Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].ClC(Cl)(Cl)[C:5]1[CH:10]=[CH:9][N:8]2[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=[C:7]2[N:6]=1>C(#N)C>[N:6]1[C:7]2[N:8]([C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:9]=[CH:10][C:5]=1[OH:1]
Reactant: [OH-]
Reactant: ClC(Cl)(Cl)c1ccn2c(n1)nc1ccccc12
Agent: [Na+]
Solvent: CC#N
Product: Oc1ccn2c(n1)nc1ccccc12
Yield: 100 %

Procedure:
Sodium hydroxide (36.5 ml, 36.5 mmol) was added to a solution containing 2-(trichloromethyl)-benzo[4,5]imidazo[1,2-a]pyrimidine (8.04 g, 28.1 mmol) in Acetonitrile (Volume: 122 ml). Heated the reaction to 90 C for 30 minutes. Cooled the reaction to room temperature and concentrated. Added ice to the resulting residue, followed by 35 mL of 1M HCl. Filtered the solid and dried under vacuum to afford crude benzo[4,5]imidazo[1,2-a]pyrimidin-2-ol (5.2 g, 28.1 mmol, 100% yield).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]([CH2:7][O:8][CH2:9][CH2:10][P:11]([O:15][CH3:16])([O:13][CH3:14])=[O:12])=[CH2:6])C.[OH-].[Na+]>C(O)C>[CH3:14][O:13][P:11]([CH2:10][CH2:9][O:8][CH2:7][C:5](=[CH2:6])[C:4]([OH:17])=[O:3])([O:15][CH3:16])=[O:12]
Reactant: C=C(COCCP(=O)(OC)OC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C(COCCP(=O)(OC)OC)C(=O)O

Procedure:
Specifically, the reaction of 2-[4-(dimethoxyphosphoryl)-2-oxabutyl]-acrylic acid ethyl ester with sodium hydroxide with elimination of ethanol gives 2-[4-(dimethoxyphosphoryl)-2-oxa-butyl]-acrylic acid:
Reaction SMILES: [C:1]([NH:3][CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:8][CH:7]=1)#N.CN>O>[CH3:1][NH:3][CH:4]=[N:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:8][CH:7]=1
Reactant: N#CNC=Nc1ccc(-c2c[nH]cn2)cc1
Agent: CN
Solvent: O
Product: CNC=Nc1ccc(-c2c[nH]cn2)cc1
Yield: 70.9 %

Procedure:
Twenty grams of N-cyano-N'-[4-(imidazol-4-yl)-phenyl]-formamidine was added in one portion to 35% methylamine in water (70 ml). A few minutes after the addition, the solid N-methyl-N'-[4-(imidazol-4-yl)-phenyl]-formamidine separated out of the solution. This solid was collected by filtration, washed with water, and dried to yield 13.45 gm of the desired product, which was recrystallized from acetone.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([C:28]([O:30]C)=[O:29])[CH:21]=3)[C:9]2=[O:32])[CH2:4][CH2:3]1.[OH-].[Na+].Cl>CO.O1CCCC1>[C:28]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][N:10]1[C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=2[N:8]([C@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)[C:9]1=[O:32])([OH:30])=[O:29]
Reactant: COC(=O)c1cc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C#N)cc32)ccc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C#N)cc32)cc1C(=O)O
Temperature: 600 °C

Procedure:
To a solution of 1-(trans-4-hydroxycyclohexyl)-3-(4-methoxy-3-methoxycarbonylbenzyl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one (120 mg) in methanol (10 mL) and tetrahydrofuran (2 mL) was added 1N-aqueous sodium hydroxide solution (3 mL) and the mixture was stirred at 600° C. for an hour. After the solution was acidified with 1N-hydrochloric acid, the organic solvent of the solution was removed by evaporation. The aqueous layer was diluted with water and extracted with a mixture of chloroform and methanol (4:1). The separated organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 3-(3-carboxy-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-5-cyano-2,3-dihydro-1H-benzimidazole-2-one as a colorless powder (88.8 mg).
Reaction SMILES: [CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.Cl[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1>CN(C=O)C>[CH2:1]([C:3]1([N:9]2[CH2:18][C:17]3=[CH:19][NH:20][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][N:14]=4)[C:10]2=[O:21])[CH2:8][CH2:7][N:6]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCNCC1
Reactant: Clc1ccncn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC1(N2Cc3c[nH]c4nccc(c34)C2=O)CCN(c2ccncn2)CC1
Temperature: 140 °C
Yield: 51.2 %

Procedure:
4-(4-Ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one (10 mg, 0.035 mmol), triethylamine (0.049 mL, 0.352 mmol), and 4-chloropyrimidine (8 mg, 0.070 mmol) were dissolved in DMF (1.5 mL) and heated under microwave irradiation at 140° C. for 30 min. The solution was concentrated in vacuo and purified via preparative HPLC 10% to 40% B in A and gave 6.5 mg of the title compound as its TFA salt. 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.14 (dd, 1H, J=7.6, 1.3 Hz), 7.51 (s, 1H), 7.37 (s, 1H), 7.11 (d, 1H, J=7.5 Hz), 5.14 (s, 2H), 4.27 (m, 1H), 4.11 (m, 1H), 3.86-3.87 (m, 1H), 3.80-3.82 (m, 1H), 2.86 (m, 1H), 2.73 (m, 1H), 2.38 (m, 1H), 2.24-2.31 (m, 4H), 0.99 (t, 3H, J=7.6 Hz). MS (ES) [M+H] found 363.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.C([O:23]O)(C)(C)C>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[OH:23][N:3]1[C:4]([CH3:17])([CH3:16])[CH2:5][CH:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:15])[CH2:7][C:2]1([CH3:18])[CH3:1]
Reactant: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1
Reactant: CC(C)(C)OO
Agent: [Mo]
Agent: [C-]#[O+]
Product: CC1(C)CC(N2CCCCCC2=O)CC(C)(C)N1O

Procedure:
A sample of 25.2 g (0.1 mole) of N-(2,2,6,6-tetramethylpiperidine-4-yl)-ε-caprolactam is refluxed for 2 hours with 50 ml of 4M tert-butylhydroperoxide in the presence of 0.2 g of molybdenum hexacarbonyl, Mo(CO)6 as described in Example 1, to provide 26.6 g of red solid (99% crude yield). Crystallization from hexane gives orange crystals, m.p. 152°-159° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[NH:5][C:4]2([CH2:15][N:14](C(OCC3C=CC=CC=3)=O)[CH2:13]2)[N:3]=1>C(O)C.[Pd]>[F:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:2]([NH2:1])=[N:3][C:4]1([CH2:13][NH:14][CH2:15]1)[NH:5]2
Reactant: NC1=NC2(CN(C(=O)OCc3ccccc3)C2)Nc2cccc(F)c21
Agent: [Pd]
Solvent: CCO
Product: NC1=NC2(CNC2)Nc2cccc(F)c21
Reaction time: 48 h
Yield: 99 %

Procedure:
Phenylmethyl 4'-Amino-5'-fluorospiro[azetidine-3 ,2'(1'H)-quinazoline]-1 -carboxylate (Example 249, 1 g, 2.94 mmol) in ethanol (50 ml) containing 10% palladium on carbon catalyst (0.1 g) was stirred under hydrogen at 3 atmospheres pressure for 48 h. The catalyst was removed by filtration and the filtrate concentrated to leave the crude title compound as a gum (0.6 g), MS (+CI) 207 ([M+H]+).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[NH2:8][C:9]([NH2:11])=[NH2+:10].[F:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[CH:20]([CH2:22][C:23](OCC)=[O:24])[N:19]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:18]2=[O:32]>>[F:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[CH:20]([CH2:22][C:23]([NH:10][C:9]([NH2:11])=[NH:8])=[O:24])[N:19]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:18]2=[O:32]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2c(F)cccc2C(=O)N1CC(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Product: CC(C)CN1C(=O)c2cccc(F)c2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 20 h
Yield: 21.4 %

Procedure:
N-[(7-Fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is prepared as described in Example 1, starting with 1.29 g of potassium tert-butoxide, 1.32 g of guanidinium chloride and 0.67 g of ethyl (7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours, and is then filtered. The filtrate is taken up in 40 cm3 of water and 60 cm3 of ethyl acetate. After separation of the phases by settling, the organic phase is separated out and the aqueous phase is extracted with twice 60 cm3 of ethyl acetate. The organic extracts are combined, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (0.6 kPa) at a temperature in the region of 55° C. The evaporation residue is taken up in diethyl ether and concentrated to dryness again under the same conditions, and then taken up in water and concentrated to dryness again under the same conditions. The residue is purified by chromatography under argon pressure (50 kPa), on a column of silica gel (particle size 15-40 μm), eluting with a mixture of dichloromethane/methanol (90/10 by volume). The fractions comprising the expected product are combined and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 20° C. The residue is taken up in diisopropyl ether, triturated, filtered and then dried. 0.15 g of N-[(7-fluoro-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine is thus obtained in the form of a pale yellow solid melting at 205° C. 1H NMR (300 MHz, d6-(CD3)2SO, δ in ppm): 0.74 (d, J=6.5 Hz: 3H); 0.89 (d, J=6.5 Hz: 3H); 2.06 (mt: 1H); 2.38 (dd, J=15 and 7.5 Hz: 1H); 2.90 (dd, J=15 and 4.5 Hz: 1H); 3.04 (dd, J=13.5 and 4.5 Hz: 1H); 3.56 (dd, J=13.5 and 10 Hz: 1H); 5.23 (dd, J=7.5 and 4.5 Hz: 1H); from 6.20 to 7.00 (broad multiplet: 2H); from 7.35 to 7.60 (mt: 3H); from 7.50 to 8.20 (broad multiplet: 2H).
Reaction SMILES: [F:1][C:2]([F:16])([C:5]([F:15])([F:14])[C:6]([F:13])([F:12])[C:7]([F:11])([F:10])[CH2:8][OH:9])[CH2:3][OH:4].[F:17][C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[C:22]([F:27])[C:21]([F:28])=[C:20](F)[C:19]=1[F:30].C(N(CC)CC)C.C(O)(=O)C>CN1C(=O)CCC1.O>[OH:9][CH2:8][C:7]([F:10])([F:11])[C:6]([F:13])([F:12])[C:5]([F:14])([F:15])[C:2]([F:16])([F:1])[CH2:3][O:4][C:20]1[C:19]([F:30])=[C:18]([F:17])[C:23]([N+:24]([O-:26])=[O:25])=[C:22]([F:27])[C:21]=1[F:28]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1c(F)c(F)c(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)CO)c(F)c1F
Yield: 67.2 %

Procedure:
A mixture of 2,2,3,3,4,4,5,5-octafluoro-1,6-hexanediol (7.86 g) was treated with pentafluoronitrobenzene (2.13 g) and triethylamine (1.39 mL) in NMP (15 mL) at room temperature for 1 hr. The mixture was diluted with water, acidified with acetic acid, and extracted with ethyl ether. The extract was washed with water and brine; dried (MgSO4) and concentrated. Excess diol was removed by distillation and the residual oil purified by chromatography to give 4-(6-hydroxy-2,2,3,3,4,4,5,5-octafluorohexyloxy)tetrafluoronitrobenzene (3.06 g).
Reaction SMILES: [NH2:1][CH:2]1[C:14](=[O:15])[N:4]2[C:5]([C:11]([OH:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:29]([NH:31][C:32]1[S:33][C:34]([Br:44])=[C:35]([C:37](=[N:41][O:42][CH3:43])[C:38](O)=[O:39])[N:36]=1)=[O:30].C(=O)(O)[O-].[Na+:49]>C(OCC)(=O)C.CO.CN(C)C=O>[CH:29]([NH:31][C:32]1[S:33][C:34]([Br:44])=[C:35]([C:37](=[N:41][O:42][CH3:43])[C:38]([NH:1][CH:2]2[C:14](=[O:15])[N:4]3[C:5]([C:11]([O-:13])=[O:12])=[C:6]([CH2:9][OH:10])[CH2:7][S:8][C@H:3]23)=[O:39])[N:36]=1)=[O:30].[Na+:49]
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Reactant: NC1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1nc(NC=O)sc1Br
Yield: 43.2 %

Procedure:
A solution of 7-amino-3-hydroxymethyl-3-cephem-4-carboxylic acid (2.5 g.) and trimethylsilylacetamide (10.6 g.) in dry ethyl acetate (60 ml.) and a mixture of dimethylformamide (0.75 ml.), phosphoryl chloride (0.88 ml.), 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 2.5 g.) and dry ethyl acetate (7.0 ml.) were stirred at -20° to -10° C. for an hour. The reaction mixture was added to aqueous solution (50 ml.) of sodium bicarbonate (3.3 g.), under ice-cooling. Methanol (2 ml.) was added to the mixture and stirred under ice-cooling for 30 minutes. The mixture was washed with ethyl acetate twice. After removing the ethyl acetate, the aqueous solution was adjusted to pH 6.5 with sodium bicarbonate and allowed to stand in a refrigerator. The solution was adjusted to pH 5.0 with 6N-hydrochloric acid and subjected to column chromatography on non-ionic adsorption resin HP-20 (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), washed with water (200 ml.) and then eluted with 20% isopropyl alcohol (400 ml.). The eluate was evaporated in vacuo. The residue was pulverized with acetone (80 ml.), and the precipitates were collected by filtration and dried to give sodium 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-hydroxymethyl-3-cephem-4-carboxylate (syn isomer, 1.9 g.).
Reaction SMILES: [Br:1]Br.[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=1>C(O)(=O)C>[Br:1][C:11]1[C:12](=[O:15])[NH:13][CH:14]=[C:9]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][N:3]=2)[CH:10]=1
Reactant: O=c1ccc(-c2cnccn2)c[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=c1[nH]cc(-c2cnccn2)cc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3 ml of bromine are added to a stirred suspension of 5-(2-pyrazinyl)-2(1H)-pyridone (9.0 g) in 300 ml of glacial acetic acid warmed to a temperature of 50° C. The mixture is stirred at RT overnight, cooled in an ice bath to 16° C. and filtered. The filtered yellow solid is suspended in 100 ml of distilled H2O, to which sodium bisulfite is gradually added until the solid appears tan. A saturated potassium carbonate solution is slowly added until the pH is adjusted to 7.4, and the suspension is filtered. The filtered solid is washed with H2O and dried under high vacuum at 100° C. for 4 hours, giving the desired 3-bromo-5-(2-pyrazinyl)-2(1H)-pyridone which is recrystallized from methanol, M.P. >250° C.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][C:4]=1[O:5][CH2:6][C:7]#[N:8])=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:14][N:13]([CH3:15])[C:10]1[CH:11]=[CH:12][C:3]2[CH:1]=[C:6]([C:7]#[N:8])[O:5][C:4]=2[CH:9]=1
Reactant: CN(C)c1ccc(C=O)c(OCC#N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccc2cc(C#N)oc2c1

Procedure:
15.3 parts of the nitrile is dissolved in 100 parts by volume of dimethylformamide and stirred with 10 parts of potassium carbonate for 15 hours at 70°C. The whole is then diluted with 1,000 parts of water, filtered by suction and the filter residue is dried. For further purification it is sublimed at 80°C and 1 mm and the sublimate is recrystallized from methylcyclohexane. The 6-dimethylaminobenzofuran-2-carbonitrile is obtained in the form of colorless crystals having a melting point of 70° to 71°C which dissolve in benzene with an intense blue-violet fluorescence.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:40][OH:41].C(N(CC)CC)C>C(O)C>[OH:41][NH:40][C:1]([C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][C:12]=2[NH:22][C:23](=[O:38])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:36][CH2:35][CH2:34][N:33]([CH3:37])[CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[CH:6]=[CH:7][CH:8]=1)=[NH:2]
Reactant: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c(NC(=O)c2ccc(N3CCCN(C)CC3)cc2)c1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1ccc(CNc2cccc(C(=N)NO)c2)c(NC(=O)c2ccc(N3CCCN(C)CC3)cc2)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethyl 4-[(3-cyanophenylamino)methyl]-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate (1.42 g) was dissolved in 30 ml of ethanol, then 291 mg of hydroxylamine hydrochloride and 0.78 ml of triethylamine were added and the mixture was stirred at 60° C. for 24 hours. The reaction solution was concentrated in vacuo and the resulting residue was purified by silica gel column chromatography using chloroform-methanol-aqueous ammonia (100:0:0 to 92:8:0.8) to give a crudely purified product, ethyl 4-([{3-(N-hydroxycarbamimidoyl)phenyl]amino}methyl)-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate. The crudely purified product was further purified by ODS column chromatography using 0.002N aqueous solution of hydrochloric acid-methanol (100:0 to 88:12) as an eluting solvent and freeze-dried to give 1.03 g of ethyl 4-([{3-(N-hydroxycarbamimidoyl)phenyl]amino}methyl)-3-[4-(4-methyl-1,4-diazepan-1-yl)benzoylamino]benzoate hydrochloride.
Reaction SMILES: Br.[CH:2]([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]2[CH:16]=1)([CH3:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:13][C:10]3[CH:11]=[CH:12][C:7]4[N:8]([CH:16]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:6]=4)[CH:9]=3)=[O:31])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cn2cc([N+](=O)[O-])ccc2n1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: Br
Product: CC(C)c1cn2cc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)ccc2n1

Procedure:
Conducting the operations similar to those of Example 1 using 2-isopropyl-6-nitroimidazo[1,2-a]pyridine hydrobromide and 4′-fluoro[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=1[C:10]([OH:12])=O.C(N(CC)CC)C.[CH2:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:28]>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[CH2:27]([N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10](=[O:12])[C:9]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:8]=1[Br:7])[CH3:28]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Reactant: CCNc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(C(=O)c1cc([N+](=O)[O-])ccc1Br)c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
Oxalyl chloride (1.65 ml, 2.3 g, 18.3 mmol) was added dropwise to a solution of 2-bromo-5-nitrobenzoic acid (3 g, 12.2 mmol) in dichloromethane (12 ml). N,N-Dimethylformamide (0.01 ml) was added to the reaction mixture via syringe, the reaction mixture was stirred at 23° C. for 4 hour. The reaction mixture was concentrated in vacuo, and the residue was taken up in dichloromethane (24 ml), and DMAP (10 mg) and triethylamine (3.4 ml, 2.5 g, 24.3 mmol) were added. N-Ethylaniline (1.8 ml, 1.8 g, 14.6 mmol) was added over a 10 min period. After 18 hours at this temperature, 1:1 ethyl acetate/hexanes (30 ml) was added, and the organics were washed with 1N HCl (2-30 ml portions) and saturated aqueous sodium chloride (30 mL). The organics were dried over anhydrous sodium sulfate and concentrated. Purification of the residue by recrystallization from ethyl acetate/hexanes afforded N-ethyl-2-bromo-5-nitro-N-phenyl-benzamide (3.8 g, 60%).
Reaction SMILES: [C:1]([N:9]1[CH2:21][C:20]2[C:19](=[O:22])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O-].[Na+]>CO>[C:1]([N:9]1[CH2:21][C:20]2[C:19](=[O:22])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]([CH3:23])[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[O-]
Reactant: O=C(c1ccccc1)N1Cc2[nH]c3ccccc3c(=O)c2C1
Agent: [Na+]
Solvent: CO
Product: Cn1c2c(c(=O)c3ccccc31)CN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
14.51 g (50 mmol) of the 2-benzoyl-1,2,3,4-tetrahydro-9H-pyrrolo[3,4-b]quinolin-9-one are dissolved in 50 ml of a 1 N solution of sodium methylate in absolute methanol, the solution concentrated by evaporation, the residue taken up in 150 ml of dimethyl formamide and 3.15 ml of methyl iodide are added. After stirring for 4 hours at room temperature, appoximately 100 ml of water are added to the mixture, filtration is effected and the residue is washed with water and dried. The 2-benzoyl-1,2,3,4-tetrahydro-4-methyl-9H-pyrrolo-[3,4-b]quinolin-9-one used in Example 1 is obtained. M.P. 285° (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].[CH3:36][C:37]1[N:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([NH:43][C:40]3[CH:41]=[N:42][C:37]([CH3:36])=[CH:38][CH:39]=3)[C:27]=2[S:26][CH:25]=1)=[O:23]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Reactant: Cc1ccc(N)cn1
Product: Cc1ccc(Nc2ncnc3c(C(=O)Nc4cc(C(=O)Nc5cccc(C(F)(F)F)c5)ccc4C)csc23)cn1

