Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].Br[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[O:29][CH3:30].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+].Cl>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])([CH3:10])[CH3:11])=[CH:4][C:3]=1[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15]
Reactant: CC(C)C(=O)c1ccc(F)c(NC(=O)OC(C)(C)C)c1
Reactant: COc1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)C(=O)c1ccc(F)c(NC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A mixture of 1-[4-fluoro-3-(tert-butoxycarbonyl -amino)phenyl]-2-methyl-1-propanone (0.11 g), 2-bromo-4-fluoroanisole (0.057 mL), palladium(II) acetate (4.5 mg), tri(tert-butyl)phosphine tetrafluoroborate (5.8 mg) and sodium tert-butoxide (96 mg) in tetrahydrofuran (1 mL) was stirred at 70° C. under an argon atmosphere for 3 days. To the reaction mixture was added water, and the mixture was stirred for 10 minutes. The mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 1-[4-fluoro-3-(tert-butoxycarbonylamino)phenyl]-2-(5-fluoro -2-methoxyphenyl)-2-methyl-1-propanone (45 mg). This material was dissolved in hydrochloric acid (4 mol/L ethyl acetate solution, 3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: n-hexane/ethyl acetate=4/1 -3/1) to give the title compound (25 mg).
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=1.C([Sn]([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(CCCC)CCCC)CCC>O1CCOCC1.C(OCC)(=O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][CH2:22][CH3:23])[CH:18]=3)[CH:13]([C:24]3[CH:29]=[CH:28][C:27]4[O:30][CH2:31][O:32][C:26]=4[CH:25]=3)[CH:12]2[C:33]([O:35][CH3:36])=[O:34])=[C:7]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1-c1ccccc1)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a slurry of anhydrous LiCl (46 mg, 1.1 mmol) and tetakis(triphenylphosphine)-palladium(0)(24 mg, 0.02 mmol) in dry dioxane (3 mL) was added a solution of Methyl (1RS,2RS,3RS)-3-(4-Methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (95 mg, 0.16 mmol) and tri(but-1-yl)stannylbenzene (319 mg, 0.87 mmol) in dioxane (1 mL). The mixture was refluxed under Argon for 17 h, cooled to room temperature, diluted with ethyl acetate (5 ml) and the resulting solution washed sequentially with brine and water. The organic layer was dried (MgSO4 anhydrous), filtered through a short pad of silica gel and concentrated in vacuo to yield an oil. The product was purified by flash column chromatography (silica gel, gradient elution from hexanes to 10% ethyl acetate/hexanes) to afford the title compound as a white solid. (92 mg, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CCO.C(Cl)Cl.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Reaction time: 16 h

Procedure:
Degoussa-type catalyst (50% Pd/C, 45 mg) was added to a solution of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester CXVI (0.40 g, 1.2 mmol) in EtOH/DCM (6/1, 40 ml). The resulting mixture was hydrogenated in a Parr apparatus at 50 psi of H2 for 16 hours, filtered through celite, and the filter cake was washed with EtOH and DCM. The filtrate was concentrated, affording 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester CXVII.
Reaction SMILES: [F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=[O:26])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH3:27]I.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[C:14]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[N:17]([CH3:27])[C:16]2=[O:26])=[CH:13][C:5]2[N:6]([CH2:10][C:11]#[CH:12])[C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: C#CCn1c(=O)oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCn1c(=O)oc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc21
Yield: 22.2 %

