Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@@H:5]([C:18]([O:20]C)=[O:19])[CH2:4][CH2:3]1.O[Li].O.Cl>C1COCC1.O.CO>[CH3:1][C@H:2]1[N:7]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][C@@H:5]([C:18]([OH:20])=[O:19])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CC[C@H](C(=O)O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 119 %

Procedure:
To a solution of 3-methyl 1-(phenylmethyl) (3S,6R)-6-methyl-1,3-piperidinedicarboxylate (15 g, 51.5 mmol) in THF/water/CH3OH (10/5/1, 480 mL) was added LiOH.H2O (2.59 g, 61.8 mmol), and the reaction mixture was stirred at room temperature for about 1 hour. The mixture was acidified with 1N HCl until the pH was ˜5, and then concentrated in vacuo. The resulting residue was extracted with EtOAc (2×300 mL) and CHCl3 (2×300 mL), and the combined organic layers were dried (MgSO4), filtered and concentrated in vacuo to afford the crude title compound (17 g). LC-MS (ES) m/z=278 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:37][C:38]([Si:41]([CH3:55])([CH3:54])[O:42][CH2:43][C@@H:44]1[CH2:53][N:52]2[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]2)[CH2:46][NH:45]1)([CH3:40])[CH3:39].CC(C)([O-])C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>C1(C)C=CC=CC=1.CCOC(C)=O>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C:13]([CH3:33])([CH3:34])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:45]3[C@H:44]([CH2:43][O:42][Si:41]([C:38]([CH3:40])([CH3:39])[CH3:37])([CH3:54])[CH3:55])[CH2:53][N:52]4[C@H:47]([CH2:48][O:49][CH2:50][CH2:51]4)[CH2:46]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[Cl:31])[CH3:17])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:35])[CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCOC[C@@H]2CN1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(Cl)cc1-c1ccc(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2C[C@H]3COCCN3C[C@H]2CO[Si](C)(C)C(C)(C)C)cc1-c1ccc(F)cc1Cl
Temperature: 100 °C
Yield: 25 %

Procedure:
2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(2-chloro-4-fluorophenyl)-3-pyridinyl]-N,2-dimethylpropanamide (D57, 60 mg, 0.11 mmol),), (7S,9aS)-7-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)octahydropyrazino[2,1-c][1,4]oxazine (D51, 37 mg, 0.13 mmol), sodium t-Butoxide (13 mg, 00.1375 mmol) were degassed together in toluene (1.2 mL) for 10 minutes before adding bis(dibenzyleneacetone) palladium (6 mg, 0.011 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11 mg, 0.0275 mmol) and heating at 100° C. for 30 minutes under microwave conditions. Added more bis(dibenzyleneacetone) palladium (6 mg, 0.011 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (11 mg, 0.0275 mmol) and heated for a further 30 minutes at 100° C. under microwave conditions. Diluted with EtOAc, washed with sat NaHCO3 solution ×1, brine ×1, dried (MgSO4). Filtered. Solvent evaporated under reduced pressure. Residue purified eluting with 0-100% EtOAc/Pent. Solvent evaporated to afford a brown gum of the title compound in 25% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[C:15]1([C:21]2[CH:31]=[CH:30][C:24]([CH:25]=[CH:26][C:27](O)=O)=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:27](/[CH:26]=[CH:25]/[C:24]3[CH:30]=[CH:31][C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:22][CH:23]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccc(-c2ccccc2)cc1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(-c4ccccc4)cc3)nc2n(CC)c1=O
Yield: 39 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 3.12 g (13.9 mmol) of 4-phenylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.90 g (yield 39%) of Compound 163 as yellow flocculent precipitates.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][CH:8]([F:10])[F:9])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])=[N:3]1.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[CH3:1][N:2]1[C:6]([O:7][CH:8]([F:9])[F:10])=[C:5]([Cl:19])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[F:18])=[N:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2F)cc1OC(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccc(Cl)cc2F)c(Cl)c1OC(F)F
Yield: 98.1 %

