Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH:18]([CH:20]1[O:24][C:23]([NH:25][CH3:26])=[N:22][C:21]1=[O:27])[CH3:19])=[CH:12][NH:13]2)C1C=CC=CC=1>C(O)C.O1CCCC1.[C].[Pd]>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([CH:18]([CH:20]1[O:24][C:23]([NH:25][CH3:26])=[N:22][C:21]1=[O:27])[CH3:19])=[CH:12][NH:13]2
Reactant: CNC1=NC(=O)C(C(C)c2c[nH]c3cccc(OCc4ccccc4)c23)O1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CNC1=NC(=O)C(C(C)c2c[nH]c3cccc(O)c23)O1
Reaction time: 24 h
Yield: 64.3 %

Procedure:
5-[1-(4-benzyloxyindol-3-yl)ethyl]-2-methylamino-2-oxazolin-4-one (149 mg) was dissolved in a mixture of ethanol and tetrahydrofuran (5:1.6 ml). 10% palladium-carbon (45 mg) was added and the whole was hydrogenated for 24 hours at room temperature under normal pressure. The catalyst was removed from the mixture by filtration and 10% palladium-carbon (45 mg) was added again. The whole was hydrogenated for additional 24 hours at room temperature under normal pressure. The reaction mixture was filtered to remove the catalyst. The filtrate was concentrated to give a residue, which was subjected to silica gel chromatography. Elution with hexane-acetone (1:1) provided the titled compound (72 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][OH:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:11][CH2:10][CH2:9][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCN(C)c1ccccc1

Procedure:
A 1 L flask was charged with 2-(N-methylanilino)ethanol (8) (151.3 g, 1 mole), methylene chloride (250 mL), and triethylamine (151 g, 1.48 mole). Acetic anhydride (153.35 g, 1.5 mole) was added to the solution at room temperature through an addition funnel. The product (7) was collected by vacuum distillation (122 g, bp 110° C. at 400 micron Hg).
Reaction SMILES: [CH:1]1([C:6]2[NH:7][C:8]3[CH2:9][C:10]([CH3:38])([CH3:37])[CH2:11][C:12](=[O:36])[C:13]=3[CH:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:15]=2[C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([C:6]2[C:15]([C:16](=[O:27])[C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=3)=[C:14]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([F:35])[CH:29]=3)[C:13]3[C:12](=[O:36])[CH2:11][C:10]([CH3:38])([CH3:37])[CH2:9][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC(C1CCCC1)=C(C(=O)c1ccc(C(F)(F)F)cc1)C2c1ccc(F)c(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2-c2ccc(F)c(F)c2)C1

Procedure:
0.9 g (1.7 mmol) of 2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-3-(4-trifluoromethylbenzoyl)-4,6,7,8-tetrahydro-1H-quinolin-5-one were oxidized at room temperature within one hour to give the pyridine, using 4.5 g of manganese dioxide (activated) in 25 ml of methylene chloride. The manganese dioxide was separated off and the methylene chloride was distilled off, and the mixture was then filtered off with suction using petroleum ether. This gave 0.8 g of crystals of melting, point: 210-212° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>O>[C:11]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)(=[O:13])[CH3:12]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 4 h

Procedure:
To 3-amino-5-t-butylisoxazole (2.80 g), acetic anhydride (6 ml) is added, and the resultant mixture is allowed to stand at room temperature for 4 hours. The reaction mixture is mixed with chilled water (50 ml), and the precipitated crystals are filtered. The crystals are washed with water and dried to give 3-acetylamino-5-t-butylisoxazole (3.39 g). This substance is recrystallized from hexane to give crystals melting at 120.5° to 121.0° C.
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([NH:11][C:12]([NH2:14])=[O:13])[CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:11]([CH:7]2[CH2:10][CH2:9][CH2:8]2)[C:12](=[O:13])[NH:14][C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)O
Reactant: NC(=O)NC1CCC1
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)[nH]c(=O)n1C1CCC1
Reaction time: 2 h

Procedure:
To a solution of 30 g (0.35 mol) cyanoacetic acid and 100 ml of acetic anhydride was added 36.1 g (0.32 mol) of cyclobutylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling, white crystals were filtered off and washed with ethanol. Yield 36.4 g (63%) (VII). This was suspended in 100 ml of hot water and 50 ml of 2N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes. After cooling, white crystals were filtered off. Yield 3.6 g (20%) (VIII) NMR.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)[C:9]=2[F:34])=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(OCC)(=O)C.CC(O)C>[ClH:1].[Cl:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:24][NH:25][CH3:26])[C:9]=2[F:34])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2cccc(OC)c2)c(-c2cccnc2Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.4 %

Procedure:
To a solution of tert-butyl ({5-(2-chloropyridin-3-yl)-4-fluoro-1-[(3-methoxyphenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (501 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 321 mg, 73%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][NH2:20])[CH3:16]>>[CH2:15]([N:17]([CH2:21][CH3:22])[CH2:18][CH2:19][NH:20][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)[CH3:16]
Reactant: CCN(CC)CCN
Reactant: Clc1ccc(Oc2ccccc2)cn1
Product: CCN(CC)CCNc1ccc(Oc2ccccc2)cn1

Procedure:
To a solution of 3.9 g 6-chloro-3-phenoxypyridine in 5 ml n-butnaol, is added 22 g β-diethylaminoethylamine and the solution is refluxed for 72 hours. The mixture is concentrated at reduced pressure. The residue is shaken with 500 ml dichloromethane and excess dilute sodium hydroxide. The organic phase is separated, dried and distilled; bp 115°-145° C./0.1 mm. The oil is chromatographed over 150 g basic alumina (Woelm, grade I) in toluene and eluted with 0.4% MeOH in toluene. The fractions containing pure product are combined, concentrated and distilled to give 6-(β-diethylaminoethylamino)-3-phenoxypyridine; bp 143°-145° C./0.1 mm.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CC(C)([O-])C.[K+].I[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([C:3]1[N:7]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Reactant: ICCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)n2CCCc2ccccc2)cc1
Yield: 9.4 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54 mmol) was alkylated according to the procedure of Example 40 using potassium tert-butoxide (1.08 mL of a 1 M solution, 1.08 mmol) and 1-Iodo-3-phenylpropane (0.093 mL, 0.60 mmol) to afford the title compound (0.020 g, 10%).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:20]([OH:22])[CH3:21]>C(C(C)=O)C>[N:1]1([C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[O:12][CH2:21][CH2:20][OH:22])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(O)Cl
Reactant: Oc1cccc(-n2ccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OCCOc1cccc(-n2ccnc2)c1
Yield: 49.9 %

Procedure:
A slurry of 16.0 g (0.10 mole) of 3-(imidazol-1-yl)phenol and 42 g (0.3 mole) of potassium carbonate in 100 ml of methyl ethyl ketone was heated to reflux with stirring. The mixture was treated with 25.5 g (0.3 mole) of chloroethanol by dropwise addition over a 2 hr period. The mixture was heated at reflux for an additional 18 hr then treated with an additional 16.1 g (0.2 mole) of chloroethanol and 27.6 (0.2 mol) of potassium carbonate. After an additional 22 hr heating at reflux all starting material was consumed. The reaction mixture was filtered and the filtrate was concentrated. The residue was partitioned between methylene chloride and 0.1N sodium hydroxide solution. The organic layer was concentrated and the residue was crystallized from ethyl acetate to give 10.2 g (50%) of the title compound as tan crystals, mp 81.0°-83.0° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1.[CH:18](O)=O>>[C:16]([C:14]1[CH:13]=[CH:12][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=3)[CH:18]=[N:1][C:2]=2[CH:15]=1)#[N:17]
Reactant: O=CO
Reactant: N#Cc1ccc(Nc2cccc(I)c2)c(N)c1
Product: N#Cc1ccc2c(c1)ncn2-c1cccc(I)c1
Temperature: 90 °C

