Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:23][C:24]([CH3:26])=O>>[CH:24]([NH:1][CH2:2][CH:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2)([CH3:26])[CH3:23]
Reactant: CC(C)=O
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Product: CC(C)NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Yield: 41 %

Procedure:
Using a method similar to Example 204, using 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-nicotinamide (intermediate 20, 297 mg, 1.00 mmol), acetone (116 mg, 2.00 mmol), and NaBAH3CN (125 mg, 2.00 mmol) gives the title compound (139 mg) as a white foam. Mass spectrum (ion spray): m/z=340 (M+1); 1HNMR (CDCl3): 8.57 (s, 1H), 8.13 (d, 1H), 7.21-7.13 (m, 2H), 6.90-6.87 (m, 2H), 6.27 (br. s, 2H), 2.97 (m, 1H), 2.91-2.75 (m, 3H), 2.62-2.41 (m, 2H), 1.83-1.63 (m, 4H), 1.07 (d, 6H).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>CN(C)C=O>[C:17]([NH:20][CH2:21][CH2:22][NH:23][C:2](=[O:3])[NH:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][C:13](=[O:16])[NH:14][CH:15]=2)=[CH:6][CH:5]=1)(=[O:19])[CH3:18]
Reactant: O=C=Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: CC(=O)NCCN
Solvent: CN(C)C=O
Product: CC(=O)NCCNC(=O)Nc1ccc(-c2c[nH]c(=O)cn2)cc1

Procedure:
In a manner similar to Example 13b, 5-[4-(isocyanato)phenyl]-2(1H)-pyrazinone is reacted with 2-acetamidoethylamine (1 g) in dimethylformamide (5 ml) for 17 hours at room temperature to form the title compound, m.p. 238°-44° C.; δ(DMSO-d6) 1.80 (s, 3H, COCH3), 7.94, 8.08 (2s, 2H, pyrazinone H's).
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([C:21]4([F:29])[F:28])[CH2:19]2)[CH2:25]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:30]1(B(O)O)[CH2:32][CH2:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]1([C:2]2[C:3]([O:16][CH2:17][C:18]34[CH2:19][CH:20]5[CH2:26][CH:24]([CH2:23][CH:22]([C:21]5([F:28])[F:29])[CH2:27]3)[CH2:25]4)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC23CC4CC(C2)C(F)(F)C(C4)C3)cc1F
Temperature: 100 °C
Yield: 65.8 %

