Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:19][C:18]=1[C:26]1[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: OB(O)c1ccc(F)c(-c2ccncc2)c1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1-c1ccncc1
Yield: 55.4 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (100 mg, 0.43 mmol) was coupled to 4-fluoro-3-(pyridin-4-yl)benzeneboronic acid (121 mg, 0.56 mmol) as described in Example 3 part g), affording 5-(4-fluoro-3-pyridin-4-ylphenyl)-2-trifluoromethyl[1,8]naphthyridine (88 mg, 55%). δH (360 MHz, CDCl3) 7.41-7.47 (1H, m), 7.52-7.63 (5H, m), 7.85 (1H, d, J 8.8), 8.52 (1H, d, J 8.4), 8.73-8.74 (2H, m), 9.30 (1H, d, J 4.2). m/z (ES+) 370 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=2[CH:5]=[C:4]([F:14])[CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl[C:31]1[N:36]=[C:35]([NH:37][C@@H:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]2[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:34]([Cl:49])=[CH:33][N:32]=1.C(=O)([O-])[O-]>COCCO.C(Cl)Cl.CO>[Cl:49][C:34]1[C:35]([NH:37][C@@H:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]2[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[N:36][C:31]([NH:1][C:2]2[C:12]3[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=3[CH:5]=[C:4]([F:14])[CH:3]=2)=[N:32][CH:33]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: Nc1cc(F)cc2c1OCCNC2=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: COCCO
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2cc(F)cc3c2OCCNC3=O)ncc1Cl
Temperature: 25 °C
Yield: 46.1 %

Procedure:
9-Amino-7-fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (59 mg, 0.30 mmol), 10-Camphorsulfonic acid (11 mg, 0.047 mmol) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.104 g, 0.306 mmol) in 2-Methoxyethanol (5 mL) were heated at 110° C. under an atmosphere of Nitrogen for 2 days. The mixture was cooled to r.t., neutralized with 100 mg MP-Carbonate and conc. in vacuo. The residue was partially taken up in DCM/MeOH, and the remainder was powdered onto Celite, then chromatographed (2×12 g silica gel, ISCO, 0-100% EtOAc:hexane, then 10% MeOH) to afford N-{(1R,2R)-2-[5-Chloro-2-(7-fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a beige solid (69 mg, 46%). MP=177-181° C.; LCMS: 499 (M+H); 1H-NMR (CDCl3): 8.27 (dd, 1H, J=2.6, 10.9 Hz), 7.98 (1H, s), 7.62 (s, 1H), 7.03 (dd, 1H, J=2.9, 8.6 Hz), 6.95 (m, 1H), 6.85 (m, 1H), 6.02 (d, 1H, J=7.0 Hz), 4.21 (m, 1H), 4.15 (m, 1H), 3.82 (m, 1H), 3.32 (m, 3H), 2.98 (s, 3H), 2.33 (m, 1H), 2.18 (m, 1H), 1.87 (m, 1H), 1.78 (m, 1H), 1.64 (m, 1H), 1.41 (m, 2H), 1.22 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[N:21]=[C:20]2[C:22]([Br:28])=[CH:23][C:24]([Cl:27])=[C:25]([Br:26])[C:19]2=[N:18]1)[C:14]#[N:15]>C1COCC1>[Cl:27][C:24]1[CH:23]=[C:22]([Br:28])[C:20]2=[N:21][N:17]([CH2:16][C:13]([NH:12][C:7](=[O:8])[C:6]3[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)([C:14]#[N:15])[CH3:29])[N:18]=[C:19]2[C:25]=1[Br:26]
Reactant: CC(N)(C#N)Cn1nc2c(Br)cc(Cl)c(Br)c2n1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Br)cc(Cl)c(Br)c2n1)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-cyanobenzoyl chloride (0.16 mmole) in THF was added to a solution of 2-amino-3-(5-chloro-4,7-dibromo-2H-benzotriazol-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 53) in THF mixed with TEA (3% v./v.). The reaction mixture was stirred 12 hours at room temperature then heated to 45° C. for 6 hours before solvent was evaporated under reduced pressure. The resulting crude product was dissolved in DMSO and purify by semi-preparative HPLC. The desired fractions were collected and evaporated under reduced pressure. The title compound was isolated as solid residue (10.8 mg) that was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=521, RT=0.66 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[N:15]=[C:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[O:13][C:12]1=[O:20]>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N:11]2[N:15]=[C:14]([C:16]([CH3:17])([CH3:19])[CH3:18])[O:13][C:12]2=[O:20])[CH:4]=1
Reactant: CC(C)(C)c1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)o1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nn(-c2cc(N)ccc2Cl)c(=O)o1
Temperature: 80 °C
Yield: 90.2 %

