Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:17][CH:18]1[CH2:22][CH2:21][CH2:20][C:19]1=O.Cl>C(OCC)C.CCCCCC>[CH3:17][C:18]1[CH2:22][CH:21]=[C:20]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)[CH:19]=1
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: CC1CCCC1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(c2ccc(C(C)(C)C)cc2)=CC1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
1-Bromo-4-t-butylbenzene (18 mL, 104 mmol) was dissolved in diethyl ether (100 mL) and added dropwise at −30° C. with a solution (66 mL, 104 mmol, 1.57 N) of n-butyllithium in hexane. The resultant solution was warmed to room temperature, stirred night and day and added dropwise at −20° C. to a solution of 3-methyl-2-cyclopentanone (10 g, 104 mmol) in diethyl ether (10 mL). Immediately after dropwise addition, the solution was warmed to room temperature and stirred for 3 hours. After termination of the reaction, the reaction solution was added with dilute hydrochloric acid and subjected to layer separation. The organic layer was dried with magnesium sulfate and then had the solvent distilled off under reduced pressure. The crude product was distilled under reduced pressure (105 to 115° C./0.16 mmHg) to obtain 1-methyl-3-(4-t-butylphenyl)-cyclopentadiene (15.3 g, yield: 69%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.[OH-].[Na+]>S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:8][CH:7]=1
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)c1ccc(CCCCO)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(CCCCOCCCCBr)cc1
Temperature: 25 °C

Procedure:
To 1,1-dimethylethyl 4-(4-hydroxybutyl)benzoate (0.85 g, 3.4 mmol, e.g. which can be as prepared in Intermediate 23) was added 1,4-dibromobutane (1.22 ml, 10.2 mmol, 3 equivalents, commercially available e.g. from Aldrich), tetra-n-butylammonium bisulphate (0.034 g, 0.1 mmol, 0.03 equivalents) and aqueous sodium hydroxide solution (50% w/v NaOH, 5 ml). The resultant biphasic mixture was stirred at room temperature over the weekend (this can be e.g. about 64 hours), diluted with water (20 ml) and extracted with diethyl ether (50 ml). The organic extract washed with water (20 ml), dried (Na2SO4) and evaporated to dryness. The residue was purified by passing through a 50 g silica SPE cartridge eluting with cyclohexane (100 ml), 9:1 cyclochexane:ethyl acetate (100 ml), 4:1 cyclohexane:ethyl acetate (200 ml) and 1:1 cyclohexane:ethyl acetate (100 ml). The 4:1 cyclohexane:ethyl acetate fraction containing the product was evaporated to give the title compound (1.05 g). LCMS showed TRET=4.14 min with: MH+=385 (trace), and [MH]++18 adduct=402/404 (Bromine isotope pattern).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-])=O)=[C:7]([CH:9]=1)[NH2:8]>[Pd].C(OCC)(=O)C.CO>[NH2:8][C:7]1[CH:9]=[C:3]([N:2]([CH3:13])[CH3:1])[CH:4]=[CH:5][C:6]=1[NH2:10]
Reactant: CN(C)c1ccc([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)c1ccc(N)c(N)c1
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
A solution of 5-dimethylamino-2-nitroaniline (1.94 g, 10.7 mmol) in 4:1 ethyl acetate/methanol (200 ml) was treated with 5% palladium on carbon (1.12 g) and stirred under an atmosphere of hydrogen at room temperature for 20.5 h. The suspension was quickly filtered through celite, the residue washed with methanol and the combined filtrate and washings concentrated to give the crude 2-amino-4-(dimethylamino)aniline as a dark brown oil, which was used without further purification in the next step.
Reaction SMILES: [CH:1]1[C:2]2[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15][N:14]([CH:22]3[CH2:24][CH2:23]3)[C:3]=2[CH:4]=[C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]=1[F:7].[Cl-].[Na+].[OH-:27].[Na+].Cl.[OH2:30]>>[CH2:23]1[CH:22]([N:14]2[C:3]3[C:2](=[CH:1][C:6]([F:7])=[C:5]([N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[CH:4]=3)[C:17](=[O:18])[C:16]([C:19]([OH:21])=[O:20])=[CH:15]2)[CH2:24]1.[CH2:17]1[CH:16]([C:19]([O-:21])=[O:20])[O:30][C:3](=[O:27])[CH2:2]1
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Agent: [Cl-]
Product: O=C1CCC(C(=O)[O-])O1