Procedure:
To a solution of tert-butyl 5-chloro-4-((4,4-difluoroadamantan-1-yl)methoxy)-2-fluorobenzoate (1.50 g, 3.48 mmol), cyclopropylboronic acid (0.45 g, 5.22 mmol), potassium phosphate (3.33 g, 15.7 mmol) and tricyclohexylphosphine tetrafluoroborate (0.13 g, 0.35 mmol) in toluene (60 mL) and water (3 mL) under a nitrogen atmosphere was added palladium acetate (0.08 g, 0.35 mmol). The reaction mixture was heated to 100° C. for 18 hours and then cooled to ambient temperature. Water (20 mL) was added and the mixture was filtered through a pad of diatomaceous earth and the solid was washed with ethyl acetate (150 mL). The organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by crystallization (ethyl acetate and hexanes) afforded the title compound as colorless solid (1.00 g, 66%): 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=8.4 Hz, 1H), 6.47 (d, J=12.6 Hz, 1H), 3.57 (s, 2H), 2.29 (br s, 2H), 2.02-1.95 (m, 6H), 1.75-1.68 (m, 6H), 1.57 (s, 9H), 0.93-0.87 (m, 2H), 0.65-0.60 (m, 2H); MS (ES+) m/z 459.2 (M+23).
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:45])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[CH3:44].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:45])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[CH3:44]
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Reactant: Cc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(C)c2)cc1
Reaction time: 6 h
Yield: 90.6 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (125 mg, 0.40 mmol), 4-[N′-(2-bromophenyl)ureido]-3-methylphenylacetic acid (146 mg, 0.40 mmol) and N,N-dimethylaminopyridine (49.0 mg, 0.40 mmol) in DMF (10 ml) was added EDC.HCl (84.1 mg, 0.44 mmol) at rt, and the resulting mixture was stirred for 6 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:4) as eluent to give methyl 4-[1-[4-[N′-(2-bromophenyl)ureido]-3-methylphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (238 mg, 90%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ 1.92 (s, 3 H), 2.09–2.27 (m, 3 H), 2.42–2.50 (m, 1 H), 3.22–3.41 (m, 2 H), 3.88 (s, 3 H), 4.39 (d, J=4.4 Hz, 1 H), 4.64 (br s, 1 H), 5.00 (t, J=6.8 Hz, 1 H), 6.72 (s, H), 6.81–6.93 (series of m, 8 H), 7.22–7.42 (series of m, 6 H), 8.01 (d, J=8.4 Hz, 2 H), 8.13 (d, J=8.0 Hz, 1H); MS (FAB) m/z, 656 (M+), 658 (M++2).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[CH3:23][NH:24][CH3:25]>>[CH3:23][N:24]([CH2:2][C:3]1[N:7]2[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)[CH3:25]
Reactant: CNC
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1)=NC2
Product: CN(C)Cc1nnc2n1-c1ccccc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, 1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine was reacted with dimethylamine to give 1-[(dimethylamino)-methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 182°-183.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]([F:26])([F:25])[CH:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[CH2:19][CH2:18][NH:17]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[S:24][CH:23]=[CH:22][C:21]=4[CH:16]3[C:15]([F:14])([F:26])[F:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: FC(F)(F)C1NCCc2sccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2sccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 4-trifluoromethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.N(CCO)(CCO)CCO.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: N#Cc1ccccc1Cl
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Agent: [F-]
Solvent: CS(C)=O
Solvent: O
Solvent: OCCN(CCO)CCO
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 85.6 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 15.8 g of potassium fluoride in 50 ml of p-xylene, 40 ml of triethanolamine and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 mg of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.0 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13].[Cl:16]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:11]([Cl:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1c(N)ccc2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1c(N)c(Cl)cc2ccccc12
Temperature: 60 °C
Reaction time: 7 h
Yield: 32.9 %

Procedure:
A mixture of methyl 2-amino-1-naphthoate (0.7 g, 3.48 mmol) in acetonitrile (15 mL) was treated with N-chlorosuccinimide (490 mg, 3.65 mmol), stirred at 60° C. for 7 hours, cooled to room temperature, stirred overnight, concentrated, and purified by flash column chromatography on silica gel with 10% ethyl acetate/n-hexane to provide the desired product (270 mg). MS (ESI(−)) m/e 234 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.10 (d, 1H), 7.75 (d, 1H), 7.46 (dt, 1H), 7.26 (dt, 1H), 6.62 (s, 2H), 3.95 (s, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](=[O:6])[CH3:5].[Br:9]Br>CCOCC>[Br:9][CH2:5][C:4](=[O:6])[C:3]([CH3:8])([CH3:7])[CH2:2][Cl:1]
Reactant: BrBr
Reactant: CC(=O)C(C)(C)CCl
Solvent: CCOCC
Product: CC(C)(CCl)C(=O)CBr
Yield: 79.2 %

Procedure:
134.5 g (1 mol) of 1-chloro-2,2-dimethyl-butan-3-one were dissolved in 500 ml of ether. 51 ml (1 mol) of bromine were added dropwise at room temperature, with slight cooling, at a rate such that the bromine was steadily consumed. The solution was then stirred into 1,000 ml of ice-water and the organic phase was separated off, rinsed with 250 ml of water, dried over sodium sulphate and distilled. 169 g (80% of theory) of 1-bromo-4-chloro-3,3-dimethyl-butan-2-one of boiling point 95°-106° C./13 mm Hg were obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH3:36][N:37]([CH3:43])[S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH2:42][CH2:41][S:38]([N:37]([CH3:43])[CH3:36])(=[O:40])=[O:39])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(CCS(=O)(=O)N(C)C)CC3)cc1OCC2

