Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[O:12][CH:11]=[C:10]([CH2:13][OH:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:30])[C@@H:18](/[CH:19]=[C:20](/[F:26])\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@H:17]1[C:27](O)=[O:28]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:30][C:16]1([CH3:15])[C@@H:18](/[CH:19]=[C:20](/[F:26])\[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C@H:17]1[C:27]([O:14][CH2:13][C:10]1[CH:9]=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:12][CH:11]=1)=[O:28]
Reactant: OCc1coc(Cc2ccccc2)c1
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)OCc2coc(Cc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
Under nitrogen atmosphere, to a mixture of 0.50 g of 5-benzyl-3-furylmethyl alcohol, 0.62 g of (1R)-cis-2,2-dimethyl-3-((E)-3-ethoxy-2-fluoro-3-oxo-1-propenyl)-cyclopropanecarboxylic acid, 0.1 g of 4-dimethylaminopyridine and 7 ml of dichloromethane was added 0.60 g of N,N-dicyclohexylcarbodiimide, and the mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.69 g of 5-benzyl-3-furylmethyl (1R)-cis-2,2-dimethyl-3-((E)-3-ethoxy-2-fluoro-3-oxo-1-propenyl)cyclopropanecarboxylate (hereinafter, referred to as the present compound (1)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8].[OH:27]O>>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[O:27])[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8]
Reactant: OO
Reactant: Nc1c(Br)cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc1Br
Product: Nc1c(Br)cc(S(=O)CCCCOc2ccc3[nH]c(=O)ccc3c2)cc1Br

Procedure:
Prepared analogous to Example 123 from 6-[4-(3,5-dibromo-4-amino-phenylmercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([OH:44])=[C:39]([C:41](=[O:43])[CH3:42])[CH:40]=1.O>O1CCCC1>[Br:1][CH2:42][C:41]([C:39]1[CH:40]=[C:35]([Cl:34])[CH:36]=[CH:37][C:38]=1[OH:44])=[O:43]
Reactant: [Br-]
Reactant: CC(=O)c1cc(Cl)ccc1O
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
Phenyltrimethylammonium tribromide (0.44 g, 1.17 mmol) was added to a solution of 5′-chloro-2′-hydroxyacetophenone (0.20 g, 1.17 mmol) in tetrahydrofuran (6 mL) and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:1) to give the title compound (220.7 mg, 75.6%) as an yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([OH:14])=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.CN1CCOCC1.C(Cl)(=O)OCC(C)C.[CH2:30]([NH:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O1CCCC1.CN(C)C=O>[CH2:37]([N:36]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:12]([C:11]1[C:2](=[O:1])[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:14])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCNCCCCCC
Reactant: O=C(O)c1cc2ccccc2[nH]c1=O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCCCCN(CCCCCC)C(=O)c1cc2ccccc2[nH]c1=O
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
In a mixture of 50 ml of tetrahydrofuran and 250 ml of N,N-dimethylformamide were dissolved 9.46 g of 1,2-dihydro-2-oxoquinoline-3-carboxylic acid and 5.06 g of N-methylmorpholine, and after cooling to −15° C., 6.83 g of isobutyl chlorocarbonate was added dropwise over 10 minutes. After stirring at −15° C. for 10 minutes, 9.73 g of dihexylamine was added dropwise over 5 minutes. After stirring at −15° C. for 4 hours and then at room temperature overnight, the reaction mixture was concentrated under reduced pressure, and the residue, after addition of ethyl acetate, was washed with water, 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane to give 13.51 g of N,N-dihexyl-1,2-dihydro-2-oxoquinoline-3-carboxamide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](OC)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:11][CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: COC(=O)c1cc2ccccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCc1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude product 3 (324 g) was dissolved in anhydrous ethyl ether. The solution was kept under inert atmosphere (nitrogen or argon) and cooled to 0° C. in an ice bath. A 1M solution of lithium aluminum hydride in ether (620 ml) was added dropwise, while stirring, over a period of 1 hour. The solution was then washed with 2N HCl (4×1,000 ml), with 2N KOH (2×500 ml), and with water (1,000 ml). The material was dried over magnesium sulfate, filtered, and the solvent evaporated. The crude product was distilled in vacuo, yielding approximately 155.36 g (1.05 mol). The boiling point is 110° C. at 1.5 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:13]2[N:14]=[C:15]3[C:21]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:20][N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:16]3=[N:17][CH:18]=2)[CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:36][S:37][CH2:38][CH2:39]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:25][C:23]([CH3:26])([CH3:24])[C:22]([C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:4]3[CH:5]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:7]=[C:2]([O:1][CH2:39][CH2:38][S:37][CH3:36])[CH:3]=3)[N:14]=2)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:20]=1)=[O:27]
Reactant: CSCCO
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(O)cc(N4CCCC4)c3)nc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CSCCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCCC2)c1
Reaction time: 2 h

