Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][N:7]=1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([N:57]1[CH:61]=[C:60]([CH2:62][C:63]2[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=2)[N:59]=[CH:58]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:59]2[C:60]([CH2:62][C:63]3[CH:68]=[CH:67][C:66]([C:69]#[N:70])=[CH:65][CH:64]=3)=[CH:61][N:57]=[CH:58]2)=[CH:8][N:7]=1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: OCc1ccc(-c2cccs2)nc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(Cc2cncn2Cc2ccc(-c3cccs3)nc2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(thien-2-yl)-5-hydroxymethylpyridine (255 mg, 1.33 mmol) and diisopropylethylamine (0.464 mL, 2.66 mmol) in dichloromethane (7 mL) at -78° C. is added trifluoromethane-sulfonic anhydride (0.224 mL, 1.33 mmol) and the mixture stirred at -78° C. for 1 hour. To this mixture is added a solution of 1-trityl-4-(4-cyanobenzyl)-imidazole (566 mg, 1.33 mmol) in dichloromethane (5 mL). The mixture is allowed to warm to ambient temperature and stirred for 2 hours. The solvent is evaporated in vacuo. The residue is dissolved in methanol (50 mL), heated at reflux for 1 hour, and the solvent is evaporated in vacuo. The residue is partitioned between dichloromethane and sat. aq. NaHCO3 solution. The organic layer is dried, (Na2SO4) and the solvent evaporated in vacuo. The residue is chromatographed to afford the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].C(N(CC)CC)C.[B]1OC(C)(C)C(C)(C)O1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].Cl[C:38]1[C:39]2[CH:49]=[CH:48][C:47](=[O:50])[N:46]([C:51]3[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=3[F:58])[C:40]=2[N:41]=[C:42]([S:44][CH3:45])[N:43]=1>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].O>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([C:38]2[C:39]3[CH:49]=[CH:48][C:47](=[O:50])[N:46]([C:51]4[C:56]([F:57])=[CH:55][CH:54]=[CH:53][C:52]=4[F:58])[C:40]=3[N:41]=[C:42]([S:44][CH3:45])[N:43]=2)[CH:3]=1
Reactant: Cc1ccc(N)cc1I
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)O[B]OC1(C)C
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CSc1nc(-c2cc(N)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 3-iodo-4-methylaniline (110.0 mg, 0.47 mmol) in dioxane (1.0 mL) was added (under argon) triethylamine (0.26 mL, 1.86 mmol), palladium diacetate (5.2 mg, 0.023 mmol), 2-(dicyclophexyl phosphino)biphenyl (33.0 mg, 0.093 mmol), and pinacolborane (0.20 mL, 1.40 mmol). The mixture was stirred at about 80° C. for about 1 hour, cooled to room temperature (rt), and added with water (0.2 mL), barium hydroxide octahydrate (440.0 mg, 1.40 mmol) and 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (180.0 mg, 0.47 mmol). The mixture was heated at about 100° C. under stirring for about 1 hour, cooled to room temperature, filtered through celite, and diluted with brine (5.0 mL). The mixture was then extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated. Purification via the CombiFlash system then afforded the title compound (155.0 mg, 75%): LC-MS m/z 411 (M+H)+, 2.60 min (ret. time).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](/[CH:15]=[CH:16]\[CH3:17])[C@H:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.Cl[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:35]([CH3:38])([CH3:37])[CH3:36])=[C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=2[F:34])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[Li+]>CS(C)=O>[CH3:38][C:35]([C:23]1[C:24]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=2[F:34])=[CH:25][C:20]([CH2:19][O:1][C:2]2[CH:7]=[CH:6][C:5]([C@H:8](/[CH:15]=[CH:16]\[CH3:17])[C@H:9]([CH3:14])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=2)=[CH:21][CH:22]=1)([CH3:36])[CH3:37]
Reactant: C/C=C\[C@@H](c1ccc(O)cc1)[C@H](C)C(=O)OC
