Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-])=O)[C:21]=1[NH2:29])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[CH2:1]([N:8]([CH2:16][C@H:17]([OH:30])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[C:21]=1[NH2:29])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1c(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cccc(OC[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
(S)-[3-(N,N-Dibenzylamino)-2-hydroxypropoxy]-2-amino-3-nitrobenzene (10.6 g, 26.0 mmol) was suspended in 1 L of 2:1 ethanol/water at ambient temperature and treated with excesses of sodium bicarbonate (26.22 g, 0.31 mol) and sodium hydrosulfite (54.34 g, 0.31 mol). The orange reaction mixture slowly became colorless over 1 hour, and the mixture was left to stir at ambient temperature for 16 hours. The suspension was filtered, and the filtrate concentrated in vacuo to a leave a white solid. This residue was partitioned between chloroform and water, and the organic layer washed twice with brine. The combined organic extracts were concentrated in vacuo to give 8.8 g of a brown oil. The compound was recrystallized rapidly from toluene to give 7.96 g (81%) of pale brown needles. NMR.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][C:23]2=O>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][C:23]2=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCCc2c(F)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 60% sodium hydride (4.12 g) in toluene (200 ml) was added dropwise ethyl diethylphosphonoacetate (20.4 ml) under ice-cooling, and the mixture was stirred at room temperature for 45 min. Then, a solution of 5-fluoro-3,4-dihydro-2H-naphthalen-1-one (15.3 g) in toluene (50 ml) was added dropwise, and the mixture was stirred at 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give ethyl (5-fluoro-3,4-dihydro-2H-naphthalen-1-ylidene)acetate.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[N:28][C:27]([C:30]([CH3:32])=[CH2:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:19][CH2:20][N:21]([C:24]3[CH:29]=[N:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][N:25]=3)[CH2:22][CH2:23]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C=C(C)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
4-(4-Benzyl-phthalazin-1-yl)-5′-isopropenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (50 mg, 0.118 mmol) is dissolved in MeOH (2 mL). Palladium hydroxide (25 mg) is added to the flask capped with a septum and balloon of hydrogen. The reaction is stirred 3 h at room temperature. Filter through a small pad of silica gel and wash behind with EtOAc. Concentrate the filtrate in vacuo. The residue is purified by flash chromatography on silica gel (EtOAc/Heptane) to afford the title compound (17.6 mg, 35%).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:9]([CH3:17])=[C:10]([CH3:16])[CH2:11][CH2:12]OCC)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N>Br>[CH2:19]([N:18]1[CH2:12][CH2:11][C:10]([CH3:16])=[C:9]([CH3:17])[CH:8]1[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOCCC(C)=C(C)C(Cc1ccccc1)NCc1ccccc1
Agent: Br
Agent: N
Product: CC1=C(C)C(Cc2ccccc2)N(Cc2ccccc2)CC1
Yield: 23.2 %

Procedure:
