Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:19]=[C:18]([N:20]2[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26]C(=O)[O-])[CH2:21]2)[C:17]2[C:12](=[CH:13][C:14]([CH3:30])=[CH:15][CH:16]=2)[N:11]=1.CO>CCOC(C)=O.[Pd]>[NH2:26][C@H:22]1[CH2:23][CH2:24][CH2:25][N:20]([C:18]2[C:17]3[C:12](=[CH:13][C:14]([CH3:30])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[OH:3])[N:19]=2)[CH2:21]1
Reactant: Cc1ccc2c(N3CCC[C@H](NC(=O)[O-])C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Agent: N#N
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2c(N3CCC[C@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 4 h
Yield: 49.6 %

Procedure:
Pd/C (175 mg, 10% weight Pd on carbon) was added to a round bottom flask and the flask was flushed with N2. To this flask was then added MeOH (10 mL). After purging the flask again with N2, (S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate (1.75 g, 3.74 mmol) dissolved in EtOAc (60 mL) and MeOH (50 mL) was added. After flushing the flask 3 times with N2, and evacuating it under vacuum, H2 was passed through the vigorously stirring mixture for 4 h until hydrogenation was complete. The mixture was filtered through a pad of Celite. The filtrate was concentrated to afford 2-(4-((S)-3-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.62 g, 50%). LC/MS: m/z 335.5 (M+H)+ at 1.50 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][C:11](=[CH:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=C1CCN(Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C=C1CCN(Cc2ccccc2)CC1
Temperature: 45 °C
Reaction time: 1 h
Yield: 114.4 %

Procedure:
To a solution of ester 203 (8.06 g, 31.1 mmol) in THF (100 mL) was added an aqueous solution of LiOH (1.96 g, 46.6 mmol) in water (30 mL) and the reaction mixture was allowed to stir at 45° C. for 60 min. Then more LiOH (0.5 g, 11.9 mmol) was added to the heating solution. After further heating for 8 h, the reaction mixture was concentrated, extracted with AcOEt. The extract was concentrated and the residue was combined with the white solid which was collected by filtration from the aqueous phase. The combined solid materials were dissolved in DCM, treated with 2N HCl in diethyl ether (10 mL) and the mixture was diluted with benzene, evaporated and dried under vacuum to give (presumably) mono-hydrochloride salt of the acid 204 (8.23 g, 99% yield).
Reaction SMILES: Cl[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.C1C[O:29]CC1.C[Si](C)(C)[O-].[K+].Cl>O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[C:5](=[O:29])[NH:10][N:9]3[C:8](=[O:11])[NH:6][N:7]=[C:2]3[C:3]=2[C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[CH:17][CH:16]=1
Reactant: C1CCOC1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)c(Cl)nn12
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]n2c(=O)[nH]nc2c(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
To a r.b. flask was added 6-chloro-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (100 mg, 0.256 mmol), prepared as described in Example 1F, THF (5 ml) and potassium trimethylsilanolate (132 mg, 1.026 mmol). The reaction mixture was stirred at 85° C. for 1.5 hrs. After this time, the solution was cooled to RT and the reaction was diluted with water (25 ml). The pH of the solution was adjusted to 4 with 1N HCl. The resultant solution was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water (20 ml), saturated NaCl (20 ml). The organic layers was dried (MgSO4), filtered and concentrated to give the title compound, 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine-3,6(2H,5H)-dione (90 mg, 95% yield) as yellow solid. MS (M+H)=372.9.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[C:26]([NH:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CC(N)c1ccc(OC)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CC(NC(=O)c1ccccc1)c1ccc(OC)c(OC)c1
Yield: 100.2 %

