Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=O>C(O)(=O)C>[CH2:10]([O:9][C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:16]([C:18]3[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[N:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1c[nH]nc1N
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 5.0 g. of 3-amino-4-carbethoxypyrazole and 7.84 g. of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone in 25 ml. of glacial acetic acid is refluxed for 6 hours and then evaporated in vacuo to an oil. This oil is treated as described in Example 1, giving the desired product, m.p. 97°-99° C.
Reaction SMILES: [Li+].[BH4-].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][C@@H:12]3[N:18]([CH:19]=2)[C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:64][CH3:65])[C:23]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[C:61]([O:62][CH3:63])=[CH:60][C:33]5[C:34](=[O:59])[N:35]6[CH:50]=[C:49]([C:51]7[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=7)[CH2:48][C@H:36]6[C:37](=O)[N:38](COCC[Si](C)(C)C)[C:32]=5[CH:31]=4)=[CH:24][C:15]=2[N:14](COCC[Si](C)(C)C)[C:13]3=O)=[CH:6][CH:5]=1.CCO>C1COCC1>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][C@@H:12]3[N:18]([CH:19]=2)[C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:64][CH3:65])[C:23]([O:25][CH2:26][CH2:27][CH2:28][O:29][C:30]4[C:61]([O:62][CH3:63])=[CH:60][C:33]5[C:34](=[O:59])[N:35]6[CH:50]=[C:49]([C:51]7[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=7)[CH2:48][C@H:36]6[CH:37]=[N:38][C:32]=5[CH:31]=4)=[CH:24][C:15]=2[N:14]=[CH:13]3)=[CH:6][CH:5]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(N)cc7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.7 %

Procedure:
Fresh LiBH4 (183 mg, 8.42 mmol) was added to a stirred solution of the SEM-dilactam 10 (428 mg, 0.42 mmol) in THF (5 mL) and EtOH (5 mL) at room temperature. After 10 minutes, delayed vigorous effervescence was observed requiring the reaction vessel to be placed in an ice bath. After removal of the ice bath the mixture was allowed to stir at room temperature for 1 hour. LC/MS analysis at this point revealed total consumption of starting material with very little mono-reduced product. The reaction mixture was poured onto ice (100 mL) and allowed to warm to room temperature with stirring. The aqueous mixture was extracted with DCM (3×30 mL) and the combined organic layers washed with H2O (20 mL), brine (30 mL) and concentrated in vacuo. The resulting residue was treated with DCM (5 mL), EtOH (14 mL), H2O (7 mL) and silica gel (10 g). The viscous mixture was allowed to stir at room temperature for 3 days. The mixture was filtered slowly through a sinter funnel and the silica residue washed with 90% CHCl3: 10% MeOH (˜250 mL) until UV activity faded completely from the eluent. The organic phase was washed with H2O (50 mL), brine 60 mL), dried (MgSO4) filtered and evaporated in vacuo to provide the crude material. The crude product was purified by flash chromatography (97% CHCl3: 3% MeOH) to provide the pure C2/C2′ aryl PBD dimer 11 (185 mg) 61% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:15][C@@H:16]([C:25]([OH:27])=O)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][CH2:15][C@@H:16]([C:25]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCCNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](COCCNC(=O)OCc1ccccc1)C(=O)N1CCCC1

Procedure:
Starting from (S)-3-(2-{[benzyloxycarbonyl]-amino}-ethoxy)-N-(tert-butyloxycarbonyl)-alanine and pyrrolidine, the expected product is obtained according to the procedure described in Step A of Example 3.
Reaction SMILES: [N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][N:16](CC5C=CC(OC)=CC=5OC)[C:17]4=[O:20])=[CH:13][C:12]=3[CH3:32])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[CH:19]=[C:18]4[C:14]([CH2:15][NH:16][C:17]4=[O:20])=[CH:13][C:12]=3[CH3:32])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CN2Cc3cc(C)c(Cc4ccc(-n5cccn5)cc4)cc3C2=O)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)NC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
To a solution of 6-(4-(1H-pyrazol-1-yl)benzyl)-2-(2,4-dimethoxybenzyl)-5-methylisoindolin-1-one (0.24 g) in trifluoroacetic acid (4.34 mL) was added anisole (0.23 mL), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.15 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6].Cl.O1CCCC1>CO>[CH3:1][O:2][N:3]=[C:4]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:5]([NH:7][CH:8]1[C:28](=[O:29])[N:10]2[C:11]([C:25]([OH:27])=[O:26])=[C:12]([CH2:15][S:16][C:17]3[N:21]([CH2:22][C:23]#[CH:24])[N:20]=[N:19][N:18]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48.9 %

