=3)[CH:9]=[CH:8]2)=[CH:4][CH:3]=1>O1CCCC1.CO.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C@@H:16]4[O:45][C@H:44]([CH2:46][OH:47])[C@@H:35]([OH:36])[C@H:26]([OH:27])[C@H:17]4[OH:18])[CH:14]=3)[CH:9]=[CH:8]2)=[CH:55][CH:56]=1
Reactant: Cc1ccc(Cn2ccc3ccc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)cc32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(Cn2ccc3ccc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)cc32)cc1

Procedure:
A solution of 1-[1-(4-methylbenzyl)-1H-indol-6-yl]-1-deoxy-2,3,4,6-tetra-O-benzyl-β-D-glucopyranose and 10% palladium-carbon powder (0.12 g) in tetrahydrofuran (3 mL) and methanol (3 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (0.035 g).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([OH:9])=[O:8].[C:11](Cl)(=O)[C:12](Cl)=O.CCO>C(Cl)Cl.CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH3:10])[C:6]=1[C:7]([O:9][CH2:11][CH3:12])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1ncc(I)c1C(=O)O
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(I)cnn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
4-Iodo-1-methyl-1H-pyrazole-5-carboxylic acid (301.68 g, 1.2 moles) was slurried in 1.2 L of DCM and DMF (2.3 g, 31 mmol) followed by addition of oxalyl chloride (115 mL, 1.3 moles) over 37 minutes and then stirred at room temperature for 3 h. To the resulting solution was added EtOH (750 mL, 12.9 mol) over 5 min followed by stirring at room temperature for 2 h. The crude product solution was concentrated to dryness in vacuo and then reconstituted in 1.2 L of warm heptane followed by filtration. The filtrate was concentrated by removing 500 mL of heptane, resulting in precipitation of solids. The solids were collected via filtration and dried to afford ethyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylate as a white solid (297.6 g, 89% yield).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=O.[CH2:6]1[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[CH:9][C:8]=2[O:7]1.C(O)(=O)C>O>[CH2:6]1[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH:16]=[CH:2][C:1]([OH:5])=[O:4])=[CH:9][C:8]=2[O:7]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C=CC(=O)c1ccc2c(c1)OCO2

Procedure:
44 g of glyoxylic acid, 50 wt.% in water, are heated under reduced pressure to eliminate the major part (80%) of the water present; there are then introduced into the reaction medium 49.2 g of 3',4'-methylenedioxy-acetophenone, and 100 cm3 of acetic acid.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.Br[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C(=O)OCc1ccccc1)C1CCCNC1
Reactant: Brc1ccncc1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OCc1ccccc1)C1CCCN(c2ccncc2)C1
Yield: 77 %

Procedure:
A mixture of benzyl methyl(piperidin-3-yl)carbamate (6.32 mmol, 1.0 eq.), 4-brompyridine HCl (2.5 g, 12.64 mmol, 2.0 eq.) and DIPEA (5.7 ml, 31.6 mmol, 5.0 eq.) in n-butanol (40 ml) was refluxed for 24 hours. The reaction mixture was concentrated and the residue was taken up in DCM (200 ml) and washed with sat. NaHCO3 solution (3×100 ml), water (100 ml) and sat. NaCl solution (100 ml). The org. phase was then dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 5% MeOH in DCM). Yield: 77% (1.6 g, 4.92 mmol)
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[C:24]=1[CH2:25]Br>ClC(Cl)C>[Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH2:25][C:24]2[C:27]([C:31]([F:32])([F:34])[F:33])=[CH:28][CH:29]=[CH:30][C:23]=2[F:22])[CH:7]=1
Reactant: Fc1cccc(C(F)(F)F)c1CBr
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC(Cl)Cl
Product: O=c1[nH]c(=O)n(Cc2c(F)cccc2C(F)(F)F)cc1Br
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A suspension of 5-bromouracil (31.0 g) in 300 mL of dichloroethane is treated with N,O-bis(trimethylsilyl)acetamide (80 mL). The reaction mixture is heated under nitrogen. The solution is cooled to ambient temperature, 2-fluoro-6-(trifluoromethyl)benzyl bromide (50 g) is added and the reaction mixture is heated overnight under the nitrogen. The reaction is cooled, quenched with MeOH, and partitioned between dichloromethane and water. The organic layer is washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product is triturated with ether, filtered, and washed with ether three times providing 40.7 g of 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]pyrimidine-2,4(1H,3H)-dione 5a. MS (CI) m/z 366.0, 368.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][C:10](C=O)=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].N1C=CC([CH:24]=[O:25])=N1.COC1C=CC(CCl)=CC=1>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH:24]=[O:25])=[CH:11][CH:10]=[N:9]2)=[CH:15][CH:16]=1
Reactant: COc1ccc(Cn2ccc(C=O)n2)cc1
Reactant: O=Cc1cc[nH]n1
Agent: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nccc2C=O)cc1
Reaction time: 8 h
Yield: 12.26 %