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and 6-methylpyridine-3-amine to obtain the title compound (see Table 1).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:21])[CH2:5][C:4]([CH3:23])([CH3:22])[NH:3]1.[CH2:25](Br)[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)(Cl)Cl.CCCCC.O.C(OC)(C)(C)C>[CH3:22][C:4]1([CH3:23])[CH2:5][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([O:20][CH2:25][CH2:26][CH2:27][CH3:28])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:21])[CH2:7][C:2]([CH3:24])([CH3:1])[NH:3]1
Reactant: CCCCBr
Reactant: CC1(C)CC(N2C(=O)c3ccc(C(=O)O)cc3C2=O)CC(C)(C)N1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOC(=O)c1ccc2c(c1)C(=O)N(C1CC(C)(C)NC(C)(C)C1)C2=O
Reaction time: 15 h

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed the HALS-acid of Example 1 (3.3 g (0.01 mol), n-butylbromide (3.13 g, 0.022 mol), ADOGEN 464® (Ashland Chemical Co.) (0.19 g), sodium carbonate (6.64 g, 0.044 mol) and 50 ml of dimethylformamide. The reaction was heated to 80°-90° C. for 2 hours, allowed to stand at ambient temperature for 15 hours then heated again at 80°-90° C. for 6.5 additional hours. The mixture was transferred to a separatory funnel with 100 ml methyl t-butyl ether and 500 ml water. The phases were agitated then allowed to separate. The ether solution was retained and the aqueous solution was extracted with 100 ml fresh ether. The combined ether extracts were dried with anhydrous magnesium sulfate and stripped using aspirator and high vacuum systems. A white solid residue was isolated using a small amount of pentane (the product is quite soluble in this solvent). The product was 3.0 g of white crystals melting at 90°-92° C. The infrared spectrum (chloroform) showed a broad carbonyl absorption at 1700 cm-1 (imide and ester). The NMR spectrum showed the anticipated aromatic ring (7.7-8.5 ppm, multiplet, 3H), the --N--C--H and --O--CH2 merged (4.2-4.8, triplet and multiplet, 3H) and the rest of the HALS group and butyl group [0.9-2.3 ppm, several multiplets including two singlets (1.2 and 1.3 ppm)].
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13]O)[CH2:7]1>>[Cl:3][CH2:13][CH2:12][CH2:11][N:8]1[CH2:9][CH2:10][C@H:6]([F:5])[CH2:7]1
Reactant: OCCCN1CC[C@H](F)C1
Reactant: O=S(Cl)Cl
Product: F[C@H]1CCN(CCCCl)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
0.143 g (1.2 mmol) of thionyl chloride was added to a solution (ice bath) of 0.143 g (1.0 mmol) of 3-[(3S)-3-fluoropyrrolidin-1-yl]propan-1-ol. The reaction mixture was stirred for 2 h at 50° C. and concentrated in vacuo to give 0.103 g (50%, 3 steps) of (3S)-1-(3-chloropropyl)-3-fluoropyrrolidine.