Procedure:
A solution of 16.2 grams (0.059 mole) of 1-methyl-5-difluoromethoxy-3-(2-fluoro-4-chlorophenyl)pyrazole and 8.5 grams (0.064 mole) of N-chlorosuc-cinimide in about 500 mL of N,N-dimethylformamide was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was poured into about 1600 mL of water and then extracted with two portions of diethyl ether. The combined extracts were washed with one portion of aqueous 10% lithium chloride and two portions of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 18.0 grams of 1-methyl-5-difluoromethoxy-4-chloro-3-(2-fluoro-4-chlorophenyl)pyrazole. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:20]([NH:22][C:23](=O)[O:24]C1C=CC=CC=1)[CH3:21]>CN(C)C=O>[CH2:20]([NH:22][C:23]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:24])[CH3:21]
Reactant: Nc1nccc(Oc2ccc3[nH]ccc3c2)n1
Reactant: CCNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(N)n3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Sodium hydride (157 mg, 3.93 mmol) was suspended in N,N-dimethylformamide (10 ml) under nitrogen atmosphere, and 4-(1H-5-indolyloxy)-2-pyrimidinamine (826 mg, 3.65 mmol) was gradually added while the reaction mixture was stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice-water bath, phenyl N-ethylcarbamate (633 mg, 3.83 mmol) was added, the reaction mixture was heated to room temperature, and the solution was stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography (eluent; ethyl acetate:hexane=3:1 to 4:1) to yield the title compound (691 mg, 2.32 mmol, 63.7%) as white powder.
Reaction SMILES: [F:1][C:2]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:25][CH:26]([CH3:28])[CH3:27].[Li+].[OH-].Cl>C1COCC1>[F:1][C:2]1[C:3]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)=[O:7])=[CH:19][C:20]=1[O:21][CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OC(C)C)c(F)c(OC(C)C)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)Oc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(OC(C)C)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
A suspension of methyl 4-(4-fluoro-3,5-diisopropoxybenzamido)benzoate (10) (32 mg, 51% purity, 82 μmol) in THF (1 mL) and 2M LiOH (0.16 mL, 0.33 mmol) was stirred at RT for 20 h, then at 45° C. for 2 h. The mixture was allowed to cool to RT and was acidified by the addition of 1M HCl. The mixture was partitioned between EtOAc (10 mL) and water (10 mL) and the phases were separated. The organic solution was washed with brine (3× mL), then dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC to afford 4-(4-fluoro-3,5-diisopropoxybenzamido)benzoic acid (AAA-119) (8 mg, 38%) as a white solid: m/z 376 [M+H]+ (ES+), 374 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 10.37 (1H, s), 7.93 (2H, d), 7.83 (2H, d), 7.35 (2H, d), 4.73 (2H, sep), 1.32 (12H, d). NB acid proton not visible.
Reaction SMILES: C([C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1)=O.[Cl:26][O-].[Na+]>>[Cl:26][C:3]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:6]=2[O:5][CH:4]=1
Reactant: [O-]Cl
Reactant: CS(=O)(=O)Nc1cc2occ(C=O)c(=O)c2cc1Oc1ccccc1
Agent: [Na+]
Product: CS(=O)(=O)Nc1cc2occ(Cl)c(=O)c2cc1Oc1ccccc1

Procedure:
3-Formyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with sodium hypochlorite to obtain 3-chloro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:7]([C:18](=[O:22])[CH2:19][O:20][CH3:21])[C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:17])[CH3:6])=[O:4]>CO.[Ni]>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:18](=[O:22])[CH2:19][O:20][CH3:21])[C:8]1[C:9]([CH3:17])=[CH:10][CH:11]=[CH:12][C:13]=1[NH2:14])[CH3:6])=[O:4]
Reactant: COCC(=O)N(c1c(C)cccc1[N+](=O)[O-])C(C)C(=O)OC
Agent: [Ni]
Solvent: CO
Product: COCC(=O)N(c1c(C)cccc1N)C(C)C(=O)OC

Procedure:
257.4 g of N-(1'-methoxycarbonylethyl)-N-methoxyacetyl-2-methyl-6-nitroaniline are dissolved in 2.6 liters of anhydrous methanol and the solution is hydrogenated for 26 hours at 20°-25° C. and under normal pressure in the presence of 26 g of raney nickel (uptake of H2 : 56.2 liters=100% of theory). The catalyst is then removed by filtration, the filtrate is concentrated, and the oily residue is crystallised by adding diethyl ether. Yield: 170.8 g of compound 2 with a melting point of 86°-88° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:17])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)n1nc(CBr)c2ccccc21
Temperature: 25 °C

Procedure:
A stirring solution of 53.4 g (0.23 mol) of 1-tert-butoxycarbonyl-3-methylindazole, prepared as in Part B, in 1.0 L of CCl4 is heated to reflux, and then a mixture of 45.1 g (0.25 mol, 1.1 equiv) of N-bromosuccinimide and 5.7 g (23.5 mmol, 0.1 equiv) of benzoyl peroxide is added portionwise over 5 min as a solid. The resulting solution is heated at reflux for 4.5 h, then cooled to RT. The reaction mixture is filtered through a pad of Celite to remove the precipitated succinimide, and the solvent is removed in vacuo. Purification of the crude material by gradient silica gel flash column chromatography using hexane/EtOAc 15/1 to hexane/EtOAc 3/1 as eluent afforded 43.2 of the title compound as a white solid: 1H NMR (CDCl3, 300 MHz) δ8.20 (d, 1H, J=7.8), 7.88 (d, 1H, J=7.8), 7.60 (dd, 1H, J=7.3, 7.3), 7.41 (dd, 1H, J=7.3, 7.3), 4.91 (s, 2H), 1.77 (s, 9H); ;TLC Rf =0.56 (EtOAc/Hexane 1/5).
Reaction SMILES: [CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6]C(C1C=C(C2C=CC(CSCCOC3C=CC=CC=3)=CC=2)C=CC=1)=O.[O:33]([CH2:40][CH2:41][S:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[C:50]1[C:51]([C:56](O)=[O:57])=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)CCCN>C1COCC1>[CH3:1][N:2]([CH3:32])[CH2:3][CH2:4][CH2:5][NH:6][C:56]([C:51]1[C:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH2:43][S:42][CH2:41][CH2:40][O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:57]
Reactant: O=C(O)c1ccccc1-c1ccccc1CSCCOc1ccccc1
Reactant: CN(C)CCCNC(=O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNC(=O)c1ccccc1-c1ccccc1CSCCOc1ccccc1

Procedure:
2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (3-dimethylamino-propyl)-amide was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid (3-dimethylamino-propyl)-amide. 2′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-2-carboxylic acid (0.7 g, 1.92 mmol, 1 eq.) in anhydrous THF was treated with 1,1-carbonyldiimidazole (0.32 g, 1.96 mmol, 1.02 eq.) and 3-(dimethylamino)propylamine (0.30 g, 2.30 mmol, 1.2 eq.). When complete, the reaction was worked up as described leaving an orange oil.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:24][OH:25])[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:50][O:51][C:52](=[O:60])[C:53]1[CH:58]=[CH:57][CH:56]=[C:55](O)[CH:54]=1>O1CCCC1>[CH:15]1([O:20][C:21]2[CH:22]=[C:23]([CH2:24][O:25][C:55]3[CH:54]=[C:53]([CH:58]=[CH:57][CH:56]=3)[C:52]([O:51][CH3:50])=[O:60])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)c1cccc(O)c1
Reactant: COc1ccc(CO)cc1OC1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCc2ccc(OC)c(OC3CCCC3)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diisopropylazodicarboxylate (1.2 ml, 5.99 mmol, 1.2 eq)was added to a mixture of (1.10 g,4.99 mmol, 1.0 eq) 3-cyclopentyloxy-4-methoxybenzyl alcohol, (1.44 g, 5.49 mmol, 1.1 eq) triphenylphosphine, and (0.75 g, 4.99 mmol, 1.0 eq) methyl-3-hydroxy-benzoate in 30 ml of anhydrous tetrahydrofuran. After stirring for 18 hours at room temperature the reaction mixture was concentrated in vacuo and chromatographed on a silica gel column, eluting with 10%, then 15% ethyl acetate-hexane to yield 897 mg, 50%, of a clear oil. High Resolution Mass Spectra: Calc'd 356.1624. Found: 356.1600.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][C:13]=3[F:15])[C:8]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]([N:27]=[C:28]=[O:29])([CH3:26])([CH3:25])[CH3:24]>O1CCOCC1>[C:23]([NH:27][C:28](=[O:29])[O:22][C:19]1[CH:18]=[CH:17][C:16]([C:8]2[C:9]3[C:14](=[C:13]([F:15])[CH:12]=[CH:11][CH:10]=3)[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=2)=[CH:21][CH:20]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Reactant: CC(C)(C)N=C=O
Solvent: C1COCCO1
Product: CC(C)(C)NC(=O)Oc1ccc(-c2nn(C3CCCC3)c3c(F)cccc23)cc1
Yield: 49.3 %