Procedure:
Electrolytic iron powder (93.5 g) was suspended in 5% acetic acid (187.2 ml), and the suspension was heated to 80° C.. A solution of 3-(2-chloro-5-nitrophenyl)-5-(1,1-dimethylethyl) -1,3,4-oxadiazol-2(3H)-one (47.21 g) in acetic acid (167.5 ml) and ethyl acetate (167.5 ml) was added thereto. The resultant mixture was heated at a temperature of 70° C. for 3 hours. The reaction mixture was subjected to filtration on celite while hot. The filtrate was extracted with ethyl acetate, and the extract was washed with water and sodium bicarbonate solution and dried. Removal of the solvent under reduced pressure gave 3-(5-amino-2-chlorophenyl) -5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (38.28 g). m.p., 126.0° C..
Reaction SMILES: [CH2:1]([N:13]([CH:31]([CH3:37])C(OCC)=O)[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH:25]([OH:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CCC[C:71]([O:73][CH2:74][CH3:75])=[O:72])CCOC1C=CC(CCC(O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]([CH2:31][CH2:37][C:71]([O:73][CH2:74][CH3:75])=[O:72])[CH2:14][CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH:25]([OH:30])[C:26]([F:28])([F:29])[F:27])=[CH:21][CH:22]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN(CCOc1ccc(/C=C/C(O)C(F)(F)F)cc1)C(C)C(=O)OCC
Reactant: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(CCC(O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN(CCOc1ccc(CCC(O)C(F)(F)F)cc1)CCC(=O)OCC
Yield: 92 %

Procedure:
[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino]propanoic acid, ethyl ester (620 mg, 1.17 mmol) was hydrogenated as described in the preparation of 4-[N-dodecyl-N-2-[4-[3-hydroxy-4,4,4-trifluorobutyl]phenoxy]ethylamino]butanoic acid, ethyl ester (Example 48) and afforded the title compound (573 mg, 92%) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13]C=O)[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@@H:9]1[C:16]([O:18][CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.42 h

Procedure:
To a solution of (2R,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (2.08 g: 7.6 mmole) in methanol (21.0 ml), aqueous 1N-sodium hydroxide (7.6 ml) is added under ice cooling. The mixture is stirred at the same temperature for 25 minutes to give (2R, 4S)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (1.86 Yield: 100%. Colorless oil.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@@H:24]([OH:51])[C@@H:25]([O:43][Si](CC)(CC)CC)[C@@H:26]([O:39]CCF)[C@H:27](N2C=C(C)C(N)=NC2=O)[CH2:28][OH:29])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.C(OC(=O)C1C=CC=CC=1)(=[O:61])C1C=CC=CC=1>CN(C=O)C.C(OCC)(=O)C>[CH2:23]([OH:22])[C@H:24]([C@@H:25]([C@@H:26]([C@@H:27]([CH2:28][OH:29])[OH:61])[OH:39])[OH:43])[OH:51]
Reactant: CC[Si](CC)(CC)O[C@@H]([C@@H](OCCF)[C@@H](CO)n1cc(C)c(N)nc1=O)[C@H](O)COC(c1ccccc1)(c1ccc(OC)cc1)c1ccc(OC)cc1
Reactant: O=C(OC(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 434 %