Reactant: COc1ccc(F)c(-c2cc(CCl)ccc2C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: CS(C)=O
Product: C/C=C\[C@@H](c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1)[C@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A reaction mixture of (2S,3R,Z)-methyl 3-(4-hydroxyphenyl)-2-methylhex-4-enoate 41.3 (34.0 mg, 145 μmol), 5-(chloromethyl)-2-(1,1-dimethylethyl)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl A (44.5 mg, 145 μmol) and cesium carbonate (94.5 mg, 290 μmol) in DMSO (1.0 mL) was stirred at room temperature for 16 hours. Lithium hydroxide (0.4 mL, 3.33M in water) and DMSO (1.5 mL) were added, and the resulting mixture was stirred at ambient temperature for 16 hours. The reaction mixture was purified by HPLC (reverse phase) to give the title compound 41. 1H NMR (500 MHz, CD3CN) δ ppm 1.17 (d, J=7.09 Hz, 3H) 1.23 (s, 9H) 2.76 (m, 1H) 3.78-3.82 (m, 4H) 5.04 (s, 2H) 5.53-5.57 (m, 1H) 6.85 (dd, J=5.87, 3.18 Hz, 1H) 6.90-6.98 (m, 3H) 7.07-7.12 (m, 2H) 7.18 (d, J=8.56 Hz, 2H) 7.44 (dd, J=8.31, 1.96 Hz, 1H) 7.64 (d, J=8.31 Hz, 1H). MS ESI (neg.) m/e: 489.2 (M−H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:20][CH3:21].[C:22]([Cu])#[N:23].CN(C=O)C>C(OCC)(=O)C>[CH3:21][O:20][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=2)[C:2]=1[C:22]#[N:23]
Reactant: N#C[Cu]
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3c(C#N)c(OC)ccc3c2)cc1
Temperature: 120 °C
Reaction time: 4 h
Yield: 29.7 %

Procedure:
A mixture of 1-bromo-2-methoxy-6-(4-methoxyphenyl)naphthalene (0.76 g, 2.21 g), CuCN (0.24 g, 2.66 mmol) and DMF (10 mL) was stirred at 120° C. for 4 hr. The reaction mixture was cooled to room temperature, slurried with ethyl acetate, filtered through silica, and evaporation of the solvent, and purification by silica column chromatography (20% ethyl acetate-hexanes) yielded 0.19 g (30%) of the title compound as a pale yellow solid: mp 182–185° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.09 (3H, s), 7.03 (2H, d, J=8.73 Hz), 7.29 (1H, d, J=9.12 Hz), 7.63 (2H, d, J=8.73 Hz), 7.88 (1H, dd, J=1.98 Hz, J=8.73 Hz), 7.97 (1H, d, J=1.98 Hz), 8.09 (1H, d, J=9.12 Hz), 8.14 (1H, d, J=8.73 Hz).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]([O:10][CH2:11][CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N+:20]([O-:22])=[O:21])[CH3:13])=[O:9]>C1COCC1.CCOCC.O>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:12]([CH3:13])[CH2:11][O:10][C:8]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])([O-:22])=[O:21]
Reactant: C1CCNCC1
Reactant: CC(COC(=O)Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC(COC(=O)N1CCCCC1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.9 %

Procedure:
A solution of piperidine (22.8 mL, 230 mmol) in anhydrous THF (50 mL) was added dropwise to a solution of 2-(2-nitrophenyl)propyl chloroformate (28.20 g) in anhydrous THF (100 mL). The reaction mixture was then brought to reflux for 3 h and stirred at room temperature overnight. The solvent was evaporated to afford light brown oil. The mixture was diluted with ether (100 mL) and water (100 mL) was added. The organic phase was separated and the aqueous phase was re-extracted with ether (3×50 mL). The organic extracts were combined and dried over MgSO4, filtered, and the solvent was removed in vacuo. The residue was purified on a silica gel column. Elution of the column with 20% ethyl acetate in hexanes gave 16.54 g (56.6 mmol, 63.6% yield, 56.6% total yield) of 2-(2-nitrophenyl)propoxycarbonyl piperidine. 1H-NMR (600 MHz, DMF-d7): δ 7.88 (d, J=8.1 Hz, 1 H, Ar—H), 7.74 (m, 2 H, Ar—H), 7.53 (t, J=7.1 Hz, 1 H, Ar—H), 4.23 (m, 2 H, CH2), 3.54 (m, 1 H, CH), 3.24 (m, 4H, CH2), 1.50 (m, 2 H, CH2), 1.35 (m, 7 H, CH2 and CH3). 