Procedure:
1.393 G (corresponding to 1 g of Ciprofloxacin) of each salt obtained in Examples 1-3 was dissolved in water to a 10 mL volume. An adequate amount of sodium chloride was added to the resulting solution to make it isotonic. The isotonic solution was diluted with saline to give a solution containing the salt as an active ingredient in the concentration of 1% (calculated in terms of Ciprofloxacin). The solution thus obtained was adjusted to pH 4.3 with a 2N sodium hydroxide or 2N hydrochloric acid solution.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2[C@H](O)C[C@@H]1C
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1c2ccccc2[C@H](OCc2ccccc2)C[C@@H]1C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
20 mg of cis-1-acetyl-4-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 2 mL of tetrahydrofuran, and 3 mg of sodium hydride was added to the solution under ice cooling. The mixture was stirred for 30 minutes under ice cooling. 15 of benzyl bromide was further added to the solution, and the resulting mixture was stirred for one whole day. Water was added to the reaction liquid, and the mixture was extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated brine, dehydrated over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (ethyl acetate:hexane=1:2), and thus 9 mg (yield 31%) of the title compound was obtained as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=CC=CC=1)=[O:10].[Br:22]C1C(=O)NC(=O)NC=1>>[Br:22][C:5]1[C:6](=[O:8])[NH:7][C:2](=[O:1])[N:3]([C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:21])=[O:10])[CH:4]=1
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Reactant: O=C(NCCCCc1ccccc1)n1ccc(=O)[nH]c1=O
Product: CCCCCCNC(=O)n1cc(Br)c(=O)[nH]c1=O
Yield: 62 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of compound of Example 1, starting from 5-bromouracil (0.03 g, 1.57 mmol). The crude was purified by column chromatography using a Teledyne ISCO apparatus (petroleum ether:EtOAc from 60:40 to 100% EtOAc) to afford the title compound (0.31 g, 62%) as white powder. 1H NMR (400 MHz, DMSO-d6): δ 0.87 (t, J=6.5 Hz, 3H), 1.24-1.32 (m, 6H), 1.40-1.61 (m, 2H), 3.26 (td, J=7.0, 5.7 Hz, 2H), 8.47 (s, 1H), 9.07 (t, J=5.7 Hz, 1H), 12.20 (s, 1H). 13C NMR (101 MHz, CDCl3): δ 14.12, 22.65, 26.61, 29.23, 31.49, 41.63, 100.15, 138.41, 148.91, 150.70, 158.08. MS (ESI) m/z: 317 [M-H]−.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]([OH:30])([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[CH3:21])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>C(OCC)(=O)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:20]([CH3:21])[C:15]([C:13]1[CH:12]=[CH:11][NH:10][C:9](=[O:8])[CH:14]=1)([OH:30])[C:16]([F:19])([F:18])[F:17]
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCc2ccccc2)c1)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Reaction time: 2 h
Yield: 90.1 %

Procedure:
2-(2-Benzyloxy-pyridin-4-yl)-3-(2,4-dichloro-phenyl)-1,1,1-trifluoro-butan-2-ol (Example 54, 300 mg) was dissolved in ethyl acetate (10 mL) and the flask was flushed with argon. Palladium on activated charcoal (10% Pd, 75 mg) was added and the mixture was hydrogenated for 2 hours with vigorous stirring. The suspension was filtered and the catalyst was washed with methanol. The filtrate was concentrated in vacuo and the residue was dried in high vacuum to give the title compound as a light brown powder (217 mg). MS (m/e, ISP neg. ion): 364.4 (M−H+)−.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21].[CH:22](N1CCOCC1)=[O:23]>C1COCC1.Cl>[Cl:13][C:14]1[C:15]([F:21])=[C:16]([C:17]([F:20])=[CH:18][CH:19]=1)[CH:22]=[O:23]
Reactant: Fc1ccc(Cl)c(F)c1
Reactant: O=CN1CCOCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(Cl)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.43M in hexane, 20.2 mmol, 14.1 ml) was added dropwise at 0° C. to a solution of diisopropylamine (2.91 ml, 22.2 mmol) in THF (80 ml). After 30 min. at 0° C., the solution was cooled to -78° C. and 1-chloro-2,4-difluorobenzene (3 g, 20.2 mmol) in THF (10 ml) added dropwise. After 30 min., 4-formylmorpholine (4.1 ml) was added and the mixture warmed to room temperature over 1 h, diluted with 1N HCl, extracted twice with ethyl acetate, the extracts washed with brine, dried over sodium sulphate and evaporated to give a mobile yellow oil (2.2 g), MS (+EI) 178/177/176/175 (M+), 1H NMR (CDCl3) 10.34 (1H, s), 7.66-7.60 (1H, m), 7.00 (1H, dt, J6.9 Hz, 1.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:11][C:12]([F:13])([F:14])[F:15]
Reactant: Nc1ccc(C(=O)O)cc1OC(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(CO)cc1OC(F)(F)F
Temperature: 80 °C
Yield: 64 %