10 ml of 48% hydrobromic acid is added to 1 g of 1-phenyl-2-(N-benzyl)amino-3,4-dimethyl-6-ethoxy-3-hexene obtained according to the procedure described in Example 13 and the mixture is refluxed for 5 minutes. After cooling, the mixture is neutralized with an aqueous ammonia and extracted with ethyl ether. The ether layer is washed with water and dried with sodium sulfate. The solvent is removed by distillation. The residue is dissolved in 10 ml of acetone. 1 g of sodium hydrogen carbonate is added to the solution and refluxed for 5 hours. Insoluble matters are removed by filtration. The solvent is distilled off. The residue is purified by a silica gel chromatography using chloroform, methanol and acetic acid (90:10:5). As the result, 0.2 g of 1,2-dibenzyl-3,4-dimethyl-1,2,5,6-tetrahydropyridine is obtained. The free amine is dissolved in acetone and oxalic acid is added to the solution to obtain the oxalate of 1,2-dibenzyl-3,4-dimethyl-1,2,5,6-tetrahydropyridine.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:32]([OH:34])[CH3:33])/[CH:3]=[CH:4]/[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14]/[C:15](/[CH3:31])=[CH:16]/[C:17]([O:19]CCCCCCCCC(O)=O)=[O:18])[O:8][CH2:7]1.[OH-:35].[Na+]>>[CH3:1][C@@H:2]([C@@H:32]([OH:34])[CH3:33])[C:3]1[O:35][C:4]=1[CH2:5][C@@H:6]1[C@@H:11]([OH:12])[C@@H:10]([OH:13])[C@H:9]([CH2:14]/[C:15](/[CH3:31])=[CH:16]/[C:17]([OH:19])=[O:18])[O:8][CH2:7]1
Reactant: [OH-]
Reactant: C/C(=C\C(=O)OCCCCCCCCC(=O)O)C[C@@H]1OC[C@H](C/C=C/[C@@H](C)[C@H](C)O)[C@@H](O)[C@H]1O
Agent: [Na+]
Product: C/C(=C\C(=O)O)C[C@@H]1OC[C@H](CC2=C([C@@H](C)[C@H](C)O)O2)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Pseudomonic acid C (80 mgs) was dissolved in 0.1 M sodium hydroxide (20 ml) and stirred overnight at room temperature. After evaporation to low volume the solution was adjusted to pH 2 (5 M HCl), saturated with sodium chloride and extracted with ethyl acetate. The combined extracts were dried (MgSO4) then evaporated to dryness and chromatographed on silica (2 g) eluting with gradient of 0 to 8% methanol/chloroform. Fractions containing pure product (by hplc and tlc) were combined to give monic acid C (40 mgs, 74%), νmax (KBr) 3400 (broad) 1692 (broad), 1644, 1238, 975 cm-1 ; λmax (EtOH) 218 nm (ε9679); δH (CD3OD) 0.97 (3H, d, J 8 Hz, CH3 -17), 1.08 (3H, d, J 7 Hz, CH3 -14), 2.13 (3H, s, CH3 -15), 5.4 (2H, m, H-10, H-11), 5.67 (1H, s, H-2); δC (CD3OD) 170.2 (C1), 159.0 (C3), 135.8, 129.7 (C10, C11), 118.6 (C2), 76.2 (C5), 72.5 (C7), 71.6 (C13), 70.0 (C6), 65.8 (C16), 45.3 (C12), 44.1 (C4), 43.7 (C8), 33.7 (C9), 20.4 (C14), 19.3 (C15), 16.7 (C17). (Found: 284.1624. C16H28O6M.+ -C2H4O requires 284.1623).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:35][C:34](=[O:36])[CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:35][C:34](=[O:36])[CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:29])[F:30])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: O=C1CNC1
Product: O=C1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)C1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-oxo-azetidin-1-yl)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and azetidin-3-one following General Procedure C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[CH:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Oc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1cccc(Br)c1)OCC
Yield: 95.2 %

Procedure:
To a solution of 3-bromophenol (1.68 g, 9.77 mmol) in N,N′-dimethylformamide (32 mL), sodium hydride (purity 50%) (516 mg, 10.7 mmol) was added under ice-cold conditions, and bromoacetaldehyde diethylacetal (1.76 mL, 11.7 mmol) was added at 0° C., and the resultant mixture was stirred at 120° C. overnight. The reaction solution was added with water at room temperature and extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, concentrated in vacuo, and purified using silica-gel column chromatography (hexane). 1-Bromo-3-(2,2-diethoxyethoxy)benzene (2.69 g. yield >100%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([Br:9])[C:3]=1[O:10][CH3:11].[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:12]([O-:14])=[O:13])=[C:4]([Br:9])[C:3]=1[O:10][CH3:11]
Reactant: O=[N+]([O-])O