Procedure:
1-(4-methoxy-benzyl)-1H-pyrazole-3-carbaldehyde: Sodium hydride, 60% in oil (0.229 g, 5.72 mmol), was suspended in DMF (5 mL) at 0° C. under nitrogen with stirring. A solution of 1H-pyrazole-3-carbaldehyde (0.5 g, 5.20 mmol) in DMF (5 mL) was added over 5-10 minutes via syringe. The resulting mixture was stirred at 0-5° C. for 10-15 min followed by addition of 4-methoxybenzyl chloride (0.815 mL, 5.98 mmol). Stirring was continued overnight allowing ice bath to melt and the reaction to assume rt. The reaction mixture was diluted with water and extracted 3× with EtOAc. The combined extracts were washed with water and brine, then dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in methylene chloride and charged to a 120 g silica gel cartridge which was eluted with a 30 min gradient from 0-40% EtOAc in hexane. The major product was 1-(4-methoxybenzyl)-1H-pyrazole-3-carbaldehyde (0.768 g, 68.3%) which was obtained as a colorless oil. 1HNMR (500 MHz, CDCl3) δ: 9.99 (1H, s), 7.38 (1H, s), 7.22 (2H, d, J=8.2 Hz), 6.90 (2H, d, J=8.8 Hz), 6.80 (1H, d, J=2.7 Hz), 5.32 (2H, s), 3.81 (3H, s). Evaporation of the fractions from the minor peak yielded 1-(4-methoxybenzyl)-1H-pyrazole-5-carbaldehyde as a crystalline solid (0.138 g, 12.26%). 1HNMR (500 MHz, CDCl3) δ: 9.85 (1H, s), 7.59 (1H, d, J=2.2 Hz), 7.26 (2H, d, J=8.8 Hz), 6.91 (1H, d, J=2.2 Hz), 6.83 (2H, d, J=8.8 Hz), 5.67 (2H, s), 3.77 (3H, s).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][C@@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[C:23](F)[C:22]=1[Cl:31].O.CN(C)C=O>C(N(CC)CC)C>[C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:24]2[CH:23]=[C:22]([Cl:31])[C:21]([Cl:20])=[CH:26][C:25]=2[N+:27]([O-:29])=[O:28])[C@@H:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)c(Cl)c1
Reactant: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)CCN1c1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 94.2 %