Procedure:
A flask was charged with 1-[2-(3-hydroxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (140 mg, 0.28 mmol), 2-methylsulfanyl-ethanol (reagent A, 0.03 ml, 0.34 mmol), triphenylphosphine (reagent B, 89 mg, 0.34 mmol). THF (1.5 ml) was added and the mixture cooled (ice bath) under nitrogen atmosphere. Diisopropyl azodicarboxylate (reagent C, 0.07 ml, 0.34 mmol) was added via syringe and the material was warmed to ambient. After 1 hour a further 1.2 equivalents each of reagents A, B and C were added. After 2 hours repeat. The mixture was stirred overnight. The crude was loaded onto 2 preparative TLC plates eluting with 20% EtOAc in hexanes. The product band was collected providing 2,2-dimethyl-1-[2-[3-(2-methylsulfanyl-ethoxy)-5-pyrrolidin-1-yl-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one, 82 mg as a yellow viscous oil.
Reaction SMILES: [C:1]1([C:13](=O)[C:14]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22](C(OC(C)(C)C)=O)[CH:21]=2)(C)[C:15](OC)=[O:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[NH2:37][NH2:38].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(=O)C>[C:1]1([C:13]2[NH:38][NH:37][C:15](=[O:16])[C:14]=2[C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: COC(=O)C(C)(C(=O)c1cn2c3c(cccc13)CCC2)c1cn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: NN
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(-c2cn3c4c(cccc24)CCC3)c1-c1c[nH]c2ccccc12
Yield: 17 %

Procedure:
To a solution of tert-butyl 3-(1-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-methoxy-2-methyl-1,3-dioxopropan-2-yl)-1H-indole-1-carboxylate (6) (0.26 g, 0.52 mmol) in glacial acetic acid (2 mL) was added hydrazine (35% in H2O, 0.25 mL) followed by a catalytic amount of camphor sulfonic acid (10 mg). The reaction mixture was then microwaved at 210° C. for 10 hours. The solvent was then removed under reduced pressure and the residue partitioned between dichloromethane (10 mL) and aqueous Na2CO3 (20 mL). The organic layer was separated, dried using Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase (HPLC, C-18) chromatography using trifluoroacetic acid as a modifier to give the desired product (7) (0.033 g, 17% yield) as a white solid. 400 MHz 1H NMR (CDCl3) δ: 11.44 (s, 1H), 11.18 (s, 1H), 7.91 (d, J=4.2 Hz, 1h), 7.6 (d, J=1.4 Hz, 1H), 7.37-7.28 (m, 2H), 7.15-7.1 (m, 1H), 7.08-6.96 (m, 2H), 6.95-6.88 (m, 1H), 6.82 (t, J=6.8 Hz, 1H), 4.08-3.88 (m, 2H), 2.9-2.78 (m, 2H), 2.08-1.96 (m, 2H), 1.82 (s, 3H); LCMS [M+H]: 369.
Reaction SMILES: [CH:1]([C:4]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:6]=[CH:7][N:8]=1)([CH3:3])[CH3:2].[Li]CCCC.[CH3:20][Sn:21](Cl)([CH3:23])[CH3:22]>C1COCC1.CCOC(C)=O>[CH:1]([C:4]1[N:5]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[C:6]([Sn:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: COCCOCn1ccnc1C(C)C
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCn1c([Sn](C)(C)C)cnc1C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.4 %