Procedure:
To a mixture of 7-[2-methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.4 g) in methanol (10.0 ml) were added conc. hydrochloric acid (0.52 g) and tetrahydrofuran (5.0 g) and the mixture was stirred for 2 hours and 10 minutes at room temperature. After the evaporation of the reaction mixture, to the residue were added water and ethyl acetate and then the resulting mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium carbonate. The aqueous layer was separated, washed with ethyl acetate (x2) and then concentrated. The concentrate was adjusted to pH 3.0 with 10% hydrochloric acid and the precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.65 g).
Reaction SMILES: Cl.[OH:2][NH3+:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([OH:34])[CH2:12][CH2:13][CH:14]2[C:17](=[O:18])[N:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH:15]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C>C(O)(C)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:15]2[CH:14]([CH2:13][CH2:12][CH:11]([C:8]3[CH:7]=[CH:6][C:5]([F:4])=[CH:10][CH:9]=3)[OH:34])[C:17](=[O:18])[N:16]2[C:19]2[CH:26]=[CH:25][C:22]([C:23]([NH:3][OH:2])=[NH:24])=[CH:21][CH:20]=2)=[CH:32][CH:31]=1
Reactant: [NH3+]O
Reactant: N#Cc1ccc(N2C(=O)C(CCC(O)c3ccc(F)cc3)C2c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(N2C(=O)C(CCC(O)c3ccc(F)cc3)C2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
279 mg of hydroxylammonium hydrochloride were added to a solution of 280 mg of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-fluorophenyl)-4-oxoazetidin-1-yl]benzonitrile (11) and 0.65 ml of triethylamine in 15 ml of isopropanol. The mixture was stirred at room temperature for 12 h. The reaction solution was extracted twice with ethyl acetate/water. The organic phases were dried over magnesium sulfate and concentrated. This gave the product of molecular weight 451.48 (C25H23F2N3O3); MS (ESI): 452.10 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17]1([CH:23]([NH2:34])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][CH2:12][C:13](=[O:15])[NH:34][CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:31])([F:32])[F:33])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(c1ccccc1)c1ccccc1C(F)(F)F
Reactant: O=C(O)CNC(=O)CCc1ccccc1
Agent: Cl
Product: O=C(CCc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccccc1C(F)(F)F

Procedure:
Prepared in analogy to example 1.1 from mmol (3-phenyl-propionylamino)-acetic acid (CA [56613-60-6]) and rac-C-phenyl-C-(2-trifluoromethyl-phenyl)-methylamine hydrochloride (CA [49703-62-0]).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=O.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:14]=1[CH:15]=[N:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=Cc1cc(I)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(NN=Cc2cc(I)ccc2F)cc1
Yield: 98.1 %

Procedure:
4-hydrazinylbenzoic acid (1.54 g, 10 mmol), 2-fluoro-5-iodobenzaldehyde (2.52 g, 10 mmol) and caesium carbonate (3.27 g, 10 mmol) was stirred in DMF (10 mL) at r.t. for 70 min. Water (40 mL) was then added and the clear solution was acidified with aqueous HCl (1.7 M). The light yellow precipitate that formed was collected by filtration, washed with water and dried in vacuo to give 4-(2-(2-fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (3.77 g, 98%)
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:17])[O:15][CH3:16])[CH:10]=[CH:11][CH:12]=1)=[O:6].[CH3:19]I>>[CH3:18][N:2]([CH3:1])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH3:19])[C:14](=[O:17])[O:15][CH3:16])[CH:10]=[CH:11][CH:12]=1)=[O:6]
Reactant: CI
Reactant: COC(=O)Nc1cccc(C(=O)C=CN(C)C)c1
Product: COC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1

Procedure:
A 9.93 g portion of [3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]carbamic acid, methyl ester was alkylated as described in Example 3, using 6.82 g of methyl iodide, giving 10.13 g of the desired compound, mp 93°-95° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][CH2:7][N:8]([C:15](=[O:40])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([O:23][CH2:24][CH2:25][N:26]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>O1CCOCC1>[C:36]([O:35][C:33]([N:26]([C:27]1[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=1)[CH2:25][CH2:24][O:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([Cl:22])[CH:19]=1)[C:15]([N:8]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:7][CH2:6][C:5]([OH:41])=[O:4])=[O:40])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC(=O)O)c2ccccc2)c1)c1ccncc1
Yield: 92.5 %