Procedure:
Compound 9 (1.92 g, 2.58 mmol) was dissolved in anhydrous DMF (11.9 mL) and benzoic anhydride (0.87 g, 3.85 mmol) was added with stirring at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and the resulting organic phase was washed with a saturated aqueous NaHCO3 (2×100 mL) and brine (100 mL). The ethyl acetate layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The residue obtained was purified by flash silica gel column chromatography and eluted with 60% ethyl acetate in hexane to yield 6-O-(4,4′-dimethoxytrityl)-3-O-(2-fluoroethyl)-4-O-(triethylsilyl)-2-deoxy-244-N-benzoyl-5-methylcytosin-1yl)-D-altro-hexitol (2.04 g, 93.2%). In a 100 mL round bottom flask, triethylamine trihydrofluoride (2.04 mL, 12.55 mmol) was dissolved in anhydrous THF (23.2 mL). Triethylamine (0.87 mL, 6.28 mmol) was added to this solution, and the mixture was quickly poured onto 6-O-(4,4′-dimethoxytrityl)-3-O-(2-fluoroethyl)-4-O-(triethylsilyl)-2-deoxy-2-(4-N-benzoyl-5-methylcytosin-1yl)-D-altro-hexitol (2.04 g, 2.44 mmol). The resulting mixture was stirred at room temperature for 6 hours and then poured into ethyl acetate (80 mL). The organic phase was washed sequentially with water (50 mL), 5% aqueous NaHCO3 (50 mL) and brine (50 mL). The ethyl acetate layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuum under reduced pressure. The residue obtained was purified by silica gel column chromatography (30% ethyl acetate in hexanes) to afford compound 10 (1.66 g, 87.94%) as a white foam. MS (ES) m/z 724.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:38])[CH2:9][N:10]2[C:15](=[O:16])[C:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:20][CH:19]=3)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]3[N:35]=[CH:36][N:37]=[C:11]23)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.O1CCCC1.FC(F)(F)S(O[Si:58]([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59])(=O)=O>C(OCC)(=O)C>[Si:58]([O:38][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[C:25]([C:30]#[N:31])=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:19]=2)=[C:13]([CH2:32][CH2:33][CH3:34])[N:12]2[N:35]=[CH:36][N:37]=[C:11]12)([C:61]([CH3:64])([CH3:63])[CH3:62])([CH3:60])[CH3:59]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O)c2ccc(F)cc2)c2ncnn12
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(O[Si](C)(C)C(C)(C)C)c2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
To a mixture of 4′-({4-[2-(4-fluorophenyl)-2-hydroxyethyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.78 g), 2,6-lutidine (0.27 mL) and tetrahydrofuran (20 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.53 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.56 g, 58%).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH2:4]1[CH2:10][S:7](=[O:9])(=[O:8])[O:6][CH2:5]1>O1CCCC1>[CH2:1]([NH:3][CH2:5][CH2:4][CH2:10][S:7]([OH:9])(=[O:8])=[O:6])[CH3:2]
Reactant: CCN
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CCNCCCS(=O)(=O)O
Temperature: 5 °C
Yield: 56.9 %

Procedure:
Tetrahydrofuran (THF, 800 mL) was placed a 3 neck 2-L flask (equipped with a condenser) and cooled to 5° C. with an ice-bath. To the cold THF was added aqueous ethylamine (70 wt. % solution in water, 85 mL, 1.07 mol), followed by addition of a cold solution of 1,3-propane sultone (25.08 g, 201 mmol) in THF (100 mL) over 24-min period. The mixture was stirred, while cooled with an ice-bath, for 1 h. The ice-bath was removed and the mixture was stirred at room temperature overnight. It was then heated under reflux for 1 h to distill off the ethylamine. The hot mixture was biphasic. Upon cooling, a solid crystallized at the bottom of the flask. Ether (400 mL) was added and the mixture was cooled to −20° C. The supernatant was decanted. Methanol (about 120 mL) was added to the residue. The mixture was heated to reflux; and complete dissolution of the solid material was achieved. After the solution was cooled to room temperature, precipitates formed. The mixture was cooled in an ice-bath; and the solid material was collected by filtration, rinsed with cold methanol and dried in vacuo (20.66 g, pure by NMR analysis). The solid material was recrystallized from methanol (100 mL). After the mixture was cooled using an ice-bath, the solid was collected by filtration, rinsed with cold methanol, and dried in a vacuum oven at 40° C. Compound CV was obtained as white fine needles (19.12 g, 57%). The 1H and 13C NMR were consistent with the structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.[NH2:33][C:34]1[CH:35]=[C:36]([C:40]([C:42]2[C:50]3[CH:49]=[N:48][CH:47]=[N:46][C:45]=3[N:44]([CH3:51])[CH:43]=2)=[O:41])[CH:37]=[N:38][CH:39]=1>Cl.CN(C)CCCN=C=NCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]([F:15])([F:14])[F:13])=[C:6]([CH2:8][C:9]([NH:33][C:34]2[CH:39]=[N:38][CH:37]=[C:36]([C:40]([C:42]3[C:50]4[CH:49]=[N:48][CH:47]=[N:46][C:45]=4[N:44]([CH3:51])[CH:43]=3)=[O:41])[CH:35]=2)=[O:11])[CH:7]=1
Reactant: Cn1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1cc(F)ccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: Cn1cc(C(=O)c2cncc(NC(=O)Cc3cc(F)ccc3C(F)(F)F)c2)c2cncnc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCl (150 μL, 0.5M in DMF) was added to 5-fluoro-2-(trifluoromethyl)phenylacetic acid (90 μmol), N-methylmorpholine (25 μL, 150 μmol), 1-hydroxybenzotriazole (15 μmol, 0.05M in DMF) and (5-aminopyridin-3-yl)(7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 110, 75 μmol, 0.25 M in DMF). The mixture was stirred at 50° C. for 2 hours and then evaporated in vacuo and purified by prep-HPLC (method 4) to afford the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15]CC)=[O:14])[N:9]1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])[CH3:4]>C(O)C>[CH2:3]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=[O:14])[N:9]1[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)[C@H]1CC[C@H](C(=O)OCC)N1Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCC(C(=O)O)N1Cc1ccccc1
Reaction time: 36 h
Yield: 65 %