Procedure:
2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt was reacted with N,N-dimethylethenesulfonamide to give 249 as a white solid. 1H NMR δ (ppm)(DMSO-d6): 8.28 (1 H, d, J=8.29 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.01 (1 H, dd, J=8.37, 1.77 Hz), 6.85 (1 H, d, J=1.72 Hz), 5.88-5.80 (1 H, m), 4.48-4.42 (4 H, m), 3.23-3.15 (2 H, m), 2.95 (2 H, d, J=11.09 Hz), 2.74 (6 H, s), 2.68-2.60 (2 H, m), 2.09-1.98 (2 H, m), 1.73 (2 H, d, J=12.61 Hz), 1.64-1.55 (2 H, m), 1.43 (6 H, d, J=6.61 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.90 M+H+=513
Reaction SMILES: CN(C)C1C=CC=CC=1.[CH3:10][S:11][C:12]1[N:17]=[C:16](O)[N:15]2[N:19]=[CH:20][CH:21]=[C:14]2[N:13]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:16]1[N:15]2[N:19]=[CH:20][CH:21]=[C:14]2[N:13]=[C:12]([S:11][CH3:10])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1nc(O)n2nccc2n1
Solvent: CN(C)c1ccccc1
Product: CSc1nc(Cl)n2nccc2n1
Reaction time: 0.17 h

Procedure:
To a mixture of 10 mL of phosphorus oxychloride and 1 mL of N,N-dimethylaniline was added 0.5 g of 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4-ol (crude from previous step). The solution was refluxed for 30-60 minutes until all the solid dissolved. The excess phosphorus was removed under reduced pressure and the syrupy residue poured with vigorous stirring onto a mixture of ice water. After 10 minutes, the aqueous solution was extracted with ether. The ethereal layers were collected and washed with cold water, then dried with anhydrous Na2SO4. Filtration and concentration under reduced pressure gave the desired 4-chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine. MS (ES+): 201.0 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.O1CCOCC1>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a suspension of 11-aminoundecanoic acid (17) in 1:1 water/dioxane (160 mL total) was added K2CO3 (10.28 g, 74.51 mmol) followed by the slow addition over 30 min of benzylchloroformate (CbzCl, 4.55 mL, 32.29 mmol), and the mixture was stirred at room temperature for 2 h. The solid was then removed by filtration, washed with water (3×30 mL) and dried in a vacuum oven at 40° C. for 72 h to afford a white solid 18 (2.91 g, 35% yield): 1H NMR (500 MHz, CD3OD) δ 1.36 (m, 12H), 1.50 (m, 2H), 1.62 (m, 2H), 2.18 (m, 2H), 3.08 (m, 2H), 5.14 (s, 2H), 7.38 (m, 5H); m/z (ESI) 336 [M+H]+.
Reaction SMILES: [Cl-:1].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([C:11]2[CH:16]=[CH:15][C:14]([N+]([O-])=O)=[CH:13][C:12]=2[N+]([O-])=O)=[CH:7][CH:6]=1)(=[O:4])[NH2:3].NC1C=CC=CC=1>CO>[Cl-:1].[C:2]([C:5]1[CH:6]=[CH:7][N+:8]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1cc[n+](-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CO
Solvent: Nc1ccccc1
Product: NC(=O)c1cc[n+](-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-carbamoyl-1-(2,4-dinitrophenyl)pyridinium chloride (50 g, prepared in a similar manner to that described in Example 2), aniline (35 ml) and methanol (11) was stirred at ambient temperature for 48 hours. The resulting suspension was heated at 50° C. for 1 hour, then cooled and the solvent removed in vacuo. The solid residue was triturated with acetone (2×11) then collected by filtration to give 4-carbamoyl-1-phenylpyridinium chloride (33.24 g), mp 290°-292° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:60][CH:61]=[CH2:62].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:62][CH:61]=[CH2:60])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O)C2C)C(OC)CC3C)CCC1O
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (100 mg in 1.5 ml 33% methylene chloride in cyclohexane), allyl trichloroacetimidate (53 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) gave the title compounds (21 mg 4"-ether; 17 mg 3"-ether).
Reaction SMILES: [CH:1]([CH:3]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][C:4]1=[O:5])=C.[CH3:11][N:12](CCCC=C(C)C(N)=O)[CH3:13].[C:23]([O:28][CH2:29][CH2:30][OH:31])(=[O:27])[C:24]([CH3:26])=[CH2:25]>>[CH3:1][C:3]([C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:12]([CH3:13])[CH3:11])=[O:5])=[CH2:10].[CH3:26][C:24]([C:23]([O:28][CH2:29][CH2:30][OH:31])=[O:27])=[CH2:25]
Reactant: CC(=CCCCN(C)C)C(N)=O
Reactant: C=CC1CCCCNC1=O
Agent: C=C(C)C(=O)OCCO
Product: C=C(C)C(=O)NCCCN(C)C
Temperature: 40 °C