Reactant: COc1c(Br)cc(F)cc1Br
Agent: O=S(=O)(O)O
Product: COc1c(Br)cc(F)c([N+](=O)[O-])c1Br
Temperature: 4 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a stirred solution of c.H2SO4 (740 mL) at 0 to 5° C. was added 1,3-dibromo-5-fluoro-2-methoxybenzene (223.3 g, 0.786 mol). A solution of fuming nitric acid (90%, 38 mL, 0.815 mol) in c.H2SO4 (740 mL) was added dropwise, maintaining the temperature between 0 and 5° C. The reaction mixture was stirred at 3 to 5° C. for 2 hours, quenched into ice (2.2 kg) and extracted with dichloromethane (3×2 L). The combined dichloromethane extracts were washed with saturated aqueous NaHCO3 solution (2×2 L), dried over Na2SO4, filtered and the filter cake washed with DCM (3×400 mL). The filtrate was concentrated in vacuo at 40° C. to give 1,3-Dibromo-5-fluoro-2-methoxy-4-nitrobenzene as a pale orange crystalline solid (244.9 g, 95%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(C#N)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (1.0 g-see Preparation 3), 4-cyanophenethyl bromide (0.82 g), anhydrous potassium carbonate (2.0 g) and acetonitrile (30 ml) was heated under reflux for 10 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was further purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as an oil, yield 0.22 g.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[C:6]=2[C:5](=[O:18])[NH:4][C:3]1=[O:19].[OH-].[Na+].[CH3:22][CH2:23][CH2:24]Br.S(=O)(=O)(O)O>O.CO>[CH2:22]([N:4]1[C:5](=[O:18])[C:6]2[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[CH3:16])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:19])[CH2:23][CH3:24]
Reactant: CCCBr
Reactant: CC(=O)CCCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c2c(ncn2CCCCC(C)=O)n(C)c1=O
Yield: 85 %

Procedure:
A suspension of 79.2 g of 3-methyl-7-(5-oxohexyl)-xanthine in a mixture of 120 g of water and 72 g of methanol is brought into solution by the addition of 18 g of sodium hydroxide at about 60° C. 55.5 g of n-propyl bromide are then added. After boiling under reflux for 24 hours, the reaction mixture is treated with 1 ml of concentrated sulphuric acid and cooled. Unreacted 3-methyl-7-(5-oxohexyl)-xanthine is filtered off and the alcohol is distilled off in vacuo. The remaining solution is made alkaline with 4 ml of 50% sodium hydroxide solution and extracted with 350 ml of methylene chloride. 1-n-Propyl-3-methyl-7-(5-oxohexyl)-xanthine with a melting point of 76°-78° C. is obtained in 85% yield from the residue of the methylene chloride solution by recrystallisation from isopropanol. The solubility of the product in ethanol, dimethyl sulphoxide and dimethylformamide is over 10%.
Reaction SMILES: C(OC1CCN([C:11]2[CH:16]=[CH:15][C:14]([B:17]3[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]3)=[CH:13][CH:12]=2)CC1)(=O)C.BrC1C=CC([C:33]2([F:40])[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)=CC=1>CCOC(C)=O.O>[F:40][C:33]1([C:11]2[CH:12]=[CH:13][C:14]([B:17]3[O:18][C:19]([CH3:24])([CH3:25])[C:20]([CH3:22])([CH3:23])[O:21]3)=[CH:15][CH:16]=2)[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1
Reactant: CN1CCC(F)(c2ccc(Br)cc2)CC1
Reactant: CC(=O)OC1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCC(F)(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
