Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[C-:19]#[N:20].[Na+]>O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][C:19]#[N:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCc1cccc(Oc2ccccc2)c1
Yield: 91 %

Procedure:
To a solution of 218 g. m-phenoxy-benzyl chloride in 850 ml. of 96% ethyl alcohol a solution of 57.8 g. of sodium cyanide in 100 ml. of water is added at once. The reaction mixture is boiled under stirring until the starting material cannot be detected anymore by thin layer chromatography. When the reaction is completed the reaction mixture is poured into 1 liter of water and the separating oil is extracted with 3×500 ml. of benzene. The combined benzene solutions are washed with 1 liter of water and dried above sodium sulphate. Sodium sulphate is filtered off and benzene is distilled off. 190 g. (91%) of m-phenoxy-benzyl cyanide are obtained (purity more than 90%, determined by gas chromatography). Boiling point 138° C./0.2 mmHg.
Reaction SMILES: C(S[C:4]1[O:5][C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[CH:10][CH:9]=[C:8]1[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=21)C.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CO>[N:19]1([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:14])[CH:13]=2)=[CH:10][CH:9]=[C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=32)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1
Reactant: CCSc1cc(=O)c2ccc3ccccc3c2o1
Reactant: C1CNCCN1
Solvent: CO
Product: O=c1cc(N2CCNCC2)oc2c1ccc1ccccc12
Yield: 28 %

Procedure:
Prepared from 2-ethylsulphanyl-benzo[h]chromen-4-one (0.384 g, 1.5 mmol) and piperazine (1.29 g, 15 mmol). Recrystallisation from ethyl acetate provided an off white solid. (0.121 g, 0.43 mmol, 28% yield) mp 208-209° C. UV λmax=317.0, 273.0, 255.0, 216.5 nm (Methanol). 1H NMR (200 MHz, CDCl3) δ 3.01 (4H, m); 3.55 (4H, m); 5.57 (1H, s); 7.56 (2H, m); 7.66 (1H, d); 7.85 (1H, m); 8.08 (1H, d); 8.21 (1H, m). EIMS m/z (EI+): 280 (M+), 261, 238, 225, 170, 139. Anal. Calcd for C17H16N2O2.0.3H2O: C, 71.46; H, 5.81; N, 9.80. Found: C, 71.88; H, 5.91; N, 9.33.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23](#[N:30])[CH:24]=[CH:25][CH2:26][CH2:27][CH2:28][CH3:29].N12CCCN=C1CCCCC2>C(#N)C>[CH3:20][Si:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][O:16][CH2:15][N:12]1[C:8]2[N:9]=[CH:10][N:11]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][C:23]#[N:30])[CH:3]=3)[C:7]=2[CH:14]=[CH:13]1
Reactant: CCCCC=CC#N
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (6.1 g, 19 mmol) in acetonitrile (58 mL) was added crude hept-2-enenitrile (2.6 g, 23 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.49 mL, 23.4 mmol). The resulting mixture was stirred at room temperature over the weekend and then evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% of ethyl acetate in hexane, to give the desired product (6.90 g, 84%). LCMS calculated for C22H33N6OSi(M+H)+: m/z=425.2. Found: 425.4. The racemic mixture was applied on an OD-H column (3×25 cm, 5 μM), eluting with 15% ethanol and 85% hexane mixture at a flow rate of 28 mL/min to give the two desired enantiomers. First peak retention time of 9.46 min; second peak (3.45 g) retention time of 12.35 min.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=O>O>[CH3:14][CH2:13][O:12][C:8]([CH:9]1[NH:1][CH:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]1)=[O:11]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCOC(=O)C=O
Solvent: O
Product: CCOC(=O)C1NC(C(=O)O)CS1
Temperature: 25 °C
Reaction time: 50 h
Yield: 29313.2 %

Procedure:
L-Cysteine (60.4 g, 0.50 mmol) and ethyl glyoxylate (polymer, 47% toluene solution, 50.9 g, 0.234 mol) were added to water (150 ml), and the mixture was stirred at room temperature for 50 hours. The obtained solution was concentrated under reduced pressure, and the precipitated solid was collected by filtration. The obtained white solid (about 40 g) was suspended in water (100 ml), and the suspension was stirred for 16 hours at slurry state. The white crystals were collected by filtration, and dried under reduced pressure to give thiazolidine-2,4-dicarboxylic acid 2-ethyl ester as a white solid (30.08 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH:30][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([OH:1])[CH:3]=3)[CH:29]=1)=[CH:17]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL), was added and the mixture was stirred for 2 hours. The mixture was shaken; the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a red-orange gum. Recrystallization from methanol gave the product (350 mg), mp 170-171° C.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH2:24]([S:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:18](=[O:21])(=[O:20])[NH2:19])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(S)c1Oc1ccccc1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Mercapto-4-phenoxy-5-sulfamylbenzoic acid (0.6 g) is suspended in water (20 ml) and the pH is adjusted to 8 by addition of 1 N sodium hydroxide. Benzyl bromide (0.35 g) is added to the resulting solution, and the reaction mixture is stirred for 2 hours at room temperature. After cooling, the precipitated sodium salt of 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration. The salt is dissolved in hot water (60 ml) and the solution acidified by addition of 1 N hydrochloric acid. After cooling, the precipitated 3-benzylthio-4-phenoxy-5-sulfamylbenzoic acid is collected by filtration and recrystallized from aqueous ethanol to yield the desired compound with a melting point of 234°-236° C., after drying in vacuo.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].S(=O)(=O)(O)O.[CH3:16][C:17](=[CH2:19])[CH3:18].[OH-].[Na+]>C(OCC)(=O)C.O1CCOCC1>[C:17]([O:7][C:6](=[O:8])[C@H:4]([CH2:3][C:2]([CH3:10])([CH3:9])[CH3:1])[NH2:5])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)C[C@H](N)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 50.5 %

Procedure:
To a pressure bottle were added 1.5 gm (10.3 mMol) 4-methyl-(L)-leucine, 25 mL dioxane, 1.5 mL concentrated sulfuric acid and 25 mL isobutylene. The pressure bottle was stoppered and the reactants were shaken together for 18 hours. The reaction mixture was then treated with 60 mL cold 1N sodium hydroxide and 100 mL ethyl acetate. To this mixture was added sufficient 1N sodium hydroxide until the pH of the mixture was 8.5. The layers were separated and the aqueous phase was extracted well with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate and concentrated under reduced pressure to provide an oil which gradually crystallized to provide 1.05 gm (50.5%) of the title compound.
Reaction SMILES: C([O:4][C@@H:5]([CH3:9])[C:6](Cl)=[O:7])(=O)C.C([O:13][CH2:14][CH:15]([NH:21][C:22]([C:24]1[C:29]([I:30])=[C:28]([NH2:31])[C:27]([I:32])=[C:26]([C:33]([NH:35][CH:36]([CH2:42][O:43]C(=O)C)[CH2:37][O:38]C(=O)C)=[O:34])[C:25]=1[I:47])=[O:23])[CH2:16][O:17]C(=O)C)(=O)C.[OH-].[Na+]>CN(C)C(=O)C>[CH3:9][C@H:5]([OH:4])[C:6]([NH:31][C:28]1[C:29]([I:30])=[C:24]([C:22]([NH:21][CH:15]([CH2:16][OH:17])[CH2:14][OH:13])=[O:23])[C:25]([I:47])=[C:26]([C:33]([NH:35][CH:36]([CH2:42][OH:43])[CH2:37][OH:38])=[O:34])[C:27]=1[I:32])=[O:7]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: C[C@H](O)C(=O)Nc1c(I)c(C(=O)NC(CO)CO)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 15 h
Yield: 86.7 %

Procedure:
(S)-2-(Acetyloxy)propanoyl chloride (16.5 g, 110 mmol) is added, over 20 min, to a stirred solution of N,N′-bis[2-acetyloxy-1-[(acetyloxy)methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (53.3 g, 61.1 mmol) in N,N-dimethylacetamide (75 mL) while keeping the temperature of the reaction mixture below 30° C. A further amount of (S)-2-(acetyloxy)propanoyl chloride (0.9 g, 6.0 mmol) is added after 24 and 30 hours and the reaction mixture is stirred at the same temperature for additional 15 hours. 5M NaOH (90 mL, 450 mmol) is dripped over a period of 2 hours into the reaction mixture vigorously stirred at 45° C. After two hours the mixture is concentrated under vacuum and reintegrated with additional N,N-dimethylacetamide (200 mL). After two hours at room temperature the resulting suspension is filtered and the solid washed with N,N-dimethylacetamide (2×20 mL). The mother liquors, combined with the washings, are concentrated to an oily residue, which is diluted with water (200 mL) and nanofiltered. The retentate is loaded onto an Amberlite® XAD-16.00 resin column (160 mL) that is eluted with water. The eluate is concentrated and loaded onto two ion exchange resin columns (Dowex® C350 15 mL, Relite® MG1 10 mL). The eluate is concentrated and the solid residue is crystallized from ethanol to afford Iopamidol (41.2 g, 53 mmol).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[CH:6]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1.F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:3][O:4][C:5](=[O:25])[CH:6]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:22][CH:23]=1)[CH2:7][C:8]1[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.25 g, 6.3 mmol) in DMF (2 mL) under argon, 15 (2.0 g, 6.3 mmol) in dry DMF (3 mL) was added. To the resulting yellow solution, 4-fluorobenzaldehyde (0.68 mL, 6.3 mmol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and solvent was evaporated. An ethyl acetate solution of crude product was filtered through a small bed of silica gel to yield 16 (1.83 g, 69%) as oil: 1HNMR(400 MHz, DMSO-d6): δ 9.91 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.04 (d, J=5.4 Hz, 2H), 7.01 (d, J=5.4 Hz, 2H), 6.30 (t, J=2.1 Hz, 1H), 6.25 (d, J=2.1 Hz, 2H), 3.86 (t, J=7.8 Hz, 1 Hz), 3.76 (s, 6H), 3.66 (s, 3H), 3.36 (dd, J=12.6 and 8.1 Hz, 1H), 2.97 (dd, J=13.5 and 7.5 Hz, 1H); MS (EI) m/z 421 [M]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]=[C:24]1[O:28][C:26](=[O:27])[CH2:25]1>>[C:26]([O:22][CH2:21][CH2:20][N:17]1[CH2:16][CH2:15][N:14]([CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:19][CH2:18]1)(=[O:27])[CH2:25][C:24]([CH3:23])=[O:28]
Reactant: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 1.5 h

Procedure:
To 4-benzhydryl-1-piperazineethanol (18.1 g) was added diketene (5.1 g) and the mixture was heated under stirring at 70°-80° C. for 1.5 hours. The product obtained was purified by silica gel chromatography [eluent: hexaneethyl acetate (3:2)] to give 2-(4-benzhydryl-1-piperazinyl)-ethyl acetoacetate as an oil. Yield 17.1 g (73.6%). IR(Neat): 1730, 1715 cm-1. NMR(CDCl3)δ: 2.22(3H, s), 2.43(10H, broad) 3.39(2H, s), 4.18(1H, s), 4.20(2H, t, J=6), 6.64-7.73(10H, m).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[CH:20]=O)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30]>>[F:25][C:26]([F:35])([F:36])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)[CH:18]=1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CCCCCCCCCCCc1noc(-c2cccc(C=O)c2)n1
Product: CCCCCCCCCCCc1noc(-c2cccc(CNCc3ccccc3C(F)(F)F)c2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 3-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 488.4. HPLC (Condition A), Rt: 4.78 min (HPLC purity: 95.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CCO>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:47][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCc2ccccc2)NC#N)c1
Temperature: 60 °C

Procedure:
[2′-(3-Cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester (0.10 g, 0.17 mmol) and benzylamine (0.04 mL, 0.34 mmol) were combined in EtOH (1 mL) and heated to 60° C. The reaction was monitored by analytical LCMS, and additional benzylamine (0.04 mL, 0.34 mmol) was added to push the reaction to completion. Further benzylamine (0.10 mL, 0.92 mmol) was added, and the reaction was heated for a total of 48 hours. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][N:11]=[C:10]3[CH2:17][CH2:18][CH2:19][C:9]=23)[CH2:3]1.CC(O)=O>CCOC(C)=O.[Fe]>[NH2:14][C:13]1[C:8]([N:4]2[CH2:5][CH2:6][CH2:7][C:2]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:1])[CH2:3]2)=[C:9]2[CH2:19][CH2:18][CH2:17][C:10]2=[N:11][CH:12]=1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC1(NC(=O)OC(C)(C)C)CCCN(c2c(N)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A mixture of tert-butyl [3-methyl-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (100.0 mg, 0.27 mmol), AcOH (1.44 mL) and iron powder (222 mg, 3.98 mmol) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc, filtered through a short silica gel plug. The residue was rinsed with fresh EtOAc and filtered. The filtrate was concentrated under reduced pressure, diluted with EtOAc and neutralized with Na2CO3 solution. After vacuum filtration to remove insoluble impurities, the aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated under reduced pressure to give the sub-title compound as off-white powder (80 mg, 90%). LCMS calc. for C19H31N4O2 (M+H)+: m/z=347.2. Found: 347.2.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH2:21][CH:22]=[CH2:23])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:21]([CH:9]1[CH2:10][CH:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][NH:8]1)[CH:22]=[CH2:23]
Reactant: C=CCC1CC(OCc2ccccc2)CN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC1CC(OCc2ccccc2)CN1
Reaction time: 1 h

Procedure:
2-Allyl-4-benzyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester, 51, (0.76 g, 2.4 mmol) is dissolved in methylene chloride (33 mL), and trifluoroacetic acid (25 mL) is added. The reaction mixture is stirred for 1 hour and then concentrated in vacuo. MeOH (40 mL) is added and the solvent is removed in vacuo to afford the desired product in approximately quanitative yield as a viscous oil which is used without further purification.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15])#[N:10]>C(N(CC)CC)C>[C:9]([C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:7][C:2]1[C:1]([NH:8][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([C:9]#[N:10])[CH:12]=2)=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])#[N:10]
Reactant: Nc1ccccc1N
Reactant: N#Cc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Product: N#Cc1cccc(C(=O)Nc2ccccc2NC(=O)c2cccc(C#N)c2)c1

Procedure:
Using a procedure similar to Example 1D, except starting with 1,2-benzenediamine and 3-cyanobenzoyl chloride with triethylamine as base, the title compound was obtained as an off-white solid (18%); IR(KBr): 3362, 2238, 1656, 1552 cm1; NMR(300 MHz, DMSO-d6): 7.33 (m,2H); 7.64 (m, 2H); 7.73 (t, 2H, J=9.5 Hz); 8.05 (d, 2H, J=9.3 Hz); 8.24 (d, 2H, J=9.9 Hz); 8.35 (s, 2H); 10.18 (br s, 2H); MS(FD): 366.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[Br:12]Br.CCOC(C)=O.[O-]S([O-])=O.[Na+].[Na+]>O1CCOCC1>[Br:12][C:10]1[C:5]2[C:4]([Cl:11])=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[NH:8][CH:9]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Clc1nc(Cl)c2c(Br)c[nH]c2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 935 mg 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (3a) (5.0 mmol) in 100 mL of 1,4-dioxane was slowly added 256 μL of Br2 (5.0 mmol) at 0° C. over a period of 10 minutes. After stirring for 30 minutes at 0° C., the reaction mixture was poured into a mixture of 150 mL of EtOAc and 150 mL of saturated aqueous Na2SO3 then filtered through celite. The aqueous phase was extracted with EtOAc (3×100 mL) and combined organic layers were washed with brine, concentrated and purified by flash column chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][C:18]3[CH:27]=[C:26]4[C:21]([CH:22]=[C:23]([C:28]([OH:30])=O)[CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH:33]1([CH2:36][NH2:37])[CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:33]1([CH2:36][NH:37][C:28]([C:23]2[CH:24]=[N:25][C:26]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([NH:17][C:15]([C:10]2[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:32])[F:31])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:16])[CH:27]=3)=[O:30])[CH2:35][CH2:34]1
Reactant: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Reactant: NCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
7-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (100 mg, 0.23 mmol) was combined with cyclopropylmethylamine (29 mg, 0.27 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53 mg, 0.27 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and triethylamine (0.13 ml, 0.92 mmol) in 1.5 ml of dichloromethane. After stirring overnight at ambient temperature, the reaction mixture was diluted with 50 ml of dichloromethane, and the organic phase washed sequentially with water, and brine, and then dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 101 mg of the title compound as a colorless solid.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6][CH:5]=1)([OH:3])=[O:2].[OH:14]O>C(O)(=O)C>[C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N+:6]([O-:14])[CH:5]=1)([OH:3])=[O:2]
Reactant: OO
Reactant: O=C(O)c1cncc2ccccc12
Solvent: CC(=O)O
Product: O=C(O)c1c[n+]([O-])cc2ccccc12

Procedure:
4-Carboxy-isoquinoline [J. Amer. Chem. Soc. 67, 1268 (1945)](10 g, 0.058 mol) is refluxed in 100 ml of acetic acid containing 13 ml of hydrogen peroxide (30%) overnight. After cooling, the solution is evaporated to dryness and the residue is purified by column chromatography (ethyl acetate/methanol/formic acid 3:2:1) to yield 4-carboxy-isoquinoline N-oxide, m.p. 280°-283°, Rf =0.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5]Cl.[C-:11]#[N:12].[Na+]>CS(C)=O.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][C:11]#[N:12])[CH:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.8 %

Procedure:
3,5-Dichlorobenzyl chloride (315.6 mg, 1.615 mmol), 0.2 molar in DMSO, was treated with sodium cyanide (158.2 mg, 3.229 mmol) and allowed to stir at ambient temperature for 24 hours. After 24 hours the reaction mixture was diluted with diethyl ether and partitioned between saturated aqueous sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and concentrated to provide the title compound (155.5 mg, 0.836 mmol, 51.8% yield) as a dark red oil.