Procedure:
A −78° C. solution of 2-isopropyl-1-((2-methoxyethoxy)methyl)-1H-imidazole (1.50 g, 7.57 mmol) in THF (30 mL) was treated drop-wise with n-BuLi (2.5N, 4.24 mL, 10.59 mmol), stirred for 10 min, then warmed to 0° C. for 45 min. The solution was re-cooled to −78° C., treated drop-wise, with trimethyltin chloride (1.0 N, 7.19 mL, 7.19 mmol), over 5 min, warmed to RT and stirred overnight. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated to dryness to afford 2-isopropyl-1-((2-methoxyethoxy)methyl)-5-(trimethylstannyl)-1H-imidazole (2.45 g, 90%). MS (ESI) m/z: 363.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C@H:10]2[C@@H:16]3[CH2:17][CH2:18][C@@H:12]([C@@H:13]4[C@H:15]3[CH2:14]4)[C@H:11]2[C:19](OC)=[O:20])=[CH:4][CH:3]=1.[CH3:23][S:24]([NH:27][C:28]1[CH:43]=[CH:42][C:31]2[NH:32][C:33]([CH2:38][C:39](O)=[O:40])=[N:34][S:35](=[O:37])(=[O:36])[C:30]=2[CH:29]=1)(=[O:26])=[O:25].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:39](=[O:40])[C:38]([C:33]3[NH:32][C:31]4[CH:42]=[CH:43][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][C:30]=4[S:35](=[O:37])(=[O:36])[N:34]=3)=[C:19]([OH:20])[C@H:11]3[C@@H:10]2[C@@H:16]2[CH2:17][CH2:18][C@H:12]3[C@@H:13]3[C@H:15]2[CH2:14]3)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1[C@H]2CC[C@H]([C@@H]3C[C@@H]32)[C@@H]1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H]([C@@H]5C[C@@H]54)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Yield: 80 %

Procedure:
The crude rac-Methyl (1R,2R,4S,5S,6R,7S)-7-{[(4-fluorophenyl)methyl]amino}tricyclo[3.2.2.02,4]nonane-6-carboxylate was dissolved in anhydrous N,N-dimethylformamide (8 mL). (7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.22 g, 0.66 mmol) was added followed by N-methylmorpholine (0.15 mL, 1.39 mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.69 mmol) was added and the mixture was stirred at 25° C. for 4 h. Triethylamine (0.28 mL, 1.98 mmol) was added and the mixture was stirred at 50° C. for 16 h. Upon cooling to 25° C., the solution was diluted with ethyl acetate (50 mL) and washed with 1.0 M aqueous hydrochloric acid solution (2×50 mL), saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a golden oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 20% ethyl acetate in dichloromethane) afforded the desired product, rac-N-{3-[(1R,2S,7R,8S,9S,11R)-3-[(4-Fluorophenyl)methyl]-6-hydroxy-4-oxo-3-azatetracyclo[6.3.2.02,7.09,11]trideca-5-en-5-yl]-1,1-dioxo-4H-1λ6,2,4-benzothiadiazin-7-yl}methanesulfonamide (0.50 g, 0.86 mmol, 80% over three steps), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.33-1.34 (10H, m), 2.30 (1H, bs), 3.06 (3H, s), 3.81 (1H, d, J=11.2 Hz), 4.48 (1H, d, J=15.6 Hz), 4.98 (1H, d, J=14.8 Hz), 7.13-7.60 (7H, m), 10.19 (1H, s). LC-MS (ESI) calcd for C27H27FN4O6S2 586.65, found 587.3 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[CH:12][N:11]=2)=[CH:5][C:4]([C:23]2[CH:33]=[CH:32][CH:31]=[C:30]([N:34]3[CH2:46][CH2:45][N:37]4[C:38]5[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=5[CH:44]=[C:36]4[C:35]3=[O:47])[C:24]=2[CH2:25][O:26]C(=O)C)=[CH:3]1.O[Li].O.C1COCC1.C(O)(C)C>O>[OH:26][CH2:25][C:24]1[C:23]([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[CH:12][N:11]=3)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[CH:33][CH:32]=[CH:31][C:30]=1[N:34]1[CH2:46][CH2:45][N:37]2[C:38]3[CH2:39][CH2:40][CH2:41][CH2:42][C:43]=3[CH:44]=[C:36]2[C:35]1=[O:47]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3cc(-c4cccc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
A 100-mL, single-necked, round-bottomed flask equipped with a magnetic stirring bar was charged with 113b (105 mg, 0.17 mmol), LiOH.H2O (35 mg, 0.83 mmol), THF (2 mL), isopropanol (2 mL), and water (1 mL). After the reaction mixture was stirred at room temperature for 3 h, it was partitioned between dichloromethane (5 mL) and water (5 mL), and the organic phase was extracted with dichloromethane (5 mL×3). The combined organic phases were washed with water (5 mL×2) and brine (5 mL×1), dried (Na2SO4), and concentrated. The crude product was re-dissolved in dichloromethane (3 mL). To this solution was added hexane (10 mL) and the resulting precipitates were filtered to give 80% yield (79 mg) of 2-(2-hydroxymethyl-3-{1-methyl-5-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4,6,7,8,9-hexahydro-2H-pyrazino[1,2-a]indol-1-one 113; MS (ESI+) m/z 594.3 (M+H).
Reaction SMILES: [C:1]12([CH2:14][CH:13]3[CH:9]1[CH2:10][CH2:11][CH2:12]3)[CH2:3][CH:2]2[C:4]([O:6]CC)=[O:5].C1(C(OCC)=O)C2(CCCCC2)C1>>[C:1]12([CH2:14][CH:13]3[CH:9]1[CH2:10][CH2:11][CH2:12]3)[CH2:3][CH:2]2[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C1CC12CC1CCCC12
Agent: CCOC(=O)C1CC12CCCCC2
Product: O=C(O)C1CC12CC1CCCC12