Procedure:
4-Amino-3-(trifluoromethoxy)benzoic acid 2.0 g (9.04 mmol) is dissolved in 50 mL of THF. Lithium aluminium hydride (1.4 g, 36.2 mmol) is added portionwise over 10 minutes. A reflux condensor is attached and the reaction mixture is refluxed for 6 h at 80° C. It is cooled to room temperature and the Fieser work up is performed (1.4 mL of water, 1.4 mL 15% NaOH, 4.2 mL of water). The granular inorganic precipitate is filtered and washed with THF. The organic fractions is combined and dried over anhydrous Na2SO4. The solvent is evaporated and the residue is purified on silica, eluting with 0-10% methanol/dichloromethane to give the title compound (1.2 g, 5.79 mmol 64%). (ESMS): ink 208.3 (M+H+).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:20]3[N:21]([CH:24]4[CH2:26][CH2:25]4)[CH:22]=[CH:23][C:19]=3[C:18](=[O:27])[N:17]2[C:28]2[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=2)=[CH:12][CH:11]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:8][C:22]1[N:21]([CH:24]2[CH2:26][CH2:25]2)[C:20]2[CH:16]([C:13]3[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=3)[N:17]([C:28]3[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=3)[C:18](=[O:27])[C:19]=2[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(N2C(=O)c3ccn(C4CC4)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3cc(Br)n(C4CC4)c3C2c2ccc(Cl)cc2)cn(C)c1=O
Temperature: 25 °C
Reaction time: 40 h
Yield: 70.9 %

Procedure:
NBS (0.497 g, 2.79 mmol) was added to a mixture of 6-(4-chlorophenyl)-1-cyclopropyl-5-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Step 240.2) (1.1 g, 2.79 mmol) in CCl4 (40 mL) at 0° C. The reaction mixture was stirred for 40 h at rt, concentrated, diluted with EtOAc/water, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH 95:5) to afford a white solid and mixed fractions. The mixed fractions were purified by SFC (column 2-EP 250×30 mm, 5 μm, 60 Å, Princeton; flow 100 mL/min; gradient: isocratic 5% B for 25 min; A: scCO2, B: MeOH) to afford a white solid. Both solids were dissolved in CH2Cl2 and concentrated to afford the title compound (935 mg, 70.8% yield) as a white solid. tR: 1.07 min (LC-MS 6); ESI-MS: 472.1/474.1 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH 95:5): Rf=0.27.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:6])([NH2:5])[CH3:4].[Br:7][CH2:8][C:9](Br)=[O:10]>C(Cl)Cl>[OH:1][CH2:2][C:3]([NH:5][C:9](=[O:10])[CH2:8][Br:7])([CH3:6])[CH3:4]
Reactant: O=C(Br)CBr
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)CBr
Temperature: 0 °C

Procedure:
35.6 g (0.4 mol) of 1-hydroxy-2-methyl-2-aminopropane are dissolved in 100 ml of absolute methylene chloride, the solution is cooled to 0° C., and 40.4 g (0.2 mol) of bromoacetyl bromide, dissolved in 100 ml of methylene chloride, are added dropwise to this solution in the course of 3 hours 50 minutes, in the absence of moisture and while maintaining the temperature of 0° C. The mixture is allowed to react further for 2 hours at room temperature. The 1-hydroxy-2-methyl-2-aminopropane hydrobromide is filtered off under suction and washed with methylene chloride. The plate yellow oil obtained from the filtrate by evaporating off the solvent is chromatographed over silica gel, using ethylene chloride/isopropanol (95:5; 9:1; 4:1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=1.BrC1C=CC([N+]([O-])=O)=CC=1C(OC)=O.[Cl:37]C1C=CC(OC)=C(B(O)O)C=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:4]1[C:5]([O:21][CH3:22])=[C:6]([C:8]2[C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH:7]=[CH:2][CH:3]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cc(F)ccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccc(Cl)c1OC
Yield: 35 %