Procedure:
To a slurry containing 5.0 g of (R)-4-carbobenzyloxypiperazine-2-carboxylic acid, 4.2 g of 1,2-dichloro-fluoro-5-nitrobenzene, 85 mL of water and 170 mL of dimethylformamide is added slowly 5.3 mL of triethylamine. The solution is heated to 50° C. for 5 hours, then at ambient temperature overnight. The dark orange solution is concentrated under reduced pressure (1-2 mm, <50° C.) to an orange oily residue. This oil is dissolved in 400 mL of ethyl acetate and washed with 100 mL of 1 N HCl (2×), with 150 mL of water (2×), and 100 mL of brine. The organic layer is dried over MgSO4, filtered and concentrated to give 8.1 g (94.2%) of title compound as an orange solid foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:39]2[CH:40]=[C:41]([CH2:45][NH2:46])[CH:42]=[CH:43][CH:44]=2)O1>O1CCOCC1.O.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>[NH2:46][CH2:45][C:41]1[CH:40]=[C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:44]=[CH:43][CH:42]=1
Reactant: CC1(C)OB(c2cccc(CN)c2)OC1(C)C
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN)c4)cc23)CC1
Temperature: 160 °C
Yield: 8.5 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs2CO3 (95 mg, 0.290 mmol) and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanamine (82 mg, 0.350 mmol) in dioxane/H2O (2 mL/0.7 mL) was bubbled argon for 5 minutes prior to addition of Pd(PPh3)4 (7.5 mg, 0.0072 mmol). The reaction mixture was heated in a microwave reactor (Smith synthesizer) for 20 minutes at 160° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine (10 mL), dried over MgSO4, filtered, concentrated, and purified by reverse phase HPLC method A (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (2.7 mg, 8.5%).
Reaction SMILES: [NH2:1][CH:2]([C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:9]=1[O:16][CH3:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH3:17][O:16][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=1[CH:2]([NH:1][CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][C:19]([F:18])([F:29])[F:30])=[CH:22][CH:23]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(N)c1c(OC)cccc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(NCc1ccc(OC(F)(F)F)cc1)c1c(OC)cccc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the chlorhydrate salt of ethyl 2-amino-2-(2,6-dimethoxyphenyl)acetate (8.43 mmol), 4-(trifluoromethoxy)benzaldehyde (1.603 g; 8.43 mmol), DIPEA (2.179 g; 16.86 mmol), NaBH(OAc)3 (2.633 g; 11.80 mmol), and acetic acid (506 mg; 8.43 mmol) in anh. DCE (9 ml) was stirred at rt, under nitrogen, for 16 h. 1 M aq. NaOH (17 ml) was added, and the separated aq. layer was further extracted with DCM (3×50 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 2-(2,6-dimethoxyphenyl)-2-((4-(trifluoromethoxy)benzyl)amino)acetate. LC-MS (conditions D): tR=0.92 min.; [M+H]+: 414.05 g/mol.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])=[CH:21][CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[C:42]([C:46]1[CH:54]=[CH:53][C:49]([C:50](Cl)=[O:51])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43]>CN1C(=O)CCC1.CCOC(C)=O>[C:42]([C:46]1[CH:47]=[CH:48][C:49]([C:50]([NH:2][C@@H:3]2[CH2:8][CH2:7][CH2:6][N:5]([C:9]3[N:10]=[C:11]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[O:26])=[CH:23][CH:24]=4)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=3)[CH2:4]2)=[O:51])=[CH:53][CH:54]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: NC(=O)c1ncc(N2CCC[C@@H](N)C2)nc1Nc1ccc(C(=O)N2CCOCC2)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(C(=O)N[C@@H]2CCCN(c3cnc(C(N)=O)c(Nc4ccc(C(=O)N5CCOCC5)cc4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of (R)-5-(3-aminopiperidin-1-yl)-3-(4-(morpholine-4-carbonyl)phenylamino)pyrazine-2-carboxamide hydrochloride (90) (120 mg, 0.27 mmol) in NMP (3 mL) was added DIEA (190 μL, 1.08 mmol) and then 4-tert-butylbenzoyl chloride (106 mg, 0.54 mmol). The mixture was stirred at RT for 1 h, diluted with 100 mL EtOAc, washed with water ×2, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 5% MeOH in DCM to isolate the title compound (91) (yield 114 mg). MS found for C32H39N7O4 as (M+H)+ 586.2, (M−H)− 584.3. UV: λ=259, 276, 286, 314, 344, 369 nm.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=O)=[O:9].Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:12](=[O:14])[C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:8](=[O:9])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Temperature: -25 °C
Reaction time: 15 h
Yield: 58.3 %

Procedure:
To a solution of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-proline (3.01 g) in DMF (25 ml) were added L-proline methyl ester hydrochloride (2.07 g), HOBt (2.54 g) and N-methylmorpholine (1.38 ml). The mixture was cooled to -25° C., added with DCC (2.85 g), and stirred at a temperature of -25°-0° C. for 3 hours and at room temperature for 15 hours. The precipitated dicyclohexylurea was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 2.56 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-proline methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.CN1C=CN=C1.[F:28][CH:29]([F:34])[S:30](Cl)(=[O:32])=[O:31].O>ClCCl>[F:28][CH:29]([F:34])[S:30]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:21])(=[O:32])=[O:31]
Reactant: COc1nc(OC)nc(C2C(=O)Nc3ccc(F)cc32)n1
Reactant: O=S(=O)(Cl)C(F)F
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3ccc(F)cc32)n1
Temperature: -10 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5-fluoro-1,3-dihydro-2H-indol-2-one (50 g) and 1-methyl-1H-imidazole (30.5 g) are introduced as initial charge in 430 ml of dichloromethane and cooled to −10° C. under nitrogen. With stirring, a solution of difluoromethanesulfonyl chloride (41.8 g) in 70 ml of dichloromethane is added dropwise at −15° C. to −5° C. over the course of 30 minutes, and the mixture is after-stirred for 4 hours at −15° C. to 0° C. 1-Methyl-1H-imidazole (2.7 g) and difluoromethanesulfonyl chloride (4.9 g) are added to the reaction mixture and stirred for 2 hours at 0° C. With ice cooling, 300 ml of water are added to the reaction mixture, the mixture is after-stirred for 30 minutes and the organic solvent is largely distilled off in vacuo. The residue is filtered, the solid product is washed twice with 150 ml of water and twice with 40 ml of acetonitrile and dried. This gives the title compound as a solid in an HPLC purity of 96% (63.9 g, 95% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.