Procedure:
To an ice bath cooled stirred suspension of methyl 3-amino-3-(3,4-dimethoxyphenyl)propionate hydrochloride (0.689 grams, 2.50 mmol) and triethylamine (0.7 milliliters, 5 mmol) in 15 milliliters of tetrahydrofuran was added 0.3 milliliters of benzoyl chloride (2.6 mmol). The cooling bath was removed after 15 minutes and the mixture stirred for an additional 45 minutes. The reaction mixture was then diluted with 15 milliliters of brine and 15 milliliters of water and then partially concentrated in vacuo to remove the tetrahydrofuran. The reaction slurry was filtered, the solid air-dried, then dried in vacuo (60° C., <1 mm) to afford 0.86 g (100%) of the product as a white powder: 1H NMR (dmso-d6, 250 MHz) δ 8.84 (d, J=8.3 Hz, 1 H, NH), 7.83 (m, 2 H, Ar), 7.60-7.35 (m, 3 H, Ar), 7.06 (s, 1 H, Ar), 6.90 (m, 2 H, Ar), 5.50-5.30 (m, 1 H, CHN), 3.75 (s, 3 H, OCH3), 3.72 (s, 3 H, OCH3), 3.46 (s, 3 H, CO2CH3), 3.05-2.75 (m, 2 H, CH2); 13C NMR (dmso-d6) δ 170.8, 165.6, 148.6, 147.9, 134.9, 134.5, 131.2, 128.3, 127.3, 118.5, 111.6, 110.6, 55.5, 55.5, 51.4, 49.7, 40.6. Anal. Calcd for C19H21NO5. Theoretical C, 66.46; H, 6.16; N, 4.08. Found C, 66.22; H, 6.05; N, 3.98.
Reaction SMILES: [OH:1][C:2]1[C:12]2[NH:11][CH:10]([O:13][CH3:14])[CH:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(N(CC)CC)C>[C:20]([O:1][C:2]1[C:12]2[NH:11][CH:10]([O:13][CH3:14])[CH:9]3[CH2:15][CH2:16][CH2:17][N:8]3[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH3:19])(=[O:22])[CH3:21]
Reactant: COC1Nc2c(ccc(C)c2O)C(=O)N2CCCC12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: COC1Nc2c(ccc(C)c2OC(C)=O)C(=O)N2CCCC12
Reaction time: 0.25 h

Procedure:
49.3 mg of 2,3,5,10,11,11a-hexahydro-9-hydroxy-11-methoxy-8-methyl-1H-pyrrolo[2,1-C][1,4]benzodiazepin-5-one was suspended in 0.5 ml of 1:1 mixture of triethylamine and acetic anhydride and stirred at 0° to 5° C. for 15 minutes under a stream of nitrogen gas. Thus, 30 mg of 2,3,5,10,11,11a-hexahydro-9-acetoxy-11-methoxy-8-methyl-1H-pyrrolo[2,1-C][1,4]benzodiazepin-5-one was obtained as a colorless powdery product. Recrystallization of the resulting product from acetone-ligroin gave a colorless needle-like crystal having a melting point of 147° to 149.5° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][CH:19]1[CH2:21][CH2:20]1>>[CH:19]1([CH2:18][N:3]2[C:4]3[C:9](=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane: 1H NMR (400 MHz, CDCl3) δ 7.48 (s, 2H), 6.57 (s, 1H), 4.04 (d, J=6.6 Hz, 2H), 2.50 (s, 3H), 1.16 (m, 1H), 0.60 (m, 2H), 0.34 (m, 2H); MS (ES) m/z 279 (M+1).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[CH:21]=1)=[C:14]2[CH2:28][CH2:29][N:30]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:44]([N:30]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)[CH2:29][CH2:28][C:14]1[C:13]2[C:17](=[CH:18][CH:19]=[C:11]([NH2:10])[CH:12]=2)[NH:16][C:15]=1[C:20]1[CH:21]=[C:22]([CH3:27])[CH:23]=[C:24]([CH3:26])[CH:25]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)OCc4ccccc4)cc3c2CCN(CCCCc2ccc([N+](=O)[O-])cc2)Cc2ccccc2)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: OCc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2ccc([N+](=O)[O-])cc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 11.5 h
Yield: 88.2 %