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 58B for the product from Example 1A. MS (CI) m/z 67 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-:27].[Na+].Cl>FC(F)(F)C(O)=O.O>[OH:27][C:1]1([CH2:7][CH2:8][N:9]2[C:13](=[O:14])[CH2:12][S:11][CH:10]2[CH2:15][CH2:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2=CCCCC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Reaction time: 4 h

Procedure:
A solution of 4-{3-[3-[2-(1-Cyclohexenyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (3.7 g., 0.01 mole) in trifluoroacetic acid (20 ml.) is allowed to stand at 25° C. for 4 hours. Excess trifluoroacetic acid is then removed by evaporation at reduced pressure. The oily residue is dissolved in a solution of sodium hydroxide (2.0 g., 0.05 mole) in water (40 ml.). The basic solution is acidified with 2 N hydrochloric acid. The title compound precipitates as a solid. Recrystallization from acetonitrile-water yields the purified title compound, m.p. 147°-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([NH:7][CH3:8])=O.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[N-:30]=[N+:31]=[N-:32].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[N:7]([CH3:8])[N:32]=[N:31][N:30]=2)[CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1cc(Br)cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: Cn1nnnc1-c1cc(Br)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
To a solution of 3-bromo-N-methyl-5-nitro-benzamide (0.6 g) in DCM (15 ml) at −15° C. was added triflic anhydride (0.6 ml) and the reaction stirred for 30 min. Sodium azide (226 mg) was added and the reaction allowed to warm to room temperature and stirred further overnight. NaHCO3(aq) was added to neutralise the reaction and the mixture extracted into EtOAc. The organic layer was separated, dried and concentrated in vacuum and the residue purified by flash chromatography (9:1 to 2:8 cyclohexane:EtOAc) to give the title compound (290 mg). Rf=0.51 (3:2 cyclohexane:EtOAc).
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:33])([CH2:23][N:24]([CH3:32])[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:26])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[N+:34]([O-])=O)C1C=CC=CC=1>[H][H].[Pd]>[CH3:1][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:33])([CH2:23][N:24]([CH3:32])[C:25]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:26])[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[NH2:34]
Reactant: [H][H]
Reactant: COC(=O)CC(=O)N(C)CC(C)(C(=O)N1CCCC1)c1ccc(N(C)Cc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Product: CNc1ccc(C(C)(CN(C)C(=O)CC(=O)OC)C(=O)N2CCCC2)cc1N