Procedure:
The 30 g of a terpolymer of vinyl caprolactam (VCap), dimethylamino propyl methacrylamide (DMAPMA), and 2-hydroxyethyl methacrylate (HEMA) powder was added to 170 g HEMA. GMA (12 g) was added drop-wise with continuous stirring. This solution was heated at 40° C. for one hour. A representative structure for the polymeric reaction is presented below, wherein x+y+z+a=100:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21](O)=[O:22])[C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:49][C@@H:50]1[C@H:55]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH2:54][CH2:53][N:52]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:51]1.[Cl-].[NH4+]>CN(C=O)C.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12]2[CH:13]=[C:14]([C:21]([NH:49][C@@H:50]3[C@H:55]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)[CH2:54][CH2:53][N:52]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])[CH2:51]3)=[O:22])[C:15]([C:17]([F:19])([F:18])[F:20])=[CH:16][C:11]=2[O:10][C:9]([CH3:25])([CH3:24])[C:8]1=[O:26]
Reactant: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)O)cc21
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccccc2)[C@@H](N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCCN1C(=O)C(C)(C)Oc2cc(C(F)(F)F)c(C(=O)N[C@H]3CN(C(=O)OC(C)(C)C)CC[C@H]3c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a solution of 4-(4-methoxybutyl)-2,2-dimethyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (739 mg) in DMF (5 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (755 mg), 1-hydroxybenzotriazole (532 mg), triethylamine (549 μl), tert-butyl (3R,4S)-3-amino-4-phenylpiperidine-1-carboxylate (653 mg), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=3/1) to give the title compound (1.25 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[S:9](=[O:11])(=[O:10])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=1)[CH3:27]
Reactant: O=C(O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CNC(=O)c1ccccc1S(=O)(=O)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 2-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.396 g (10 mmol) of glycine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[C:17](=[O:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:3]([CH3:20])=[C:4]([N:8]2[CH:17]([OH:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:19])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1N1C(=O)Cc2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1c(Br)cccc1N1C(=O)c2ccccc2CC1O
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
Step 2 A suspension of 2-(3-bromo-2-methylphenyl)isoquinoline-1,3(2H,4H)-dione (630 mg, 1.908 mmol) in methanol (100 mL) was treated with sodium borohydride (217 mg, 5.72 mmol) at rt. After 1.5 h, additional sodium borohydride (120 mg) was added. After 7 h, the mixture was concentrated and the residue was partitioned between water and DCM. The organic phase was dried and concentrated to give 2-(3-bromo-2-methylphenyl)-3-hydroxy-3,4-dihydroisoquinolin-1(2H)-one as a light yellow foam (600 mg, 95%), used without further purification. Mass spectrum m/z 332, 334 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[O:34]1[CH2:35][CH2:36][N:31]([C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH:9]3[C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:14]=3)[N:5]=[C:4]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[CH:3]=2)[CH2:32][CH2:33]1
Reactant: C1COCCN1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Product: Cc1cc(Nc2cc(N3CCOCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1

Procedure:
Staring materials: 6-chloro-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 17) and morpholine.