Procedure:
A suspension of 2-amino-(N-(3-iodophenyl))4-cyanoaniline (1,8 g, 5.36 mmol) in formic acid (20 ml) is heated to 80-100° C. for 1.5 hours. The hot reaction mixture is filtered through a cotton pad into ice-water (100 ml). The precipitate is filtered off, washed with water and dried. This crude product is dissolved in dichloromethane and is brought to precipitation by addition of petroleum ether. The product is filtered off and dried. Yield: 1.38 g (75%) of the title compound. Mp. 177-179° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[N:26]=[C:27]=[O:28]>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:27](=[O:28])[NH:26][C:20]1[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18])[C:9]#[N:10]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: N#CCC(=O)c1ccc[nH]1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: N#CC(C(=O)Nc1ccc(Cl)cc1Cl)C(=O)c1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 2.1 g of 2-pyrroloylacetonitrile in 15 ml of glyme and 1.8 g of Et3N is treated with a solution of 3 g of 2,4-dichlorophenyl isocyanate in 15 ml of glyme similarly to the preceding examples. Mildly exothermic reaction results in formation of a thick suspension of crystals. After standing overnight, dilution with dry ether and filtration gives the triethylamine salt of β-oxo-α-(2,4-dichlorophenylcarbamoyl)-β-(2-pyrrolyl)-propionitrile, m.p. 180°-2° dec., in form of the enol structure as represented by formula Ia, wherein Py is 2-pyrrolyl, R is hydrogen and Ph is 2,4-dichlorophenyl.
Reaction SMILES: C(O)(=O)C.[O:5]([CH2:12][C:13]1[CH:14]=[C:15]([NH:19][N:20]=[C:21]([C:23]([NH2:25])=[O:24])[NH2:22])[CH:16]=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]=O>O>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH:29]1[N:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:14]=2)[N:20]=[C:21]([C:23]([NH2:25])=[O:24])[NH:22]1
Reactant: NC(=O)C(N)=NNc1cccc(COc2ccccc2)c1
Reactant: O=Cc1ccccc1F
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)C1=NN(c2cccc(COc3ccccc3)c2)C(c2ccccc2F)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
Into 15 ml of acetic acid saturated with nitrogen, 2.84 g (0.01 mol) of oxamide 3-(phenoxymethyl)phenylhydrazone was dissolved, and 1.36 g (0.011 mol) of 2-fluorobenzaldehyde was added to the thus formed solution under nitrogen atmosphere and the mixture was stirred for 16 hours at room temperature. After adding water saturated with nitrogen to the mixture, the precipitated crystals were collected by filtration and dried under vacuum. The thus dried crystals were recrystallized from a mixed solvent, saturated with nitrogen, of ethyl acetate and n-hexane to obtain 3.38 g of 5-(2-fluorophenyl)-4,5-dihydro-1-[3-(phenoxymethyl)phenyl]-1H-1,2,4-triazole-3-carboxamide melting at 176°-178° C. in a yield of 86.7%.
Reaction SMILES: C([N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[NH:9][C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]=[C:12]([CH3:22])[CH:11]=1)(=O)C.[ClH:23]>CO>[ClH:23].[CH2:15]([N:14]1[C:10]([NH:9][C:5]2[NH:6][CH2:7][CH2:8][N:4]=2)=[CH:11][C:12]([CH3:22])=[N:13]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)N1CCN=C1Nc1cc(C)nn1Cc1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2=NCCN2)n(Cc2ccccc2)n1

Procedure:
1-Acetyl-2-(1-benzyl-3-methyl-5-pyrazolyl)amino-2-imidazoline (12.5 g.) was treated with HCl in methanol as described in Example II to give 7.2 g. of product, mp 198°-199°, (as the HCl salt).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Cl:23][C:24]1[C:29]([O:9][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([Br:8])[CH:5]=2)=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:26][N:25]=1
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Reactant: Oc1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask charged with 3,5-dibromophenol (1.16 g, 4.61 mmol) and potassium carbonate (1.27 g, 9.22 mmol) was added N-methylpyrrolidinone (10 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (0.920 g, 4.61 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 30 minutes, the reaction mixture was allowed to cool to room temperature. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (3×50 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 120 gram column, eluting with 0-75% CH2Cl2 in hexanes to afford the title compound. 1H NMR (CDCl3) δ 8.53 (d, J=5.0 Hz, 1H), 7.62 (d, J=5.0 Hz, 1H), 7.44-7.42 (m, 1H), 6.92-6.88 (m, 2H). LRMS (M+1)=431.5.
Reaction SMILES: [C:1](O)(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:7][C:8]1[N:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([N:18]3[CH:22]([O:23][C:24]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[O:25])[C:21]4[S:32][CH2:33][CH2:34][S:35][C:20]=4[C:19]3=[O:36])=[N:15]2)=[CH:10][CH:9]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([O:23][CH:22]2[N:18]([C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[N:17][C:8]([Cl:7])=[CH:9][CH:10]=4)[N:15]=3)[C:19](=[O:36])[C:20]3[S:35][CH2:34][CH2:33][S:32][C:21]2=3)=[O:25])[CH2:31][CH2:30]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OC1C2=C(SCCS2)C(=O)N1c1ccc2ccc(Cl)nc2n1)N1CCNCC1
Reactant: CCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCC(=O)N1CCN(C(=O)OC2C3=C(SCCS3)C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Butyric acid (0.71 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-(piperazin-1-yl)carbonyloxy-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (2.50 g.) and N,N'-dicyclohexyl-carbodiimide (1.67 g.) in anhydrous methylene chloride (50 cc.) and the mixture is stirred for 1 hour at 20° C. After filtering off the dicyclohexylurea formed, washing with methylene chloride (15 cc.) and evaporating the solvent, the residue obtained (3.8 g.) is washed with boiling ethanol (35 cc.) and then recrystallised from a mixture of acetonitrile (110 cc.) and ethanol (11 cc.). 5-(4-Butyrylpiperazin-1-yl)carbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-dithiino[2,3-c]pyrrole (1.95 g.), which melts at 248° C., is thus obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:7][C:6]1=[O:22])[CH3:4].[CH2:23]([O:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Cl)[CH3:24]>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:7]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:5]([CH2:3][CH3:4])[C:6]1=[O:22])[CH3:24]
Reactant: CCOC(=O)CCCCCCCl
Reactant: CCn1c(-c2ccccc2)c(-c2ccccc2)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(CC)c1=O

Procedure:
The product is obtained as described in example 1 from 2.1 g of NaH (80% suspension in mineral oil), 18.5 g of 1-ethyl-4.5-diphenyl-4-imidazolin-2-one, 140 cc. of DMF, 13.5 g of 7-chloroenanthic acid ethyl ester and 2.1 g of NaJ.
Reaction SMILES: [F:1][C:2]1([CH2:8][OH:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=1[S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].Cl>O1CCCC1.ClCCl>[F:1][C:2]1([CH2:8][O:9][C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][C:14]=2[S:23]([C:26]([F:27])([F:29])[F:28])(=[O:25])=[O:24])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccc(F)c(S(=O)(=O)C(F)(F)F)c1
Reactant: OCC1(F)CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(OCC2(F)CCOCC2)c(S(=O)(=O)C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 37C (0.500 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.596 g). Additional tetrahydrofuran (25 mL) was added and the mixture stirred for 30 minutes, then 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.145 g) was added as a solution in tetrahydrofuran (5 mL). After stirring for 2 hours, the reaction mixture was partioned between 1N aqueous HCl (50 mL) and dichloromethane (200 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting solid was chromatographed over silica gel (Reveleris 80 g) eluting with a gradient of 0.5% to 7.5% methanol/dichloromethane over 30 minutes (flow=40 mL/min) to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19][C:20](=O)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.[CH3:28][C:29]([S@:32]([NH2:34])=O)([CH3:31])[CH3:30]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]([CH2:18][CH2:19]/[C:20](=[N:34]/[S:32][C:29]([CH3:31])([CH3:30])[CH3:28])/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: C[C@@H](c1ccc(Br)cc1)N(CCC(=O)c1ccccc1)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccc(Br)cc1)N(CC/C(=N/SC(C)(C)C)c1ccccc1)C(=O)OC(C)(C)C
Yield: 55.8 %

Procedure:
A mixture of (S)-tert-butyl 1-(4-bromophenyl)ethyl(3-oxo-3-phenylpropyl)carbamate (30 g, 0.069 mol), (R)-2-methylpropane-2-sulfinamide (8.42 g, 0.069 mol), and Ti(i-OPr)4 (31.4 g, 0.138 mol) in THF (300 mL) was heated to reflux overnight. The mixture was treated with brine, and the precipitate was filtered. The filtrate was concentrated to give (S,Z)-tert-butyl 1-(4-bromophenyl)ethyl(3-(tert-butylthioimino)-3-phenylpropyl)carbamate (20 g, 55%) which was used in the next step without further purification. 1H NMR (CDCl3): δ=1.23 (s, 9H), 1.32 (s, 9H), 1.46 (d, 3H), 1.70-1.86 (m, 2H), 3.24-3.75 (m, 2H), 4.08 (m, 1H), 7.09-7.91 (m, 9H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][CH:8]=1.Cl.Cl.[NH2:33][CH:34]1[CH2:37][NH:36][CH2:35]1.CN1CCCC1>C(O)C>[NH2:33][CH:34]1[CH2:37][N:36]([C:20]2[C:21]([Cl:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][CH:8]=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:35]1
Reactant: NC1CNC1
Reactant: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)n1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)n1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
To 190 mg of N,N-dimethylformamide were added 57 mg of 1-(6-amino-3-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 37 mg of 3-aminoazetidine dihydrochloride, and 100 mg of N-methyl-pyrrolidine, and the mixture was stirred at 90° C. for 30 minutes. After adding 0.2 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 40 mg of the title compound as a colorless powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27].N1C=CC=CC=1.[Cl:35][C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:36]([Cl:35])(=[O:38])[O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:28])[CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCOC(=O)Cl
Temperature: 0 °C
Yield: 42.9 %

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)—N-(3-Hydroxypropyl)docosa-4,7,10,13,16,19-hexaenamide (3.0 g, 7.8 mmol) was dissolved in 40 mL of CH2Cl2 and pyridine (650 mg, 8.2 mmol) was added. Triphosgene (7.8 mmol) was then added in portions at 0° C. over a period of 15 min. The resulting reaction mixture was stirred at 0° C. until the reaction was completed, as determined by TLC. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography to afford 1.5 g of 3-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propyl carbonochloridate. (43% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[N:8][CH:7]=[C:6]2[NH:14][CH:15]=[CH:16][C:5]=12.[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Br>>[F:17][C:18]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:14]1[C:6]2=[CH:7][N:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:4]([CH2:3][O:2][CH3:1])=[C:5]2[CH:16]=[CH:15]1
Reactant: COCc1c(C(=O)OC)ncc2[nH]ccc12
Reactant: Fc1ccc(CBr)c(F)c1
Product: COCc1c(C(=O)OC)ncc2c1ccn2Cc1ccc(F)cc1F

Procedure:
The title compound was prepared by alkylation of methyl 4-methoxymethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate [prepared according to X. Doisy et al., Bioorg. Med. Chem. 1999, 7, 921-932) with 2,4-difluorobenzyl bromide in a manner similar to step 1 of example 2. 1H NMR (CDCl3) δ ppm. 8.70 (s, 1H), 7.31 (d, 1H, J=4.0 Hz), 6.71-6.98 (m, 4H), 5.36 (s, 2H), 5.12 (s, 2H), 3.92 (s, 3H), 3.38 (s, 3H). LCMS (API-ES, M+H+): 347.1