Procedure:
To a solution of 1-[6-fluoro-3-propargyl-2(3H)benzoxazolon-5-yl]-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (2.0 g) in dimethylformamide (10 g), methyl iodide (0.5 g) and sodium hydride (0.4 g) were added, and the resultant mixture was heated at 40° to 50° C. for 3 hours. After completion of the reaction, the reaction mixture was poured into water, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography to give 1-[6-fluoro-3-propargyl-2(3H) -benzoxazolon-5-yl]-3-methyl -4-trifluoromethyl-1,2,3,6-tetrahydropyrimidine-2,6-dione (0.3 g ).
Reaction SMILES: [N:1]1[NH:2][CH:3]=[C:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]=12.[H-].[Na+].I[CH2:19][C:20]([NH2:22])=[O:21]>C(#N)C>[NH2:22][C:20](=[O:21])[CH2:19][N:2]1[CH:3]=[C:4]2[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][C:5]2=[N:1]1
Reactant: NC(=O)CI
Reactant: CC(C)(C)OC(=O)N1Cc2c[nH]nc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1Cc2cn(CC(N)=O)nc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2 L three neck flask fitted with a thermometer, a mechanical stirrer and an addition funnel was charged with a suspension of tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (18.01 g, 86.5 mmol) in anhydrous acetonitrile (1.0 L). Sodium hydride (60% dispersion in oil, 4.15 g, 104 mmol) was added to the suspension in one portion under nitrogen. The reaction was stirred at room temperature for 2 h. The resulting white suspension was then cooled in an ice bath and iodoacetamide (31.95 g, 173 mmol) was added. The ice bath was then removed and the mixture was stirred 18 h at room temperature. The mixture was quenched with water (50 mL) and the solvent was removed under reduced pressure. The residue was partitioned between diluted NaCl (50 mL brine and 100 mL water) and 1.0 L EtOAc. The aqueous layer was extracted with 2×1.0 EtOAc. The organic layers were combined and dried over Na2SO4 and solvent was evaporated under reduced pressure. Crude material was purified on silica gel eluting with 20-50% EtOAc/CH2Cl2 to wash out excess iodoacetamide, and then with 2-10% MeOH/CH2Cl2 to afford a mixture of the two products which were separated on a chiral AD column by eluting with 30% MeOH/CO2 to afford the title compound (less mobile fraction). LC-MS=267.32 [M+1].
Reaction SMILES: Br[C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[C:4]([N+]([O-])=O)[CH:3]=1.S(Cl)(Cl)=O.[CH3:19][NH:20][CH3:21].C1COCC1.S(=O)(=O)(O)O>O.C(#N)C>[OH:11][C:5]1[CH:4]=[CH:3][CH:2]=[CH:10][C:6]=1[C:7]([N:20]([CH3:21])[CH3:19])=[O:8]
Reactant: CNC
Reactant: O=C(O)c1cc(Br)cc([N+](=O)[O-])c1O
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccccc1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a three neck flask was charged (50.0 g, 190.8 mmol) of 5-bromo-3-nitro-salicylic acid (Davos, 464 Hudson Terrace, Englewood, N.J. 07362), 200 ml of acetonitrile and 14 ml (191.9 mmol) of thionyl chloride. The resulting mixture was heated at 70° C. for 2 hours. The mixture was then cooled to 5-10° C. and a solution of dimethylamine in THF (2M, 210 ml, 2.2 eq.) was added slowly over one hour. The reaction mixture was then warmed to ambient temperature and stirred for another 3 hours. The mixture was mixed with 100 ml of water and acidified with sulfuric acid (2N, 45 ml) to a pH of 2. Additional 800 ml of water was added slowly over one hour while solids product precipitated out from the mixture. The suspension was cooled to 5° C. The solids were filtered and washed with water (200 ml). The wet crude product was recrystallized from 400 ml of hot ethanol to give 44.2 g (80%) of the compound of formula IV(a). Melting point: 181° C.-183° C. 1H NMR (400 MHz, DMSO): δ (ppm) 10.94 (s, 1H), 8.16 (d, 1H, J=2.5 Hz), 7.76 (d, 1H, J=2.5 Hz), 2.9 (br, 6H). 13C NMR (100.62 MHz, DMSO): 164.7, 147.5, 137.6, 135.9, 131.5, 127.4, 110.0, 37.6, 34.3. Anal. calcd. for C9H9BrN2O4 (289.08): C, 37.39; H, 3.14; N, 9.69. Found: C, 37.42; H, 2.90; N, 9.55.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](O)([CH3:10])[CH3:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([O:16][CH3:17])[CH:3]=1.O=S(Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([CH3:10])=[CH2:9])=[CH:6][C:5]([NH:12][C:13](=[O:15])[CH3:14])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(Cl)c(C(C)(C)O)cc1NC(C)=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C=C(C)c1cc(NC(C)=O)c(OC)cc1Cl
Temperature: 25 °C
Yield: 63.9 %