The title compound was synthesized according to the method described for the synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-yl acetate, except substituting 4-(4-bromophenyl)-4-fluoro-1-methylpiperidine (133 mg, 0.49 mmol). The reaction was then allowed to cool to room temperature and was diluted with EtOAc and water was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4 and concentrated to give the title compound as a brown solid (281 mg, used without further purification). 1H NMR (400 MHz, MeOD) δ 7.76 (d, J=7.7 Hz, 2H), 7.41 (d, J=7.8 Hz, 2H), 2.94-2.91 (m, 2H), 2.59 (t, J=12.0 Hz, 2H), 2.45 (s, 3H), 2.30-2.22 (m, 1H), 2.20-2.12 (m, 1H), 2.01-1.95 (m, 2H); 19F NMR (400 MHz, MeOD) δ −162.38; MS ESI 320.1 [M+H]+, calcd for [C18H27BFNO2+H]+ 320.21.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12](O)=[O:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1.S(Cl)(Cl)=O.[NH3:29]>C1(C)C=CC=CC=1>[F:1][C:2]([F:23])([F:24])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([NH2:29])=[O:13])[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:6]2=[N:7][CH:8]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1
Reactant: N
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc2cc(C(F)(F)F)cnc2n1Cc1cccc(F)c1

Procedure:
To a suspension, stirred at 20° C., of 1.5 g (4.43 mmol) of 5-trifluoromethyl-1-[(3-fluoro-phenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (WO 2008/093024) in 40 mL of dry toluene are added 3.2 mL (44.34 mmol) of thionyl chloride. The reaction mixture is stirred at reflux for 2 hours and then concentrated under reduced pressure. The resulting product is taken up in 20 mL of dichloromethane and this solution is poured dropwise into a solution of 5.81 mL (44.34 mmol) of 30% aqueous ammonia. The reaction mixture is stirred for 14 hours at 20° C. After this time, a solid is collected by filtration, and is triturated in 50 mL of diisopropyl ether. After filtering off and drying under reduced pressure, 1.5 g of the expected product are collected.
Reaction SMILES: C([CH:5]1[C:9]([C:10]2[C:18]3[O:17][C:16]([CH:19]4[CH2:21][CH2:20]4)=[N:15][C:14]=3[C:13]([C:22]#[N:23])=[C:12]([CH3:24])[C:11]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:8][CH2:7][N:6]1C(N)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:19]1([C:16]2[O:17][C:18]3[C:14](=[C:13]([C:22]#[N:23])[C:12]([CH3:24])=[C:11]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:10]=3[C:9]3[CH2:5][NH:6][CH2:7][CH:8]=3)[N:15]=2)[CH2:21][CH2:20]1
Reactant: Cc1c(-c2ccccc2)c(C2=CCN(C(N)=O)C2C(C)(C)C)c2oc(C3CC3)nc2c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(C2=CCNC2)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
tert-Butyl 3-(4-cyano-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazol-7-yl)-2,5-dihydro-1H-pyrrole-1-carboxamide (I-327) (52.0 mg, 0.118 mmol) was dissolved in dichloromethane (4 ml), and with cooling with ice, trifluoroacetic acid (2 ml) was added, followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, dissolved in chloroform, washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the residue obtained by concentration under reduced pressure was purified by preparative TLC (eluent, chloroform:methanol=10:1, v/v) and purified in slurry with isopropyl ether to obtain the entitled compound (26.0 mg, 62%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[NH:10][NH2:11].[C:12](N)(=[O:15])[CH:13]=[CH2:14].[Na]>C(O)C.C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[N:10]1[CH2:14][CH2:13][C:12](=[O:15])[NH:11]1
Reactant: C=CC(N)=O
Reactant: NNc1cc(Cl)ccc1Cl
Agent: Cl
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CCN(c2cc(Cl)ccc2Cl)N1

Procedure:
2,5-Dichlorophenylhydrazine hydrochloride (240 g, 1.1 mol) and acrylamide (100 g, 1.4 mol) is refluxed in a solution of sodium (56 g, 2.4 mol) in ethanol (1000 ml) and toluene (1000 ml) for 3 hours. Evaporation of the solvents, acidification with acetic acid dilution with water, filtration and drying (high vacuum, +100° C.) gives the 1-(2,5-dichlorophenyl)-3-pyrazolidone.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8]([C:10]2([CH2:23][CH2:24][CH2:25][CH2:26][N:43]3[CH2:44][CH2:45][N:40]([C:32]4[N:31]([CH3:30])[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[N:33]=4)[CH2:41][CH2:42]3)[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1c(N2CCNCC2)nc2ccccc21