Procedure:
This compound was prepared in a manner similar to that of methyl (5'-fluoro-2'-methoxy-4-nitro-2-biphenylcarboxylate) (EXAMPLE 107) from methyl 2-bromo-5-nitrobenzoate (0.58 g, 2.2 mmol), (PPh3)4Pd (77 mg, 0.066 mmol), and 5-chloro-2-methoxyphenylboronic acid (0.54 g, 2.9 mmol) to afford 245 mg (35%) of methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate) as a clear oil. Data for methyl (3'-chloro-2'-methoxy-4-nitro-2-biphenylcarboxylate: 1H NMR (400 MHz, CDCl3) 8.79 (d, J=2.4, 1H), 8.40 (dd, J=8.4, 2.4, 1H), 7.57 (d, J=8.5, 1H), 7.45 (m, 1H), 7.15 (m, 2H), 3.75 (s, 3H), 3.47 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH2:10][OH:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[O:6][C:5]([CH2:7][CH2:8][CH3:9])=[N:4][C:3]=1[CH2:10][O:11][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: CCCc1nc(CO)c(Br)o1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1nc(COC2CCCCO2)c(Br)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
To a solution of 1.96 g (8.91 mmol) of the compound from step 29b in 55 mL of methylene chloride at room temperature were sequentially added 7 mL of 3,4-dihydro-2H-pyran (76.7 mmol) and 1 g (3.98 mmol) of PPTS. The reaction was stirred at room temperature for 20 min, 30 mL of satd. NaHCO3 was added, and the mixture was stirred for 5 min. The organic layer was separated, and the aqueous layer was extracted with 2×50 mL of methylene chloride. The organics were combined, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 10-30% ethyl acetate in hexane, to afford, after removal of the solvent and drying, 2.70 g (100% yield) of the title product as a colorless oil. NMR (CDCl3) δ:4.75 (t, J=3 Hz, 1H), 4.57 and 4.33 (ABq, J=12 Hz, 2H), 3.93 (m, 1H), 3.56 (m, 1H), 2.72 (t, J=8 Hz, 2H), 190-1.48 (m, 8H), 1.00 (t, J=8 Hz, 3H).
Reaction SMILES: Cl.Cl.Cl[C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]1[NH:12][C:13]2[C:21]([N:22]=1)=[CH:20][C:19]1[C:18](=[O:23])[N:17]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][C:15]=1[CH:14]=2.Cl.[CH3:33][C@H:34]([NH2:41])[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.CCN(CC)CC>CCO>[CH3:33][C@H:34]([NH:41][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]1[NH:12][C:13]2[C:21]([N:22]=1)=[CH:20][C:19]1[C:18](=[O:23])[N:17]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][C:15]=1[CH:14]=2)[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2CN1CCCN1CCCC1
Reactant: C[C@H](N)Cc1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@@H](Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(CCCN1CCCC1)C3=O
Temperature: 100 °C
Yield: 47.4 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one dihydrochloride (17) (2.2 g, 4.9 mmol), (1S)-1-methyl-2-thien-2-ylethylamine hydrochloride (13b) (870 mg, 4.9 mmol) and Et3N (3.44 mL, 24.5 mmol) in EtOH (20 mL) was heated at 100° C. for 12 h. The mixture was concentrated, diluted with water (20 mL) and extracted with CHCl3 (5×20 mL) the combined organic layer was dried, concentrated to a residue that was purified on silica gel column using 10% NH4OH/methanol in CH2Cl2 to get pure 2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one (18a) (1.2 g, 51%). 1H NMR (DMSO-d6) δ 1.33 (d, 3H, J=3.0 Hz), 1.55-1.85 (m, 6H), 2.3-2.45 9 m, 6H), 3.15-3.25− (m, 2H), 3.56 (t, 2H, J=6.0 Hz), 3.95-4.15 (m, 1H), 4.51 (s, 2H), 6.15 (d, 1H, J=9.0 Hz), 6.91-6.96 (m, 1H), 7.05 (t, 1H, J=3.0 Hz), 7.31-7.36 (m, 2H), 7.66 (s, 0.5H), 7.79 (d, 1H, J=3.0 Hz), 7.93 (s, 0.5H), 11.14 (d, 1H, J=9.0 Hz), 11.24 (bs, 1H). ESI-MS m/z 517.67 (M++1).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[H-].[Na+].[CH3:54][O:55][C:56]1[CH:65]=[CH:64][C:59]([C:60](=[O:63])[CH2:61]Br)=[CH:58][CH:57]=1.O>CN(C)C=O>[CH3:54][O:55][C:56]1[CH:65]=[CH:64][C:59]([C:60](=[O:63])[CH2:61][N:2]([CH3:1])[S:3]([C:6]2[S:7][C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[C:22]([C:45]6[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=6)=[N:23][N:24]([C:26]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:25]=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:9][CH:10]=2)(=[O:5])=[O:4])=[CH:58][CH:57]=1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)CN(C)S(=O)(=O)c2ccc(-c3ncnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5-c5ccc(F)cc5)cc34)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
50 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) was dissolved in 3 mL N,N-dimethylformamide, then 3.1 mg sodium hydride was added thereto and stirred at room temperature for 0.5 hour. Under ice-cooling, a solution of 18 mg 4-methoxyphenacyl bromide in 2 mL N,N-dimethylformamide was added thereto and stirred for 1.0 hour under ice-cooling. Water was added to the reaction solution which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 47 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12]([NH:14][C:15]1([CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]2=[O:35])[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=2)[CH2:17][CH2:16]1)=[O:13])[CH3:10].[Br:36][C:37]1[CH:50]=[CH:49][C:40]2[CH:41]=[C:42]([S:45](Cl)(=[O:47])=[O:46])[CH2:43][O:44][C:39]=2[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:36][C:37]1[CH:50]=[CH:49][C:40]2[CH:41]=[C:42]([S:45]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:15]4([NH:14][C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:16][CH2:17][N:18]([C:21]5[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=5)[CH2:19][CH2:20]4)[C:30](=[O:35])[CH2:31]3)(=[O:46])=[O:47])[CH2:43][O:44][C:39]=2[CH:38]=1
Reactant: CCOC(=O)NC1(CN2CCNCC2=O)CCN(c2ccnc(C)c2)CC1
Reactant: O=S(=O)(Cl)C1=Cc2ccc(Br)cc2OC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC1(CN2CCN(S(=O)(=O)C3=Cc4ccc(Br)cc4OC3)CC2=O)CCN(c2ccnc(C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.6 %