Procedure:
A solution of 4-(1-cyclopentyl-7-fluoro-1H-indazol-3-yl)phenol (0.30 g, 1.0 mmol) and t-butyl isocyanate (0.114 mL, 1.0 mmol) in 10 mL of dioxane was heated at 80° C. for 48 hours. The reaction mixture was concentrated in vacuo. The residue was crystallized from EtOAc/hexane to give 0.195 g of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=O)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:38]=[CH:37][CH:36]=[C:33]([C:34]#[N:35])[CH:32]=1)=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1
Product: COc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c3cccc(C#N)c3)c2)cc1

Procedure:
Prepared from (3-amino-4′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G5) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light brown solid (207 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C1COCC1.[Cl-].[Na+].O>[C:20]([O:19][C:17](=[O:18])[CH2:16][N:7]1[C:8]2[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[NH:4][CH2:5][C:6]1=[O:12])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1CNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (475 mg, 2.86 mmol) in THF (10 ml) was added sodium hydride (60%, 115 mg, 2.86 mg) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature, stirred for 30 min and cooled in an ice/water bath. tert-Butyl bromoacetate (460 μl, 2.86 mmol) was added and the mixture was allowed to warm to room temperature slowly and stirred for 18 h. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between brine and EtOAc and the organic layer was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc;pet. ether 40:60) to give a white solid; yield 500 mg, 62%.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([CH3:10])[CH2:8][C:7](=[O:11])[CH2:6]1)=[O:4]>Cl>[C:3]([C@H:5]1[C@H:9]([CH3:10])[CH2:8][C:7](=[O:11])[CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)[C@H]1CC(=O)C[C@H]1C
Agent: Cl
Product: C[C@@H]1CC(=O)C[C@H]1C(=O)O
Yield: 97.8 %

Procedure:
1.18 g of (3S, 4R)-3-methoxycarbonyl-4-methylcyclopentanone was dissolved in 20 ml of 3N-HCl, and the solution was refluxed for 2 hours. The reaction mixture was allowed to stand to return to room temperature, and concentrated. The residue was concentrated under a reduced pressure, and thus 1.05 g of the titled compound was obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+]>[C:8]1([S:14]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCNS(=O)(=O)c1ccccc1
Reaction time: 4 h