Reactant: O=C(NCc1ccc(F)cc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: Cn1c(N2CCN(CCCCC3(C(=O)NCc4ccc(F)cc4)c4ccccc4-c4ccccc43)CC2)nc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-fluoro-benzylamide and 1-methyl-2-piperazin-1-yl-1H-benzimidazole.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[S:10].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH:24][OH:25]>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:24]1[C:9](=[S:10])[C:8]([CH3:15])([CH3:7])[C:12](=[O:13])[O:25]1
Reactant: ONCc1ccccc1Cl
Reactant: CC(C)(C(=O)Cl)C(=S)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C(=O)ON(Cc2ccccc2Cl)C1=S
Temperature: -40 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
A stirred solution of 9.5 grams (0.12 mole) of pyridine in 170 ml of methylene chloride under an argon atmosphere was cooled to -10° C. and a solution of 11.1 grams (0.06 mole) of dimethylthiomalonyl chloride in 30 ml of methylene chloride was added slowly. The reaction mixture was cooled to -40° C. and 9.5 grams (0.06 mole) of N-(2-chlorophenylmethyl)hydroxylamine was added in one portion. The addition caused the reaction mixture temperature to quickly rise to -20° C. The reaction mixture was stirred at -20° C. for one hour, then was diluted with 150 ml of methylene chloride. The solution was washed with 100 ml of water, two portions of 75 ml each of aqueous 2 N hydrochloric acid, and finally, 50 ml of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by column chromatography using 450 grams of silica gel. Elution was accomplished with chloroform. Early fractions from the chromatography yielded 5.3 grams of 2-[(2-chlorophenyl)methyl]-4,4-dimethylisoxazolidine-5-one-3-thione; mp 51°-53° C. Later fractions were combined to give 2.2 grams of 2-[(2-chlorophenyl)methyl]-4,4-dimethylisoxazolidine-3-one-5-thione as an oil. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[S-:12][C:13]#[N:14].[Na+].O>C(O)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][S:12][C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: N#C[S-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccc(F)cc1

Procedure:
10 g (46 mmol) of 2-bromo-1-(4-fluorophenyl)ethanone and 3.74 g (46 mmol) of sodium thiocyanate were stirred in 80 ml ethanol at 50° C. for 2 h. After addition of water the separated solid was isolated by filtration, washed and dried. Yield: 8.96 g.
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH2:27]([O:37][C:38]([NH:40][C:41]1[CH:46]=[CH:45][N:44]([CH2:47][C:48](O)=[O:49])[C:43](=[O:51])[N:42]=1)=[O:39])[C:28]1[CH:36]=[CH:35][C:34]2[O:33][CH2:32][O:31][C:30]=2[CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:48](=[O:49])[CH2:47][N:44]2[CH:45]=[CH:46][C:41]([NH:40][C:38]([O:37][CH2:27][C:28]3[CH:36]=[CH:35][C:34]4[O:33][CH2:32][O:31][C:30]=4[CH:29]=3)=[O:39])=[N:42][C:43]2=[O:51])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1ccc(NC(=O)OCc2ccc3c(c2)OCO3)nc1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccn(CC(=O)N2CCN(S(=O)(=O)c3nc4ccccc4s3)C(=O)C2)c(=O)n1)OCc1ccc2c(c1)OCO2

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [4-N-(piperonyloxycarbonyl)-cytosin-1-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 10.76 (brs, 1H), 8.36 (m, 1H), 8.28 (m, 1H), 7.92 (d, 0.6H), 7.86 (d, 0.4H), 7.73 (m, 2H), 7.03 (t, 1H), 7.00 (s, 1H), 6.92 (s, 2H), 6.03 (s, 2H), 5.08 (s, 2H), 4.84 (s, 1.2H), 4.74 (s, 0.8H), 4.47 (s, 0.8H), 4.30 (s, 1.2H), 4.24 (t, 1.2H), 4.08 (t, 0.8H), 4.01 (t, 1.2H), 3.89 (t, 0.8H).