13C-NMR (150 MHz, DMF-d7): δ 155.09 (OCOR), 151.50 (C ipso to NO2), 137.90 (C ipso to CH(CH3)CH2OCOR), 133.49 (C para to NO2), 129.31 (C para to CH(CH3)CH2OCOR), 128.44 (C ortho to CH(CH3)CH2OCOR), 124.35 (C ortho to NO2), 69.45 (CH2OCOR), 45.08 (Cα to ring N), 34.26 (CH), 26.08 (Cβ to ring N), 24.69 (Cγ to ring N), 17.91 (CH3). TLC: 20% ethyl acetate in hexanes, Rf=0.4. Mass analysis (MALDI-TOF): calculated for C15H21N2O4 293.34, found 293.24.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21]Cl)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:24][C:25]1[N:29]=[CH:28][NH:27][N:26]=1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:23])[CH2:21][S:24][C:25]3[N:29]=[CH:28][NH:27][N:26]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: Sc1nc[nH]n1
Product: O=C(CSc1nc[nH]n1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 91 %

Procedure:
Following a procedure similar to that described in Example 33, but using N-[4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenyl]-2-chloroacetamide (prepared as described in Preparation 1) and 3-mercapto-1,2,4-triazole as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as a white powder, melting at 65°-67° C., in a 91% yield.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[N:27]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:8][C:7]=1[C:33]([F:36])([F:35])[F:34]>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O.O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:25][C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:1](=[O:3])[CH3:2])[N:27]=4)=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[CH:8][C:7]=1[C:33]([F:34])([F:36])[F:35]
Reactant: CC(=O)Cl
Reactant: Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1nccc(Oc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)n1
Reaction time: 1.5 h

Procedure:
48 μl (0.68 mMol) acetyl chloride are added portionwise to a solution of 300 mg (0.68 mMol) 6-(2-amino-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (step 10.3) in 3.7 ml CH2Cl2 and 5.5 ml pyridine. After 1.5 h, the solution is diluted with EtOAc and water, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 1:1→1:3) gives the title compound: m.p.: 213-214° C.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:26][NH:27][C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29]>CS(C)=O>[CH3:26][N:27]([C@H:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:29])[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CN[C@@H](C)c1ccccc1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)c1ccc2[nH]c(=O)c(N(C)[C@@H](C)c3ccccc3)nc2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (300 mg, 1.26 mmol) in DMSO (2 mL) was added DIEA (244 mg, 1.89 mmol), and (S)—N-methyl-1-phenylethanamine (204 mg, 1.51 mmol) with stirring for 3 h at 85° C. in an oil bath. The reaction was then quenched by the addition of water (50 mL). The product was precipitated via the addition of water and collected by filtration to give (S)-methyl 3-(methyl(1-phenylethyl)amino)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (323 mg, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([Cl:23])=[N:18][C:19](Cl)=[CH:20][CH:21]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:16]1[C:17]([Cl:23])=[N:18][C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(Cl)nc1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2ccccc2)nc1Cl
Temperature: 85 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