Procedure:
To a solution of N-(4-chloro-5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)acetamide (3.2 g, 12.4 mmol) in DCM (20 mL) at −5° C., SOCl2 (3.7 g, 37.25 mmol) was added dropwise. The mixture was warmed to RT, and then stirred at reflux for 2 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether=3:1) to afford the desired product (1.9 g, 64% yield).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:18])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([C:26]#[N:27])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:19][C:20]3[N:25]=[CH:24][N:23]=[C:22]([C:26]#[N:27])[CH:21]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: N#Cc1cc(N)ncn1
Reactant: Clc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cc(Nc2nccc3nc(-c4c(Cl)cccc4Cl)sc23)ncn1
Temperature: 25 °C
Yield: 30.9 %

Procedure:
To a microwave tube was added 4-bromo-2-(2,6-dichlorophenyl)thiazolo[5,4-c]pyridine (60 mg, 0.17 mmol), 6-aminopyrimidine-4-carbonitrile (0.029 g, 0.22 mmol), Pd2(dba)3 (0.013 g, 0.017 mmol), XantPhos (0.017 g, 0.034 mmol) and Cs2CO3 (0.11 g, 0.34 mmol) in dioxane (3.0 mL). The mixture was degassed with N2 for 10 minutes and then irradiated in a microwave reactor at 160° C. for 2 hours. After cooling to room temperature the solid was removed via filtration. The filtrate was concentrated under reduced pressure and the residue was purified with reverse phase column chromatography, eluting with a 0-60% gradient of CH3CN in 0.5% NH4HCO3 to give the desired product as a white solid (21 mg, 35% yield). 1H NMR (500 MHz, DMSO-d6): δ 11.43 (s, 1H), 8.91 (s, 1H), 8.54 (d, J=5.0 Hz, 1H), 8.31 (s, 1H), 8.00 (d, J=5.0 Hz, 1H), 7.76-7.67 (m, 3H). LCMS (Method B): RT=6.30 min, m/z: 399.0 [M+H+].
Reaction SMILES: [CH2:1]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1F)=[O:6])[CH:2]([CH3:4])[CH3:3].[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:6])[CH:2]([CH3:4])[CH3:3]
Reactant: C1CCNCC1
Reactant: CC(C)CC(=O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1ccccc1N1CCCCC1
Temperature: 120 °C
Yield: 95 %

Procedure:
A mixture of isobutyl-(2-fluoro-phenyl)-ketone 13 (0.928 gm, 5 mmole), piperidine (0.645 gm, 7.82 mole) and potassium carbonate (1.08 gm, 7.82 mmole) in 4 ml of DMF was heated for 4 hrs at 120° C. After completion of the reaction (monitored by TLC), the reaction mixture was cooled and water (30 ml) was added to the reaction mixture and then extracted with ethyl acetate (1×15 ml, 2×7 ml). The combined organic layers were washed with a saturated ammonium chloride solution (2×15 ml) and subsequently dried over sodium sulphate. The solvent was removed under reduced pressure to obtain isobutyl-(2-piperidino-phenyl)-ketone 10 in 95% yield (GC showed 90% Purity). 1HNMR CDCl3, (spectrum 13): 0.92(d, 6H), 1.60(m, 6H), 2.07(m, 1H), 2.95(m, 6H), 7.05(m, 2H). 7.35(m, 2H). IR (spectrum 14) (Neat): 2841, 1657(C═O), 1570, 1435, 1345, 738
Reaction SMILES: [F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([CH2:16][CH:17]=O)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH:28]([NH2:31])([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[C:3]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])=[C:4]([C:9]([N:11]2[CH2:12][C:13]([CH2:16][CH2:17][NH:31][CH:28]([CH3:30])[CH3:29])([OH:15])[CH2:14]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)N
Reactant: O=CCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)NCCC1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 3 h
Yield: 51.7 %