Procedure:
2M Aqueous sodium hydroxide (2.54 ml) was added to a stirred solution of 3-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-phenyl-amino)-propionic acid methyl ester (1.22 g) in 1,4-dioxan (15 ml). 2M Aqueous hydrochloric acid (2.54 ml) was added after 16 h. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase was dried with brine and over sodium sulphate and then concentrated under reduced pressure to give the title compound (1.10 g) as a white foam.
Reaction SMILES: [CH3:1][C:2]([S:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[CH2:11][C:10](=O)[CH2:9]1>C1COCC1>[CH3:1][C:2]([S:5]([N:7]=[C:10]1[CH2:11][O:8][CH2:9]1)=[O:6])([CH3:4])[CH3:3]
Reactant: O=C1COC1
Reactant: CC(C)(C)S(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C1COC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a solution of 2-methyl-2-propanesulfinamide (1.47 g) and 3-oxetanone (0.85 mL) in THF (24 mL) was added Ti(OEt)4 (5.34 mL) dropwise over the course of 15 minutes at room temperature. After being stirred at 60° C. for 18 h, the reaction mixture was quenched by the rapid addition into ice cooled saturated sodium bicarbonate solution. The suspension was filtered through glass fiber filter paper, washing with ethyl acetate. The filtrate was washed with saturated sodium bicarbonate solution and brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (0.992 g, 47%). 400 M Hz 1H-NMR (CDCl3) δ: 5.80 (ddd, J=15.6 Hz, 4.1 Hz and 2.3 Hz, 1H), 5.66 (ddd, J=15.6 Hz, 4.1 Hz and 2.3 Hz, 1H), 5.52-5.41 (m, 2H), 1.27 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]1.[C:15](O)(=[O:17])[CH3:16].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:12][C:11](=[O:13])[C:10](=[C:15]([OH:17])[CH3:16])[C:9](=[O:14])[CH2:8]1
Reactant: CC(=O)O
Reactant: O=C1CC(=O)CC(c2sccc2Cl)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2sccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.9 %

Procedure:
To a solution of 5-(3-chlorothiophen-2-yl)cyclohexane-1,3-dione (2.0 g), acetic acid (0.90 g) and dimethylaminopyridine (1.6 g) in dimethylformamide (100 ml) was added dicyclohexylcarbodiimide (2.3 g), and the mixture was stirred at room temperature for 13 hours. Under reduced pressure, the solvent was evaporated, and to the residue was ethyl acetate. The mixture was washed with potassium hydrogensulfate solution and water, and to the mixture was added 1N sodium hydroxide solution. The aqueous layer was washed with diethylether and neutralized with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give oil of 5-(3-chlorothiophen-2-yl)-2-(1-hydroxyethylidene)-cyclohexane-1,3-dione (2.2 g).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH2:10][OH:11].[N+]([O-])(O)=O>>[CH3:1][C:2]1[NH:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH:10]=[O:11]
Reactant: CCCc1nc(CO)c(C)[nH]1
Solvent: O=[N+]([O-])O
Product: CCCc1nc(C=O)c(C)[nH]1

Procedure:
An 80 gm. portion of 5-methyl-2-n-propyl-4-imidazolemethanol is oxidized with 67.3 ml. of concentrated HNO3. A second portion of 101.4 gm. of the above compound is oxidized with 77 ml. of the acid. The reaction mixtures are combined, neutralized and worked up as in Example 25, giving the desired product, m.p. 126°-129° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH2:14]Cl)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:17][NH2:18]>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][NH:12][C:13](=[O:16])[CH2:14][NH:18][CH3:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN
Reactant: O=C(CCl)NCCc1ccc2c(c1)OCO2
Solvent: CCO
Product: CNCC(=O)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
N-(2-Benzo[1,3]dioxol-5-yl-ethyl)-2-chloro-acetamide (32 mg, 0.13 mmol) was dissolved in methylamine in anhydrous ethanol (33% by wt., 5 mL). The solution was allowed to stir at room temperature for 16 hours. After this time, the solution was concentrated down under N2 gas. The crude material was purified by prep-LCMS to afford 21 mg (68%) of N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-methylamino-acetamide. 1H-NMR (400 MHz, CD3OD) δ 6.73-6.65 (m, 3H), 5.89 (s, 2H), 3.46-3.39 (t, 2H), 3.31-3.29 (m, 2H), 2.74-2.70 (t, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([N:8]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)CC(C)NC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.1 %