Procedure:
To a solution of [3-(2-{benzyl-[4-(4-nitrophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]carbamic acid benzyl ester (500 mg in 25 mL dry methylene chloride) was added 0.50 mL anisole followed by 0.035 mL benzyl alcohol and the mixture stirred at room temperature. Then, 2.94 mL of a 1M solution of aluminum chloride in nitrobenzene was added dropwise. After 11.5 hours, the reaction was cooled to 0° C. and quenched by the addition of saturated aqueous sodium bicarbonate and partitioned between ethyl acetate and aqueous sodium potassium tartarate. The organic portion was washed with additional tartarate solution and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:methanol, 97:3) gave the title compound (354 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH2:28][CH2:29][CH2:30][O:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:29]3[CH2:28][CH2:27][CH2:32][O:31][CH:30]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Reactant: BrC1=COCCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2ccc(C3=COCCC3)cc2C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a stirred solution of 1.59 mmol 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and 1.44 mmol 5-bromo-3,4-dihydro-2H-pyran (CAS: 26274-19-1) in 9 ml ethanol and 21 ml toluene was added 0.08 mmol 1,1-bis(diphenylphosphino)ferrocene dichloro palladium (II) dichloromethane adduct. The mixture was heated to 80° C. and then 10 ml of a solution of 2 M aqueous sodium carbonate was added dropwise. After stirring for a further 2 h at 80° C., the reaction mixture was diluted with 50 ml water and extracted with 3×50 ml ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a yellow oil (40% yield). MS (m/e): 246.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]([OH:14])=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:19][C:20]([NH2:22])=[NH:21]>C(O)C>[NH2:21][C:20]([NH2:22])=[NH2+:19].[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]([O-:14])=[O:13])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: Cc1ccc(S(=O)(=O)CC(=O)O)cc1
Agent: O=C(O)O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)CC(=O)[O-])cc1
Product: NC(N)=[NH2+]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Guanidinium 4-methylphenylsulfonylacetate was prepared as follows: To a mixture of 4.441 g (0.0207 mol) of 4-methylphenylsulfonylacetic acid in 25 mL of ethanol was added 1.867 g (0.0104 mol) of guanidine carbonate and the mixture stirred at room temperature for 18 hr. The resultant product was then filtered off and air dried to afford 5.150 g; mp 152°-153° C. (dec). NMR was in agreement with the proposed structure. The 4-methylphenylsulfonylacetic acid was obtained from Lancaster Synthesis Inc. Windham, N. H.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(O)C.[C].[Pd]>[C:1]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2cc(C(C)(C)C)ccc2c1Cl
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2cc(C(C)(C)C)ccc2c1
Yield: 92.5 %

Procedure:
A solution of ethyl 7-tert-butyl-4-chloroquinoline-3-carboxylate (2.06 g, 7.06 mmol) and triethylamine (1.97 ml, 21.2 mmol) in ethanol (70 ml) was hydrogenated over 5% palladium-carbon (300 mg) at balloon pressure for 1.5 hours. After the catalyst was filtered through a pad of celite, the filter cake was washed with CH2Cl2. The filtrate and washings were evaporated in vacuo to give crude product, which was purified by column chromatography on silica gel with hexane-ethyl acetate (8:1) to give the title compound (1.68 g, 92.5%) as yellow colored oil. 1H NMR (270 MHz, CDCl3) δ ppm 1.43-1.51 (3H, m), 1.45 (9H, s), 4.48 (2H, q, J=7.0 Hz), 6.69-7.75 (1H, m), 7.85-7.91 (1H, m), 8.13 (1H, s), 6.79-8.82 (1H, m), 9.41-9.44 (1H, m).
Reaction SMILES: [I-:1].[Na+].Cl[C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.C(Cl)(=O)C>C(#N)C>[I:1][C:4]1[CH:9]=[C:8]([C:10]2[CH2:14][CH2:13][CH2:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Clc1cc(C2=CCCC2)ccn1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Ic1cc(C2=CCCC2)ccn1
Temperature: 25 °C