Procedure:
Triethylamine (253 mg) was added to a solution of 1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone hydrochloride (258 mg) in dichloromethane (15 ml), 7-bromo-2H-benzopyran-3-sulfonyl chloride (233 mg) was added at 0° C., and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added an aqueous sodium carbonate solution, the mixture was extracted with dichloromethane, dried, concentrated, and purified by column chromatography (dichloromethane:10% aqueous ammonia-containing methanol=20:1) to obtain colorless amorphous 4-(7-bromo-2H-benzopyran-3-sulfonyl)-1-{[4-ethoxycarbonylamino-1-(2-methyl-4-pyridyl)-4-piperidinyl]methyl}-2-piperazinone (169 mg).
Reaction SMILES: [C:1](O)(=O)[C:2]1C=CC=CC=1.[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].C(OC(=O)C)(=O)C>>[CH3:1][C:2]1[NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:17]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2ccccc2[nH]1

Procedure:
Preparation of the intermediate benzoic acid 2 is shown in Scheme 2. 1,2-phenylenediamine is condensed with acetic anhydride to form 2-methylbenzimidazole which is then reacted with benzyl halide 5 (where X is Br, Cl, I, methansulfonyl, or p-toluenesulfonyl), in the presence of base to form 6. Hydrolysis of ester 6 gives benzoic acid 2. Condensation of 3,4-diaminopyridine with acetic anhydride followed by reaction with benzyl halide 5 as described above gives a mixture of 1-, 3-, and 5-substituted imidazo[4,5-c]pyridines (compounds 8, 9, and 10) which are separated by chromatography on silica gel and convened to 2 as described above. Similarly, imidazo[4,5-b]pyridines 12, 13, and 14 are prepared from 2,3-diaminopyridine. ##STR10##