Procedure:
7 G of gamma-aminobutyric acid was dissolved in 120 mL of 1N sodium hydroxide solution, and 15 g of benzenesulfonyl chloride was dropwise added thereto under ice-cooling. 2N sodium hydroxide solution was added to the mixture to adjust the pH to 9.2 and stirred for 4 hours. The stirred mixture was washed with 50 mL of ethyl acetate, and hydrochloric acid was added thereto to adjust the pH to 2 or less. After extracting with 500 mL of ethyl acetate, this was dried with magnesium sulfate and filtered. After a concentration under reduced pressure, the obtained residue was recrystallized with ethanol solution to give 13 g of the desired product.
Reaction SMILES: [Cl-].[CH2:2]([C:5]1[S:9][CH:8]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=3)[CH:11]=[CH:12][N+:7]2([CH2:21][CH3:22])[C:6]=1[CH2:23][CH3:24])CC.[Cl-].C(C1SC2N(CC3C=CC(F)=CC=3)C=C[N+]=2C=1)(C)C.[Br-].C1(C2[N+]3C=CN(CC4C=CC=CC=4OC)C=3SC=2)C=CC=CC=1.[Cl-].COC1C=C(C=C(OC)C=1)CC1[N+]2C=CN(CC3C=CC=CC=3)C=2SC=1.[Br-].CC1[N+]2C=CN(CC3C=CC(C4C=CC=CC=4)=CC=3)C=2SC=1.[Br-].CC1C=C(C)C=CC=1CC1[N+]2C=C(C)N(CC3C=CC([Cl:140])=CC=3)C=2SC=1.[Br-].ClC1C=CC(C2[N+]3C=CN(CC#C)C=3SC=2)=CC=1.[Cl-].CC1C=C(C)C=CC=1C1[N+]2C=C(C3C=CC(C)=CC=3C)N(CC3C=CC=CC=3)C=2SC=1.[Cl-].FC1C=CC(C[N+]2C=CN3C4CCCCC=4SC=23)=CC=1.[Br-].C([N+]1C=CN2C3CCCCC=3SC=12)C#C>>[Cl-:140].[CH3:2][C:5]1[S:9][CH:8]2[N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12][N+:7]2([CH2:21][CH3:22])[C:6]=1[CH2:23][CH3:24]
Reactant: CCCC1=C(CC)[N+]2(CC)C=CN(Cc3ccc(F)cc3)C2S1
Reactant: Cc1ccc(Cc2csc3n(Cc4ccc(Cl)cc4)c(C)c[n+]23)c(C)c1
Agent: C#CC[n+]1ccn2c3c(sc21)CCCC3
Agent: C#CCn1cc[n+]2c(-c3ccc(Cl)cc3)csc12
Agent: CC(C)c1c[n+]2ccn(Cc3ccc(F)cc3)c2s1
Product: CCC1=C(C)SC2N(Cc3ccccc3)C=C[N+]12CC

Procedure:
2-n-propyl-3,4-diethyl-7-(p-fluorobenzyl)imidazo[2,1-b]thiazolium chloride, 2-i-propyl-7-(p-fluorobenzyl)imidazo[2,1-b]thiazolium chloride; 3-phenyl-7-(o-methoxybenzyl)imidazo[2,1-b]thiazolium bromide; 3-adamantyl-6-phenyl-7-(m-trifluorobenzyl)imidazo[2,1-b]thiazolium bromide; 3-(3,5-dimethoxybenzyl)-7-benzylimidazo[2,1-b]thiazolium chloride, 3-methyl-7-(p-phenylbenzyl)imidazo[2,1-b]thiazolium bromide; 3-(2,4-dimethylbenzyl)-6-methyl-7-(p-chlorobenzyl)imidazo[2,1-b]thiazolium bromide; 3-(p-chlorophenyl)-7-propargylimidazo[2,1-b]thiazolium bromide; 3,6-bis(2,4-dimethylphenyl)-7-benzylimidazo[2,1-b]thiazolium chloride; 1-(p-fluorobenzyl-5,6,7,8-tetrahydroimidazo[2,1-b]benzthiazolium chloride and 1-propargyl-5,6,7,8-tetrahydroimidazo[2,1-b]benzthiazolium bromide.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[OH:32][C:28]1[CH:27]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1cccc(O)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2cccc(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 40, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added 3-aminophenol (37.24 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. Ethyl acetate and Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 45% (58 mg, 0.140 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[H-].[Na+].[C:28](Cl)(=[O:30])[CH3:29]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([C:28](=[O:30])[CH3:29])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(=O)Cl
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)n1c2c(c(=O)n(-c3cc(C(=O)OC(C)C)c(Cl)cc3F)c1=O)CCC2
Reaction time: 2 h

Procedure:
A solution of 3.6 g of isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate in 50 ml of absolute dimethylformamide is stirred at room temperature for 2 hours with 0.43 g of a 55% sodium hydride dispersion. A solution of 0.93 g of acetyl chloride in 10 ml of absolute dimethylformamide is subsequently added dropwise during 10 minutes and the mixture is stirred for 2 hours. The reaction mixture is dissolved in 100 ml of ethyl acetate and the solution is washed thoroughly with water. The organic phase is dried over anhdrous sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a silica gel column using methylene chloride/ethyl acetate (3:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-acetyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.86 ppm (d, 1H), 7.37 ppm (d, 1H), 5.24 ppm (m, 1H), 3.13 ppm (m, 2H), 2.75 ppm (m, 2H), 2.68 ppm (s, 3H), 2.12 ppm (m, 2H), 1.36 ppm (d, 6H).