Procedure:
A solution of 1.0 g (0.005 mole) of (rac)-3-cyclopentylamino-butanoic acid ethyl ester in 25 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 25 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.0 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-butanoic acid ethyl ester (IV-3)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)[N:5]=[N:6][C:7]=1[Cl:8].[NH3:26]>C1COCC1.C(O)C>[Cl:8][C:7]1[N:6]=[N:5][C:4]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:10]=2)=[N:3][C:2]=1[NH2:26]
Reactant: Fc1ccccc1Cn1nc(-c2nnc(Cl)c(Cl)n2)c2cccnc21
Reactant: N
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nnc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
7.000 g (purity 38%, 7.090 mmol) of 3-(5,6-dichloro-1,2,4-triazin-3-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine in 200 ml of absolute THF were initially introduced. With ice-cooling, 4.254 ml (8.508 mmol) of 2N ammonia solution in ethanol were added and the mixture was stirred for 1 h at 0° C. Again with ice-cooling, 4.254 ml (8.508 mmol) of 2N ammonia solution in ethanol were added and the mixture was stirred for 1.5 h at RT. 30 ml (60.000 mmol) of 2N ammonia solution in ethanol was added and the mixture was stirred for 15 min at RT. The reaction mixture was concentrated on a rotary evaporator, suspended in 100 ml of dichloromethane, admixed with 50 ml (100.00 mmol) of 2N ammonia solution in ethanol and stirred for 2 h at RT. The mixture was concentrated on a rotary evaporator and purified by chromatography on silica gel (mobile phase: dichloromethane/methanol, gradient 20:1→10:1). The product-containing fractions were concentrated and stirred with DMSO. The solid was filtered off with suction, after-washed with acetonitrile and dried under high vacuum. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water, gradient 20:80→100:0). This gave 1.68 g of the target compound (purity 65%; 43% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([O:24]C)[CH:20]=[CH:19]3)[C:10]1=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]=[C:21]([OH:24])[CH:20]=[CH:19]3)[C:10]1=[O:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2cccc(N3CC[C@H](NC(=O)OC(C)(C)C)C3=O)c2n1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2cccc3ccc(O)nc23)C1=O
Temperature: 120 °C

Procedure:
(S)-3-(tert-Butoxycarbonylamino)-1-(2-methoxyquinolin-8-yl)-2-oxopyrrolidine, as described above in Step F, (287 mg, 0.803 mmol) and KI (240 mg, 1.44 mmol) were dissolved in AcOH (10 mL) and heated to 120° C. for 1 hour. The reaction mixture was concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[F:12][C:13]([F:25])([F:24])[C:14]1[N:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:20]([C:17]2[CH:18]=[N:19][C:14]([C:13]([F:25])([F:12])[F:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)nc1
Reactant: Nc1cccc2cccnc12
Agent: CN(C)c1ccncc1
Product: O=S(=O)(Nc1cccc2cccnc12)c1ccc(C(F)(F)F)nc1
Yield: 56.6 %

Procedure:
In a similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), 6-(trifluoromethyl)pyridine-3-sulfonyl chloride (0.31 g, 1.25 mmol) and DMAP (cat) gave the title compound (250 mg, 58%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:19][NH:20][O:21][CH3:22].C(Cl)CCl.[CH2:27]([O:34][C:35]([NH:37][C:38]1[CH:39]=[C:40]([CH2:44][C:45]([OH:47])=O)[CH:41]=[CH:42][CH:43]=1)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:22][O:21][N:20]([CH3:19])[C:45](=[O:47])[CH2:44][C:40]1[CH:39]=[C:38]([NH:37][C:35](=[O:36])[O:34][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:43]=[CH:42][CH:41]=1
Reactant: CNOC
Reactant: O=C(O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CON(C)C(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a suspension of 24.7 g (87 mmol) of (3-{[(benzyloxy)carbonyl]amino}phenyl)acetic acid in 200 mL of dichloromethane (from Step B) was added triethylamine (30.2 mL, 173 mmol) which resulted in some exotherming (+5° C.) and the suspension becoming a solution. After 10 min cooling, HOBt (13.2 g, 87 mmol), N,O-dimethylhydroxylamine HCl (8.5 g, 87 mmol) was added to the solution followed by EDC (16.6 g, 87 mmol) and the resulting mixture stirred at room temperature overnight under nitrogen atmosphere. The solution was transferred to a separatory funnel and washed with 1 M HCl which caused an emulsion. Methanol was added to break up the emulsion and the aqueous was partitioned off. The organics were dried over sodium sulfate, filtered and concentrated under vacuum. Recrystallization of the residue from 1000 mL of 70% hexane in ethyl acetate (heated to reflux and then cooled to room temperature overnight) afforded the title compound (21 g, 74%) as a white solid. LC-MS: m/z (ES) 329 (MH)+.