2,6-dichloropyridin-3-amine (9.39 g, 57.6 mmol), di-tert-butyldicarbonate (503 g, 230 mmol), DMAP (0.704 g, 5.76 mmol) and triethylamine (16.06 mL, 115 mmol) were combined in DCM (230 mL) and stirred at RT overnight. The solvent was evaporated and the residue was triturated with acetonitrile and filtered to provide di-tert-butyl(2,6-dichloropyridin-3-yl)imidodicarbonate. Di-tert-butyl(2,6-dichloropyridin-3-yl)imidodicarbonate (27.7 g, 76 mmol), phenyl boronic acid (13.95, 114 mmol) and sodium carbonate (114 mL, 229 mmol, 2M) were combined with dioxane (692 ml) and DMF (46 ml). The solution was purged with N2 for 20 min. Tetrakis(triphenylphosphine)palladium(0) (4.41 g, 3.81 mmol) was added and reaction heated to 85° C. for 3 h, then cooled to RT and stirred overnight. Reaction was poured into H2O (100 ml) and extracted with EtOAc (2×100) ml. The combined organics were washed with brine and dried over Na2SO4. Crude product was purified by flash chromatography on ISCO 330 g column. (0-20% EtOAc/Heptane). Major spot (TLC 10:1 Heptane/EtOAc) isolated to give 12.06 g of di-tert-butyl(2-chloro-6-phenylpyridin-3-yl)imidodicarbonate as a white solid. 1H NMR (CDCl3) δ 8.01 (d, J=7.0 Hz, 2H), 7.69 (d, J=8.1 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.41-7.48 (m, 3H), 1.40 (s, 18H); MS: cal'd 405 (MH+), exp 405 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH:11]([NH2:13])=[O:12]>C(OCC)(=O)C.O>[C:5]1([C:3]2[N:13]=[CH:11][O:12][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NC=O
Reactant: O=C(CBr)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(-c2cocn2)cc1
Temperature: 130 °C
Yield: 39.1 %

Procedure:
Bromoacetophenone (595 mg, 2.99 mmol) and formamide (1781 μl, 44.8 mmol) were combined and heated at 130° C. for 90 min. The reaction was cooled then dilute with ethyl acetate and water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated. The concentrate was purified by chromatography on a Biotage 25M column using a 5-8% ethyl acetate in heptane gradiant to yield 4-phenyl-oxazole (170 mg, 1.17 mmol). TLC (5% ethyl acetate in heptane) of product: Rf=0.28.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]([S:12]([NH:15]C(=O)OC(C)(C)C)(=[O:14])=[O:13])[CH2:9][CH2:8][NH:7][C:6]=2[N:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[N:24]=2)[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[C:11]2[N:10]([S:12]([NH2:15])(=[O:13])=[O:14])[CH2:9][CH2:8][NH:7][C:6]=2[N:5]=[C:4]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[N:24]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)N1CCNc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1N(S(N)(=O)=O)CCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
96 mg (0.17 mmol) of the compound from example 41A were initially charged in dichloromethane (5 ml), then 0.13 ml (1.73 mmol) of trifluoroacetic acid were added and the reaction mixture was stirred at RT overnight. The mixture was concentrated, the residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 52 mg (66% of theory) of the title compound in solid form.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C1COCC1.[CH2:16]([NH:18][CH2:19]C)C>S(Cl)(Cl)=O>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]([CH3:19])[CH3:16])=[O:5]
Reactant: CCNCC
Reactant: Nc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccccc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-aminobenzoic acid (1.0 g, 7.3 mmol) in thionyl chloride (20 mL) was refluxed for 3 hours. Excess of thionyl chloride was removed. And the residue was treated with toluene (3×10 mL) to remove the excess thionyl chloride. To the crude product obtained was added THF (20 mL) and the resulting solution was cooled to 0° C. Diethyl amine (3.78 mL, 36 mmol) was added and the resulting solution was stirred for 2 hrs at room temperature. The solvent was removed under reduced pressure and residue was taken into dichloromethane (20 mL), washed with saturated sodium bicarbonate solution (3×20 mL), water (20 mL), dried over sodium sulfate and concentrated to provide the desired product as brown oil. This crude product was used in Step 2 without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@@H:33]1[CH2:35][O:34]1>CCO>[OH:34][C@H:33]([C:24]1[CH:25]=[CH:26][C:27]2[C:28](=[O:32])[O:29][CH2:30][C:31]=2[C:23]=1[CH3:22])[CH2:35][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])=[O:21])[C:15](=[O:20])[CH2:16]1