Procedure:
To a solution of [1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]acetaldehyde (38.0 mg, 0.078 mmol) in 1,2-dichloroethane (1 mL) was added isopropylamine (27 μL, 0.31 mmol) followed by sodium triacetoxyborohydride (26 mg, 0.12 mmol). The mixture was stirred for 3 h before quenching with 1 drop of concentrated HCl. The quenched mixture was concentrated to dryness, and then purified by preparative HPLC to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{2-[(1-methylethyl)amino]ethyl}azetidin-3-ol (21.5 mg) as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO): δ 8.54 (s, 1H), 7.57 (dd, 1H), 7.38 (dd, 1H), 7.31 (m, 1H), 7.17 (m, 1H), 6.67 (m, 1H), 4.02 (m, 1H), 3.89 (m, 2H), 3.71 (m, 1H), 2.70 (m, 1H), 2.63 (m, 2H), 1.86 (s, 3H), 1.75 (m, 2H), 0.97 (d, 6H); MS (EI) for C21H23F3IN3O2: 534 (MH+).
Reaction SMILES: [NH:1]([C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[NH2:2].[OH2:12]>C(O)(=O)C>[S:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:3]1[N:1]1[C:8](=[O:12])[CH2:6][C:5]([CH3:11])=[N:2]1
Reactant: O
Reactant: NNc1nc2ccccc2s1
Solvent: CC(=O)O
Product: CC1=NN(c2nc3ccccc3s2)C(=O)C1

Procedure:
2 g (12.1 mmol) of 2-hydrazino-1,3-benzothiazole and 1.58 g (12.1 mmol) of acetoacetic ester are stirred in 40 ml of glacial acetic acid for 2 hours at 90° C. The mixture is then diluted with water and the precipitated crystals are filtered off with suction, washed again with water and dried under reduced pressure.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=O.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][NH2:16]>CO>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15]/[N:16]=[CH:2]/[C:1]([O:5][CH3:6])=[O:4]
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C=O
Agent: Cl
Solvent: CO
Product: COC(=O)/C=N/Nc1ccccc1Cl

Procedure:
To a solution of methyl glyoxylate (6.8 g, 77 mmol) in methanol (150 mL) was added 2-chlorophenylhydrazine hydrochloride (12.5 g, 77 mmol) and the mixture was heated at reflux overnight, cooled and concentrated. The residue was re-dissolved in toluene and concentrated to give the title compound of Step A.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N+]([C:10]1[C:11]2[C:12]3[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][C:13]=3[CH:20]=[CH:21][C:22]=2[S:23]([NH2:26])(=[O:25])=[O:24])([O-])=O>CN(C=O)C>[S:23]1(=[O:24])(=[O:25])[C:22]2[CH:21]=[CH:20][C:13]3[CH2:14][NH:15][CH2:16][C:17]4[C:12]=3[C:11]=2[C:10](=[CH:19][CH:18]=4)[NH:26]1
Reactant: NS(=O)(=O)c1ccc2c3c(ccc([N+](=O)[O-])c13)CNC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1(=O)Nc2ccc3c4c(ccc1c24)CNC3
Temperature: 100 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (15 mmol) is added to a solution of 7-nitro-2,3-dihydro-1H-Benz[de]isoquinoline-6-sulfonic acid amide (3 mmol) in anhydrous DMF (30 mL). The resulting solution is stirred at 100° C. for 12 hours then partitioned between ethyl acetate and water. The organic layer is dried over magnesium sulfate and concentrated to afford the title compound. The crude product can be purified by recrystallization or chromatography.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:18]C(=O)OC(C)(C)C)[C@@H:9]([OH:17])[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[NH2:18][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@@H:9]([OH:17])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.4 %

Procedure:
0.41 g (1.16 mmol) of t-butyl [(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-(2-oxo-1-pyrrolidinyl)propyl]carbamate was dissolved in 5 ml of methylene chloride, treated at 0° with 1.5 ml of 90% trifluoroacetic acid and subsequently stirred at room temperature for 5 hours. Thereafter, the reaction mixture was slowly added dropwise to 2N sodium carbonate solution, subsequently treated with 3N sodium hydroxide solution and finally extracted with methylene chloride. The methylene chloride extracts were dried over potassium carbonate and evaporated under reduced pressure, whereby there were obtained 249 mg of 1-[(2S,3S)-3-amino4-cyclohexyl-2-hydroxybutyl]-2-pyrrolidinone as an oil, MS: 255 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9]O[C:6]=2[CH2:5][CH:4]([CH3:16])[CH2:3]1.C([O-])(=O)C.[NH4+:21]>CN(C=O)C>[O:1]=[C:2]1[CH2:3][CH:4]([CH3:16])[CH2:5][C:6]2[NH:21][CH:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7]1=2
Reactant: [NH4+]
Reactant: CCOC(=O)c1coc2c1C(=O)CC(C)C2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c[nH]c2c1C(=O)CC(C)C2
Temperature: 100 °C
Yield: 37.8 %