Procedure:
Potassium hydroxide (6.7 g, 0.1 m) in ethanol (180 ml) was slowly added to a solution of trans-1-benzyl-2,5-pyrrolidine dicarboxylic acid diethyl ester in ethanol (300 ml) at room temperature. This was stirred for 36 hours. The solvent was evaporated off and the residue dissolved in water. The pH of the solution was adjusted to 8 with dilute hydrochloric acid and the solution extracted with hexane to remove the unreacted amino diester. The aqueous solution was adjusted to a pH of 5.3 and was then extracted with diethyl ether. The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated, giving 18.3 g (65%) of the title compound as an oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6](=O)[CH2:5][N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:3]1=[O:16].Cl.[NH2:19][OH:20].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]1([CH3:17])[C:6](=[N:19][OH:20])[CH2:5][N:4]([C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:3]1=[O:16]
Reactant: C[C@H](c1ccccc1)N1CC(=O)C(C)(C)C1=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](c1ccccc1)N1CC(=NO)C(C)(C)C1=O
Yield: 91.1 %

Procedure:
In 100 ml of ethanol was dissolved 11.85 g of 3,3-dimethyl-1-[1-(R)-phenylethyl]-pyrrolidine-2,4-dione. To the solution were added 8 g of hydroxylamine hydrochloride and 45 ml of triethylamine, followed by refluxing for 1 hour. The solvent was removed under reduced pressure, and to the residue was added 300 ml of chloroform. The chloroform solution was washed successively with a 10% citric acid aqueous solution and water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 11.5 g of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH:35]=[CH:34][C:33]([NH2:36])=[N:32]1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]([CH3:20])[CH3:19])/[C:13]([NH:36][C:33]2[CH:34]=[CH:35][N:31]([CH3:30])[N:32]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)O/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: Cn1ccc(N)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)O/N=C(/C(=O)Nc1ccn(C)n1)c1ccc(S(C)(=O)=O)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
This estimated 80% pure (E)-(3-chloro-4-methanesulfonyl-phenyl)-isopropoxyimino-acetic acid (130 mg, <0.39 mmol) was combined with N,N-diisopropylethylamine (162 μL, 0.93 mmol) and O-(7-azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) in acetonitrile (1.5 mL) and cooled to 0° C. 1-Methyl-1H-pyrazol-3-ylamine (33 μL, 0.34 mmol) was added and the reaction mixture was allowed to warm to 25° C. and stirred overnight. After evaporating the volatiles under a stream of nitrogen, The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isopropoxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (56 mg, 45%) as a slightly yellow solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C16H19ClN4O4S [M+] 398.08, found 399 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.34 (d, J=6.3 Hz, 6 H, 2×CH3), 3.30 (s, 3 H, SO2CH3), 3.86 (s, 3 H, NCH3), 4.57 (m, J=6.3 Hz, 1 H, OCH), 6.70 (d, J=2.3 Hz, 1 H, Ar), 7.29 (d, J=2.3 Hz, 1 H, Ar), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.69 (d, Jm=1.5 Hz, 1 H, Ar), 8.19 (d, Jo=8.2 Hz, 1 H, Ar), 9.14 (s, 1 H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C=O.CNC.CI.[Si](C#N)(C)(C)C.CC[CH2:26][CH2:27][N+:28](CCCC)(CCCC)CCCC.[F-]>C(O)(=O)C.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:26][C:27]#[N:28]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2[nH]ccc2c1
Agent: C=O
Agent: CNC
Agent: C[Si](C)(C)C#N
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: N#CCc1c[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.7 %