Procedure:
A flask was charged with sodium iodide (3.75 g, 25.0 mmol), 2-chloro-4-cyclopent-1-enyl-pyridine (450 mg, 2.5 mmol) and acetonitrile (8 mL). Acetyl chloride (0.27 mL, 3.76 mmol) was slowly added and the reaction mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature and quenched with water. Saturated Na2CO3 and 10% Na2S2O3 were added and the mixture was extracted with EtOAc (3×). The combined organics were dried over MgSO4 and concentrated. The residue was purified by chromatography (0% to 10% EtOAc/hexanes) to afford 2-iodo-4-cyclopent-1-enyl-pyridine as a white solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.[C:19]([O:23][C:24](SC1N=C(C)C=C(C)N=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25]
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To an aqueous solution (40 ml) of L-hydroxyproline methyl ester hydrochloride (8.2 g, 45.2 mmol), triethylamine (7.54 ml, 54.2 mmol) was added at room temperature, and then a solution of 2-(tert-butoxycarbonylthio)-4,6-dimethylpyrimidine (10.8 g, 45 mmol) in dioxane (80 ml) was added thereto. The reaction solution was stirred at room temperature for 1.5 hours, and then dioxane was distilled off under reduced pressure. The residue was extracted with ethyl acetate (250 ml). The organic layer was washed sequentially with a 0.1N sodium hydroxide aqueous solution, dilute hydrochloric acid, water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 5% methanol-methylene chloride) to obtain N-tert-butoxycarbonyl-L-hydroxyproline methyl ester (9.3 g, yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:14][NH2:15].[N:16]1([CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:14][N:15]1[C:4](=[O:6])[C:3]2[C:2](=[CH:10][CH:9]=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=2)[N:1]=[C:29]1[C:28]1[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH2:24][CH2:23][CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:27]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: O=Cc1cccc(OCCCN2CCCCC2)c1
Reactant: CN
Product: Cn1c(-c2cccc(OCCCN3CCCCC3)c2)nc2ccc([N+](=O)[O-])cc2c1=O

Procedure:
The intended compound was obtained according to the method of Example 15 but using 2-amino-5-nitrobenzoic acid, methylamine and 3-(3-piperidin-1-ylpropoxy)benzaldehyde.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[N:25]=[C:24]2[C:32](OCC)=[O:33])=[CH:19][C:18]=1[F:37])#[N:16].[Cl-].[Ca+2].[Cl-]>CO>[N:2]1([C:32]([C:24]2[N:23]([C:20]3[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[C:18]([F:37])[CH:19]=3)[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[N:25]=2)=[O:33])[CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1nc2cccnc2n1-c1ccc(C#N)c(F)c1
Reactant: C1CNC1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(-n2c(C(=O)N3CCC3)nc3cccnc32)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of azetidine hydrochloride (120 mg, 1.3 mmol) and N,N-diisopropylethylamine (168 mg, 1.30 mmol) in methanol (2 mL) was stirred at room temperature for 1 hour. At this point, ethyl 3-(4-cyano-3-fluorophenyl)-3H-imidazo[4,5-b]pyridine-2-carboxylate (C16) (40 mg, 0.13 mmol) and calcium chloride (15 mg, 0.13 mmol) were added, and the reaction mixture was stirred at room temperature for an additional 2 hours. After removal of solvents in vacuo, the residue was purified by reversed phase HPLC (Column: DIKMA Diamonsil C18(2), 5 μm; Mobile phase A: 0.225% formic acid in water; Mobile phase B: 0.225% formic acid in acetonitrile; Gradient: 15% to 45% B) to provide the product as a yellow solid. Yield: 4.0 mg, 12 μmol, 9%. LCMS m/z 322.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.49 (dd, J=4.8, 1.3 Hz, 1H), 8.20 (dd, J=8.2, 1.4 Hz, 1H), 7.77-7.82 (m, 1H), 7.36-7.43 (m, 3H), 4.80-4.89 (m, 2H), 4.18-4.26 (m, 2H), 2.39-2.50 (m, 2H).
Reaction SMILES: [S:1]([C:5]1[C:6]([O:8][C:9](=[O:11])[CH:10]=1)=[O:7])([OH:4])(=[O:3])=[O:2].C1(=O)OC(=[O:16])C=C1.[OH-].[Na+:20].[CH2:21]([CH2:23][NH2:24])[OH:22].Cl(O)(=O)(=O)=O>CC(C)=O>[OH:22][CH2:21][CH2:23][NH:24][CH:10]([CH:5]([S:1]([OH:4])(=[O:3])=[O:2])[C:6]([O-:16])=[O:7])[C:9]([O-:8])=[O:11].[Na+:20].[Na+:20].[Na+:20]
Reactant: O=C1C=CC(=O)O1
Reactant: NCCO
Reactant: O=C1C=C(S(=O)(=O)O)C(=O)O1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])C(NCCO)C(C(=O)[O-])S(=O)(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Sulfomaleic anhydride (prepared from a 1/1 mole ratio of SO3 /maleic anhydride by heating the mixture at 100°-110°C for 3 hours; active content, 86%), 20.7 gm (0.1 mole), was added to 100 gm of ice. The resulting solution was kept at 10°-15°C and neutralized to pH = 8.6 by slowly adding 28.4 gm of 50% sodium hydroxide. Monoethanolamine, 6.1 gm (0.1 mole), was next added slowly and the temperature allowed to rise to room temperature. After standing overnight, the reaction mixture was poured into 800 ml of acetone. The solvent was then decanted from the resulting syrupy lower layer and the latter reprecipitated three times from water with fresh acetone. The residue was then dried in a dessicator over P2O5 to give 38.8 gm of an off-white, granular product containing approximately 88% trisodium α-(12-hydroxyethylamino)-β-sulfosuccinate by titration with perchloric acid. The structure was confirmed by NMR analysis.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[CH:10]1)(=O)=O.[C:33](#[N:35])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[CH2:19]([O:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[N:9]([C@@H:8]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Br:32])[CH:27]=1)[CH2:7][CH2:6][C:33]#[N:35])[CH:10]=[CH:11]2)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CS(=O)(=O)OCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: N#CCC[C@H](c1cccc(Br)c1)n1ccc2cccc(OCc3ccccc3)c21
Yield: 74 %

Procedure:
A solution of (3R)-3-(3-bromophenyl)-3-(7-benzyloxyindol-1-yl)propan-1-yl methanesulfonate (2.50 g, 4.86 mmol prepared as in Example 3, step (i)) and tetrabutylammonium cyanide (1.96 g, 7.30 mmol) in dry acetonitrile (40.0 ml) under nitrogen was heated under reflux for 24 h. The cooled solution was evaporated to yield an orange/brown oil which was taken up in ethyl acetate (200 ml), washed with water (3×100 ml), dried (Na2SO4) and the solvent removed in vacuo. Column chromatography (ethyl acetate--light petroleum (b.p. 40-60° C.), 1:4) gave the title compound as a pale yellow oil (1.60 g, 74%). [α]D19 -129 (c=0.005 gml-1, CHCl3); Vmax (thin film)/cm-1 3064, 3033, 2932, 2872, 2247 (CN), 1575; δH (270 MHz) 2.10 (2H, m 2×propyl 3-H); 2.38 (2H, m, 2×propyl 2-H); 5.09 (2H, q, CH2Ph, 2J=10.9 Hz); 6.39 (1H, dd, propyl 1-H, 3J1,2 =9.7, 3J1,2 =5.8 Hz); 6.55 (1H, d, 3-H, 3J3.2 =3.3 Hz); 6.70 (1H, d, 6-H, Jo =7.6 Hz); 6.83 (1H, d, 4-H, Jo =7.6 Hz); 7.00 (2H, m, 5-H, 5'-H); 7.05 (1H, d, 2-H, 3J2,3 =3.0 Hz); 7.15 (1H, s, 2'-H); 7.21 (1H, d, 6'-H, Jo =8.0 Hz); 7.30 (1H, d, 4'-H, Jo =8.6 Hz); 7.38 (5H, m, 5ArH).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2([CH2:43][C:44]([OH:46])=O)[C:34]1[C:35]([O:40][CH2:41][CH3:42])=[N:36][CH:37]=[CH:38][CH:39]=1.[CH3:47][N:48]1[CH2:53][CH2:52][CH:51]([N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:50][CH2:49]1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2([C:34]1[C:35]([O:40][CH2:41][CH3:42])=[N:36][CH:37]=[CH:38][CH:39]=1)[CH2:43][C:44]([N:57]1[CH2:56][CH2:55][N:54]([CH:51]2[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]2)[CH2:59][CH2:58]1)=[O:46]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCOc1ncccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ncccc1C1(CC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2ccc(Cl)cc21
Reaction time: 0.25 h
Yield: 40.2 %

Procedure:
195 mg (1.44 mmol) of 1-hydroxybenzotriazole and 276 mg (1.44 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added to a solution of 1.00 g of [5-chloro-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid in 10 ml of dimethylformamide and, after stirring for 15 minutes, 277 mg (1.51 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 1.00 ml (7.41 mmol) of triethylamine were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate several times. The combined organic phase was extracted with water and saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was concentrated in vacuo. The residue was purified by chromatography on silica gel (12 g Redisep cartridge, mobile phase gradient from 10 to 70% methanol in dichloromethane). 311 mg of the title compound were obtained as a white foam.