Reactant: Cc1c(C(=O)CN2CCNCC2=O)ccc2c1COC2=O
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(=O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 140 °C

Procedure:
A mixture of 1-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)-2-oxoethyl]piperazin-2-one (30 mg, 0.10 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (40 mg, 0.21 mmol) in EtOH (2 mL) was heated to 140° C. in a microwave tube for 1 hour. The solution was concentrated to dryness, re-dissolved in MeOH, filtered and shot into Mass-directed HPLC for separation to give the title product. LC-MS (IE, m/z): 479 [M+1]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][NH:9][C:10](=[O:12])[CH3:11].[CH3:13][O:14][CH:15](Cl)[CH3:16].[OH-].[Na+]>CCCCCC>[CH3:13][O:14][CH:15]([N:9]([CH3:8])[C:10](=[O:12])[CH3:11])[CH3:16]
Reactant: COC(C)Cl
Reactant: CNC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(C)N(C)C(C)=O
Reaction time: 2 h

Procedure:
First 20 g of triethylamine and then a mixture of 91 g of triethylamine (1.1 moles in total) and 36.5 g (0.5 mole) of N-methylacetamide are added dropwise, at 0° C., to a solution of 94.5 g (1 mole) of α-chloroethyl methyl ether in 200 ml of hexane. After 2 hours, 44 g (1.1 moles) of technical-grade sodium hydroxide flakes are added and 20 ml of 50% strength sodium hydroxide solution are added dropwise, whilst cooling with ice, and the mixture is stirred for a further half an hour. The hexane solution is decanted, the flask is rinsed with hexane and the reaction solution is concentrated, the triethylamine employed being completely recovered in the distillate. The residue is subjected to flash distillation in vacuo. This yields 61 g (93% of theory) of N-α-methoxyethyl-N-methyl-acetamide. Boiling point (23 mm Hg): 84° C. 1H-NMR (CDCl3): 1.2-1.4 ppm (dd); 2.1 ppm (d); 2.8 ppm (d); 3.2 ppm (d); 4.95-5.15 ppm (q); 5.6-5.9 ppm (q).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].[H-].[Na+].[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1.[NH4+].[Cl-]>C1COCC1.C(#N)C.CCCCCCC.C(OCC)(=O)C.O>[CH3:1][N:2]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([F:8])=[CH:10][CH:11]=1)[C:3](=[O:5])[CH3:4]
Reactant: CNC(C)=O
Reactant: Fc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(F)cc1
Reaction time: 8 h
Yield: 97 %

Procedure:
Slowly add a solution of 375 g (5.13 mol, 112 equiv) of N-methylacetamide in THF (1.76 L) to 224 g (5.55 mol, 1.2 equiv) of sodium hydride (60% dispersion in mineral oil) as a slurry in THF (8.75 L). After 30 minutes when 25% of the solution has been added, add 875 g (4.63 mole, 1 equiv) of 4-fluorobenzylbromide and the remaining N-methylacetamide and 4-fluorobenzylbromide solutions concurrently over the next 3 h. Use a water bath to maintain the temperature below 40° C. Stir the resulting mixture overnight and pour into a mixture of 20% NH4Cl (2.5 L), water (6.5 L), and ethyl acetate (9 L). Separate the layers and back-extract the aqueous layer with ethyl acetate (4.5 L, then 2 L). Combine the organic layers and wash with water (4 L) and then brine (7 L). Dry the organic layer (Na2SO4) and remove the solvent to afford a residue. Dissolve the residue in acetonitrile (7 L) and heptane (1.75 L). Separate the layers and wash the acetonitrile layer again with heptane (1.75 L). Combine the heptane layers and back-extract with acetonitrile (0.5 L). Combine the acetonitrile layers and evaporate to afford 0.814 kg of N-methyl-N-(4-fluorobenzyl)acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH3:16][NH2:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:17][CH3:16])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 35.1 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the solid which formed was collected by filtration (6.0 g). Recrystallization from benzene yielded 2.0 g (35.1%) of tan crystals, m.p. 134°-135° C.