Procedure:
To a solution of 5-chloroindole (1.0 g, 6.8 mmol, 1.0 eq.) in a mixture of acetic acid (2 mL) and water (1 mL) were added, at 0° C., formaldehyde (720 μL, 37% in H2O, 8.9 mmol, 1.3 eq) and dimethylamine (1.23 mL, 40% in H2O, 10.9 mmol, 1.7 eq). The mixture was stirred at room temperature for 6 hours and then, quenched with ice and 5 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane and then, the organic layer was dried over MgSO4 and partially evaporated. To the solution gramine in dichloromethane (20 mL) were added, under an argon atmosphere, anhydrous toluene (40 mL) and methyl iodide (824 μL, 13.2 mmol, 2.0 eq.). The mixture was stirred at room temperature for 12 hours and then, concentrated under reduced pressure. To the residue taken up in anhydrous THF (60 mL) were added, under an argon atmosphere, TMSCN (1.25 mL, 9.9 mmol, 1.5 eq.) and TBAF (19.9 mL, 1M, 19.9 mmol, 3.0 eq.). The mixture was stirred at room temperature for 4 hours and then, concentrated under reduced pressure. The crude was taken up in ethyl acetate and the organic layer was washed with aqueous bicarbonate solution and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel pad filtration (eluent: EtOAc) to afford (5-chloro-1H-indol-3-yl)-acetonitrile as a beige solid (0.80 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[N:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]([NH2:45])[CH:36]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:45][C:37]2[CH:36]=[N:35][C:44]3[C:39]([CH:38]=2)=[CH:40][CH:41]=[CH:42][CH:43]=3)=[O:8])=[CH:4][N:3]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnc2ccccc2c1)c1ccc(Cl)nc1

Procedure:
A solution of 6-chloro-nicotinic acid (2.95 g, 18.7 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophospate (HBTU) (7.09 g, 18.7 mmol), quinolin-3-ylamine (2.7 g, 18.7 mmol), and N,N-diisopropylethylamine (8.2 mL, 46.7 mmol) in acetonitrile was heated at reflux. The resultant mixture was cooled, and the crystalline product was collected by filtration, to give a colorless solid, 3.1 g (58%). MS: m/z 284 (MH+). 1H NMR (DMSO-d6): 7.61 (t, 1 H), 7.70 (d of t, 1 H), 7.77, (d, 1 H), 8.00 (d, 2 H), 8.43 (d of d, 1 H), 8.85 (d, 1 H), 9.05 (d, 1 H), 9.14 (d, 1 H) and 10.95 (s, 1 H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:38][O:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[CH3:38][O:39][CH2:40][C:41]([N:19]1[CH2:20][CH2:21][C:15]2[N:14]=[C:13]([C:11]3[S:12][C:8]4[C:7]([N:23]5[CH2:24][CH2:25][O:26][CH2:27][CH2:28]5)=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[C:9]=4[N:10]=3)[NH:22][C:16]=2[CH2:17][CH2:18]1)=[O:42]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCc2nc(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)[nH]c2CC1
Yield: 89.4 %

Procedure:
To a suspension of 0.13 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 10 ml tetrahydrofurane were added at 0–4° C. 0.21 ml N-ethyldiisopropylamine and 0.037 g methoxyacetyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.126 g (91%) 2-methoxy-1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-ethanone as yellow solid; MS (ISP): m/e=458 (M+H+).