Procedure:
A stirred mixture of ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (15.7 g, 71 mmol) and ammonium acetate (9.54 g, 124 mmol) in N,N,-dimethylformamide (75 mL) was heated at 100° C. for 2 hour The reaction mixture was concentrated in vacuo, ice water was added, and the precipitate collected, rinsed with water then diethyl ether and dried to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (5.94 g). To this ester was added aqueous 5N sodium hydroxide (50 mL) and ethyl alcohol (10 mL) and the mixture heated at reflux for 40 minutes. The reaction mixture was cooled in an ice water bath, acidified with aqueous hydrochloric acid, and the precipitate collected, rinsed with water then diethyl ether and dried to give 4-oxo-6-methyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (5.2 g). m.p. 210-211° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27]([O:29]CC)=[O:28])[C:10]=2[C:32]([O:34]CC)=[O:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27]([OH:29])=[O:28])[C:10]=2[C:32]([OH:34])=[O:33])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1c(C(=O)OCC)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(C(=O)O)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Yield: 89.7 %

Procedure:
A mixture of diethyl 1,4-bis[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylate (4.78 g, 9.88 mmol), ethanol (75 ml), and 2N aqueous sodium hydroxide solution (75 ml) was refluxed for 2 hours. The reaction mixture was cooled and evaporated. This was acidified with HCl (2N) and the resulting cream solid was collected by filtration and washed with water. This was dried under vacuum to give the title compound (3.79 g, 8.86 mmol). LC/MS: Rt=3.15, [MH]− 427.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1.[C-:17]#[N:18].[Na+].[Cl-].[Na+]>>[C:17]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5]([CH3:16])[CH:4]=1)#[N:18]
Reactant: [C-]#N
Reactant: Cc1cc(CCl)ccc1Sc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: Cc1cc(CC#N)ccc1Sc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 1-chloromethyl-3-methyl-4-phenylthiobenzene obtained above is dissolved in N,N-dimemthylformamide (56 ml), and thereto is added finely divided sodium cyanide (18.16 g), and the mixture is stirred at room temperature overnight. To the reaction mixture are added saturated aqueous sodium chloride solution (300 ml) and ice water (300 ml), and the mixture is extracted with ethyl acetate (300 ml×3). The combined extracts are washed with saturated aqueous sodium chloride solution (200 ml×3), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-cyanomethyl-3-methyl-4phenylthiobenzene (45.95 g).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16](O)=O)=[CH:12][CH:11]=1>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:16]=1[CH2:15][O:14][C:13]1[CH:19]=[CH:20][C:10]([Cl:9])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Nc1ccccc1N
Agent: Cl
Product: Clc1ccc(OCc2nc3ccccc3[nH]2)cc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
A suspension of phenylene diamine (10.8 g, 0.1 mol) and 4-chlorophenoxyacetic acid (18.66 g, 0.1 mol) in 4M HCl (150 mL) was refluxed overnight under Ar. The reaction mixture was then cooled in an ice bath. The solid was collected and washed with H2O (150 mL). To the solid was added MeOH (100 mL), CH2Cl2 (400 mL) and 20% aqueous NaOH (300 mL). After stirring for 30 min, the organic phase was separated, filtered through phase separation filter paper, and concentrated in vacuo to give a solid. This solid was triturated with hexanes (150 mL), collected, washed with hexanes (100 mL), and dried to give 17.5 g (68%) of 52 as a pink solid. The HPLC analysis showed a purity of 100%. 1H NMR (60 MHz, d6-DMSO): δ 11.5 (br s, 1H), 6.9-7.5 (m, 8H), 5.3 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:15]([C:11]3[NH:10][CH:14]=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc[nH]1
Reactant: Nc1cc(Br)cnc1N
Product: Brc1cnc2[nH]c(-c3ccc[nH]3)nc2c1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine and pyrrole-2-carboxaldehyde.