Procedure:
Prepared analogously to Example 1d from 2-[4-(N-benzyl-methyl-amino)-3-nitro-phenyl]-2-methyl-3-(N-methoxycarbonylmethylcarbonyl-methylamino)-1-pyrrolidin-1-yl-propan-1-one and hydrogen/palladium on activated charcoal.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9](C(C)(C3C=CC=CC=3)C)[CH:10](O)[C:6]=2[C:5]([Cl:22])=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C.CCCCCC.C(OCC)(=O)C>[N+](C)([O-])=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[NH:9][CH2:10][C:6]=2[C:5]([Cl:22])=[CH:4][N:3]=1
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(Cl)ncc(Cl)c2C1O
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C1NCc2c(Cl)cnc(Cl)c21
Yield: 72 %

Procedure:
in a similar manner to Step 4 of Example 16, 4,7-dichloro-1-hydroxy-2-(1-methyl-1-phenylethyl)-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (38.8 mg, 0.115 mmol) was dissolved in nitromethane (1.6 mL), and the solution was treated with trifluoroacetic acid (0.177 mL, 2.30 mmol) and triethylsilane (55.1 mL, 0.345 mmol), followed by purification by slurry using chloroform/methanol and by preparative thin-layer chromatography (hexane/ethyl acetate=1/1) to obtain 4,7-dichloro-1,2-dihydropyrrolo[3,4-c]pyridine-3-one (16.8 mg, yield 72%).
Reaction SMILES: [CH3:1][C:2]([C@H:5]([NH2:8])[CH2:6][OH:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:8][C@H:5]([CH2:6][OH:7])[C:2]([CH3:4])([CH3:3])[CH3:1])(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a solution of S-tert-leucinol (0.20 g, 1.70 mmol), triethylamine (0.19 g, 1.87 mmol) and methylene chloride (10 mL) at 0° C., was added a solution of 4-chloro benzenesulfonyl chloride (0.36 g, 1.70 mmol) in CH2Cl2 (5 mL). After 15 minutes the ice bath was removed and the reaction allowed to reach 25° C. After 16 hours, the reaction was quenched by pouring into saturated sodium bicarbonate solution (20 mL) and additional-methylene chloride (15 mL). The organic phase was separated and washed sequentially with 1N HCl solution (20 mL), distilled water and brine, dried over MgSO4 and evaporated to give the desired product as a white solid, mp 128-130° C. (0.46 g, 94%). MS (+APCI) 292.06 ([M+H]+). Anal. Calc'd for C12H18ClNO3S: C, 49.39; H, 6.22; N, 4.80; Found: C, 49.40; H, 6.17; N, 4.79.
Reaction SMILES: [O:1]([CH2:8][CH:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)(=O)C>[O:1]([CH2:8][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C)COc2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(COc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
A suspension solution of methyl 4-(1-phenoxypropan-2-yl)benzoate (0.1 g, 0.4 mmol) and lithium hydroxide (48 mg, 2 mmol) in tetrahydrofuran (20 mL) and water (10 mL) was stirred at room temperature for 2 hours. The mixture solution was diluting with ethyl acetate (50 mL), and acidified with hydrochloric acid to PH<4. The organic layer was separated, dried over sodium sulfate, and concentrated to dry. The residue 4-(1-phenoxypropan-2-yl)benzoic acid (60 mg, 65%) was used directly for the next step without purification.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][NH:26]2)=[CH:22][CH:21]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][N:26]2[C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][CH:21]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Fc1ccc2c(c1)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2ccc(F)cc21
Yield: 67.1 %

Procedure:
The product is prepared according to the procedure described in example 5, but using 200 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, 210 mg of 6-fluoro-2,3-dihydro-1H-indole, and 194 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.12 ml of pyridine and 3 ml of N, N-dimethylformamide. 184 mg of 2-[2-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following: