Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:14]>CCO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)[C:13](=[O:14])[C:12]3[C:11](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:10]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1C(=O)Nc1ccc(C2CCCC2)cc1
Reactant: O=Cc1ccc(Cl)nc1
Solvent: CCO
Product: O=c1c2ccccc2nc(-c2ccc(Cl)nc2)n1-c1ccc(C2CCCC2)cc1
Yield: 53.9 %

Procedure:
6-chloro-3-pyridinecarboxaldehyde (0.177 g, 1.20 mmol) and CuCl2 (0.335 g, 2.40 mmol) were added to a solution of 2-amino-N-(4-cyclopentylphenyl)benzamide (0.350 g, 1.20 mmol) in EtOH (30 mL), and refluxed for 5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The organics were washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 15% to 60% EtOAc in heptane, afforded 2-(6-chloropyridin-3-yl)-3-(4-cyclopentylphenyl)quinazolin-4(3H)-one (0.260 g, 54%). Pd(PPh3)4 (0.150 g, 0.12 mmol), K2CO3 (0.270 g, 1.90 mmol), and trimethylboroxine (0.18 mL, 1.20 mmol) were added to a solution of 2-(6-chloropyridin-3-yl)-3-(4-cyclopentylphenyl)quinazolin-4(3H)-one (0.260 g, 0.65 mmol) in dioxane (15 mL) and heated to reflux temperature for 20 minutes. The reaction mixture was filtered through Celite®, washed with EtOAc. The filtrate was concentrated and purified by flash chromatography on silica gel, eluting with 30% to 100% EtOAc in heptane, to afford the title compound as a white solid (0.068 g, 27%). 1H-NMR (300 MHz, DMSO-d6): δ8.45 (s, 1H), 8.19 (d, J=7.4 Hz, 1H), 7.84-8.00 (m, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.50-7.70 (m, 2H), 7.17-7.31 (m, 4H), 7.11 (d, J=8.0 Hz, 1H), 2.85-3.06 (m, 1H), 2.38 (s, 3H), 1.85-2.09 (m, 2H), 1.34-1.84 (m, 6H). MS (APCI) m/z: 382 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][NH2:4].[CH2:11]1[O:13][CH:12]1[CH2:14][OH:15]>C1(C)C=CC=CC=1>[OH:13][CH:12]([CH2:14][OH:15])[CH2:11][NH:4][CH2:3][CH:2]([OH:1])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC(O)CN
Reactant: OCC1CO1
Solvent: Cc1ccccc1
Product: CCCCCCC(O)CNCC(O)CO
Yield: 90.4 %

Procedure:
108.8 grams of 2-hydroxyoctyl amine were dissolved in 500 ml of toluene, heated to reflux, treated within 10 minutes under stirring with 18.5 grams of glycidol and held at reflux for 2 hours. Subsequently, the solvent was drawn off and the excess amine distilled off in a vacuum. There were obtained as a residue 49.5 grams (90.5% of theory) of N-(2,3-dihydroxypropyl)-N-(2-hydroxyoctyl) amine which after recrystallization from ethylacetate gave colorless crystals having a melting point of 85°-90° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[C:14]1([CH2:20][C:21]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(Cc1ccccc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
Modification of Method A: To a mixture of 1H-pyrrolo[2,3-b]pyridine (1.0 g, 8.46 mmol) and AlCl3 (3.4 g, 25.50 mmol) in dry methylene chloride (20 mL) was added phenyl acetyl chloride (3.27 g, 21.15 mmol) at room temperature. The solution was then stirred at room temperature (RT) for 4 hrs. The mixture was poured into iced water and extracted with methylene chloride (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was then dissolved in MeOH (20 mL) and treated with 6N NaOH (5 mL) at RT for 2 hrs. Evaporated most of the solvent, the residue was acidified with 6N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by flash column to give desired product (1.3 g, 65%). MS (ES−): m/e=235.2 (M−H); LC/Method A/2.86 min.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=O)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:22].Cl.[NH2:24][CH2:25][CH2:26][O:27][NH2:28].N1C=CC=CC=1>C(O)C>[ClH:22].[ClH:22].[NH2:24][CH2:25][CH2:26][O:27][N:28]=[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(CCCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: NCCON=C(CCCCn1ccnc1)c1ccc(C(F)(F)F)cc1
Reaction time: 3 h
Yield: 39.8 %

Procedure:
A mixture of 5-(1-(1H)-imidazolyl)-1-(4-trifluoromethylphenyl)-1-pentanone (11.5 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (5.78 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 3.3 g (20%) of product, mp 115°-120° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1>>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])[CH:19]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1cccnc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccnc4)cc23)CC1
Yield: 73.8 %

Procedure:
Beginning with 7.0 mg (0.03 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.09 mMol pyridine-3-carboxylic acid, 7.4 mg of the title compound were recovered.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N+]=[N-]>>[CH2:24]([O:23][C:21]([C:20]1[NH:17][C:12]2[CH:11]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[O:16][C:13]=2[CH:14]=1)=[O:22])[CH3:25]
Reactant: O=Cc1ccc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: CCOC(=O)CN=[N+]=[N-]
Product: CCOC(=O)c1cc2oc(-c3ccc([N+](=O)[O-])cc3)cc2[nH]1

Procedure:
2-(4-Nitro-phenyl)-4H-furo[3,2-b]pyrrole-5-carboxylic acid ethyl ester is prepared from commercially available 5-(4-nitro-phenyl)furfural and ethyl azidoacetate as described hereinabove.
Reaction SMILES: [N:1]([C@H:4]([C@@H:30]1[CH2:34][C@@H:33]([CH:35]([CH3:37])[CH3:36])[C:32](=[O:38])[O:31]1)[CH2:5][CH:6]([CH:27]([CH3:29])[CH3:28])[C@H:7](OC(=O)C(C)C)[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:9]=1)=[N+]=[N-].C(CN)O>C(O)C.[Pd]>[NH2:1][C@H:4]([C@H:30]1[O:31][C:32](=[O:38])[C@H:33]([CH:35]([CH3:37])[CH3:36])[CH2:34]1)[CH2:5][C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:9]=1)[CH:27]([CH3:28])[CH3:29]
Reactant: COCCCOc1cc([C@@H](OC(=O)C(C)C)C(C[C@H](N=[N+]=[N-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1F
Agent: [Pd]
Solvent: CCO
Solvent: NCCO
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H]2C[C@@H](C(C)C)C(=O)O2)C(C)C)ccc1F

Procedure:
A solution of isobutyric acid (S)-2-[(S)-2-azido-2-((2S,4S)-4-isopropyl-5-oxo-tetrahydro-furan-2-yl)-ethyl]-1-[4-fluoro-3-(3-methoxy-propoxy)-phenyl]-3-methyl-butyl ester (1.45 g, 2.7 mmol, 1 equiv.), Pd/C (10%, 2.9 g) and ethanolamine (0.17 mL, 2.7 mmol, 1 equiv.) in ethanol (135 mL) were shaken under H2 (1 atmosphere) for 24 hours. The reaction mixture is filtered, before the solvent is evaporated to afford the product as a light grey gum. MS (LC-MS): 424 [M+H]+
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[C:5]([CH3:12])=[CH:6][C:7]([O:10][CH3:11])=[N:8][CH:9]=1.[OH-].[Na+]>C(O)(=O)C.C([O-])(=O)C.[Na+].O>[NH2:3][C:4]1[C:9]([Br:1])=[N:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH3:12]
Reactant: BrBr
Reactant: COc1cc(C)c(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(C)c(N)c(Br)n1
Reaction time: 0.33 h
Yield: 73.4 %

Procedure:
Bromine (4.8 g) was added in one portion to a mixture of 5-amino-2-methoxy-4-methylpyridine (3.9 g) in acetic acid (25 ml) and sodium acetate (4.0 g). The resulting mixture was stirred for 20 min. and then added to a solution of sodium hydroxide (15 g) in water (200 ml). The product was extracted with chloroform, dried (anhydrous magnesium sulfate), concentrated, and purified on a silica gel column (methylene chloride/ethyl acetate, 19:1→4:1) to give 4.5 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [C:1]1([NH:11][C:12]2[O:13][C:14]3[C:20]([F:21])=[C:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C1COCC1.CO>[C:1]1([NH:11][C:12]2[O:13][C:14]3[C:20]([F:21])=[C:19]([CH2:22][C:23]([OH:25])=[O:24])[CH:18]=[CH:17][C:15]=3[N:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3cccc4ccccc34)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2nc(Nc3cccc4ccccc34)oc2c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.5 %

Procedure:
Methyl (2-(1-naphthylamino)-7-fluoro-6-benzoxazolyl)acetate (1.41 g, 4.02 mmol) was dissolved in THF/methanol (21, 30 ml). To the resulting solution was added 1N NaOH (10 ml). After stirring at room temperature for 12 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(1-naphthylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.44 g, 100%) as a brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:11]([F:13])[F:12])=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[F:13][CH:11]([F:12])[C:7]1[S:8][CH:9]=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccsc1C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1ccsc1C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Thiophenecarboxylic acid (3.48 g) was dissolved in tetrahydrofuran (50 ml), and N,N,N',N'-tetramethylethylenediamine (10 ml) was added. The mixture was cooled to -78° C., and n-butyllithium (1.6M in hexane, 41.3 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, and N,N-dimethylformamide (4.6 ml) was added dropwise. The mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a mixture of 2-formyl-3-thiophenecarboxylic acid and 5-formyl-3-thiophenecarboxylic acid (2.11 g). This mixture was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (0.95 ml) and potassium carbonate (1.66 g) were added. The reaction mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-formyl-3-thiophenecarboxylic acid ethyl ester (1.75 g). 2-Formyl-3-thiophenecarboxylic acid ethyl ester (1.66 g) in methylene chloride (20 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.32 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-difluoromethyl-3-thiophenecarboxylic acid ethyl ester (1.08 g). 2-Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (7.8 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-difluoromethyl-3-thiophenecarboxylic acid (0.88 g) as crystals.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[C:28]([O:27][C:25](=[O:26])[CH2:24][N:10]1[C:8]2[N:9]=[C:4]([NH2:3])[N:5]=[CH:6][C:7]=2[CH:13]=[C:12]([C:14]2[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=2[Cl:20])[C:11]1=[O:22])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Yield: 30.1 %

Procedure:
To a suspension of NaH (60% in mineral oil, 67 mg) in 10 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (398 mg, 1.30 mmol). The mixture was heated at 45° C. to 55° C. for 40 minutes resulting in a clear solution. Tert-butyl bromoacetate (250 μL, 1.69 mmol) was added, and the solution was stirred at 50° C. for several minutes, then cooled to room temperature and poured onto 60 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with a gradient of 1:2 hexane:ethyl acetate to all ethyl acetate to provide 165 mg (30%) of [2-amino-6-(2,6-dichlorophenyl)-7-oxo-7H-pyrido[2,3-d]pyrimidin-8-yl]-acetic acid tert-butyl ester; mp 171°-173° C.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)([C:15]([OH:17])=[O:16])[CH2:10]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][C:11]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCCC(Oc2cccc(F)c2)(C(=O)O)C1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCCC(Oc2cccc(F)c2)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A reaction mixture of 3-(tert-butoxycarbonylamino)-1-(3-fluorophenoxy)cyclohexanecarboxylic acid in TFA (neat) was stirred at room temperature for 10 minutes. The product, 3-amino-1-(3-fluorophenoxy)cyclohexanecarboxylic acid, was obtained after purification by reverse phase HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1([NH2:10])[CH2:9][CH2:8][CH2:7][CH2:6]1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1([NH:10][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)CC1(N)CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CC1(NCc2ccc(F)cc2)CCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
A solution of (1-amino-cyclopentyl)-acetic acid methyl ester (318 mg, 2.02 mmol) in anhydrous methanol (10 mL) was treated with 4-fluoro-benzaldehyde (0.27 mL, 2.56 mmol) and stirred at 25° C. under a nitrogen environment. After 10 min, glacial acetic acid (0.384 mL, 6.71 mmol) and sodium triacetoxyborohydride (1.1 g, 5.05 mmol) were added sequentially, and the resulting mixture was stirred at 25° C. for 18 h. The reaction was diluted with a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give [1-(4-fluoro-benzylamino)-cyclopentyl]-acetic acid methyl ester (270 mg, 50%) as a colorless oil. LC-MS (ESI) calculated for C15H20FNO2: 265.3, found 266.2 [M+H+].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+]>Br>[OH:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[C:12](=[O:21])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2CCC(=O)N2Cc2ccncc2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CCC(c2cccc(O)c2)N1Cc1ccncc1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
A solution of 5-(3-methoxyphenyl)-1-(4-pyridinylmethyl)-2-pyrrolidinone (2.9 g) and 48% hydrobromic acid (40 ml) was heated at 100° C. for 5.5 hrs. The reaction mixture was cooled to ambient temperature, neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane (3 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, ether/0-20% methanol). The appropriate fractions were collected and concentrated to give 2.3 g (81%) of product. Recrystallization from ether/methanol gave the analytical sample, mp 148°-150° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(C#N)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(C#N)cc3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Butoxy-benzenesulfonyl)-1-(4-cyanobenzyl)-piperidine-4-carboxylic ethyl ester (10.0 g, 124 mmol) dissolved in THF:Methanol (75: 50 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield .7g (11%); off white solid; MS: 456.0 (M+H)+
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH3:21]>C1COCC1>[S:2]([C:5]1[CH:14]=[C:13]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])(=[O:3])[NH2:21]
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1S(=O)(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1S(N)(=O)=O
Yield: 80.5 %

Procedure:
A solution of 11 g (32 mmol) of methyl 2-chlorosulfonyl-4-methanesulfonylaminomethylbenzoate in 200 ml of THF is treated at 0° C. with 1.1 g (64 mmol) of NH3 gas. For work-up, the mixture is concentrated in vacuo. Extracting the residue by stirring with water and then filtration and drying in vacuo give 8.3 g (80%) of methyl 2-sulfamoyl-4-methanesulfonylaminomethylbenzoate of melting point 185–187° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][N:10]=[C:11]([C:15](Cl)=[O:16])[C:12](Cl)=[O:13])C.[OH-:18].[Na+]>ClC1C=CC=CC=1.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[N:9]=[N:10][C:11]([C:12]([OH:13])=[O:18])=[C:15]2[OH:16]
Reactant: CCc1ccccc1NN=C(C(=O)Cl)C(=O)Cl
Reactant: [OH-]
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1
Product: Cc1cccc2c(O)c(C(=O)O)nnc12

Procedure:
16.4 g of titanium tetrachloride was added to a stirred solution of 22.5 g of 53C in 160 ml of chlorobenzene, under nitrogen, at 20° C. The mixture was heated at 90°-100° C. for 5 hours and let stand over a weekend at room temperature. Then 20 ml of a solution of 26.4 g of sodium hydroxide in 330 ml of water was added, drop-by-drop, and the mixture was stirred well and stripped of solvent to form a mush. The remainder of the sodium hydroxide solution was added, and the mixture was stirred and filtered through Celite. The filtrate was acidified with 12 N hydrochloric acid and filtered. The solid was dried under reduced pressure and dissolved in 150 ml of 2 N aqueous ammonium hydroxide solution. The solution was filtered. The filtrate was acidified with 12 N hydrochloric acid and filtered. The solid was washed with water, dried under reduced pressure and dissolved in warm ethanol. The solution was filtered and the solvent was evaporated from the filtrate, to give 8-methyl-4-hydroxy-cinnoline-3-carboxylic acid (53D), as a solid, m.p.: 230° C. (with decomposition).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][C:23]([C:24]([F:27])([F:26])[F:25])=[C:18]3[N:17]([CH2:28][CH3:29])[C:16]2=[O:30])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.CCOC(C)=O>[CH2:28]([N:17]1[C:18]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[C:24]([F:26])([F:25])[F:27])[N:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)[C:16]1=[O:30])[CH3:29]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2nccc(C(F)(F)F)c21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C(F)(F)F)c21
Reaction time: 4 h
Yield: 66.9 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-1-ethyl-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (197 mg) and 10% palladium on carbon (50% wet, 68 mg) in MeOH (6.5 mL) and EtOAc (6.5 ml) was hydrogenated under balloon pressure at room temperature for 4 h. The solid was filtrated and washed with MeOH (10 ml) to remove the catalyst. The filtrate was concentrated in vacuo to give the title compound (103 mg).