Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:22]([I:23])=[CH:21][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13]CC)=O)[N:8]([CH3:16])[C:7]=3[CH:17]3[CH2:20][CH:19]([C:4]=2[CH:3]=1)[CH2:18]3.[NH3:24]>>[F:1][C:2]1[C:22]([I:23])=[CH:21][C:5]2[C:6]3[N:10]=[C:9]([C:11]([NH2:24])=[O:13])[N:8]([CH3:16])[C:7]=3[CH:17]3[CH2:20][CH:19]([C:4]=2[CH:3]=1)[CH2:18]3
Reactant: N
Reactant: CCOC(=O)c1nc2c(n1C)C1CC(C1)c1cc(F)c(I)cc1-2
Product: Cn1c(C(N)=O)nc2c1C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 44 °C
Yield: 77 %

Procedure:
A pressure tube containing a solution of ethyl 8-fluoro-9-iodo-3-methyl-3,4,5,6-tetrahydro-4,6 methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (389 mg at 77% purity LCMS-UV215) in methanolic ammonia (6 mL of 7.0M ammonia in methanol) was warmed to 44° C. for 48 hr. After cooling to room temperature, a 0.5 mL aliquot of the precipitous solution was sampled and the solid collected by filtration. The filtrate was pooled back into the reaction mixture and concentrated in vacuo to furnish the crude title compound (329 mg at 77% purity LCMS-UV215) as a tan solid which was used for the next step without further purification. The colourless solid isolated by filtration for characterisation purposes was analysed: 1H NMR (500 MHz, CDCl3) δ 1.69-1.74 (m, 2H), 2.92-3.00 (m, 2H), 3.47 (td, J=7.49, 3.63 Hz, 1H), 3.57 (td, J=8.28, 3.63 Hz, 1H), 4.00 (s, 3H), 5.39 (br. s., 1H), 6.81 (d, J=8.51 Hz, 1H), 7.36 (br. s., 1H), 8.73 (d, J=6.94 Hz, 1H); M+H=398.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH2:17][CH3:18])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1.CO>[OH-].[OH-].[Pd+2].CCOC(C)=O>[CH2:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12)[CH3:18]
Reactant: CCN1CCCC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCN1CCCC2CNCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-benzyl-1-ethyloctahydro-1H-pyrrolo[3,4-b]pyridine (2.58 g) in the mixture solvent of MeOH and EtOAc was added a catalytic amount of 20% Pd(OH)2/C. The mixture was stirred for 2 h at room temperature under H2 and filtered. The filtrate was concentrated in vacuo and the residue was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 155.2 (M+1).
Reaction SMILES: [N:1]1([CH2:6][C:7]#[C:8][C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2C(OC(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)C.[ClH:24]>CO>[ClH:24].[ClH:24].[NH:10]1[CH2:11][CH2:12][CH2:13][C@@H:9]1[C:8]#[C:7][CH2:6][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C#CCN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: C(#C[C@H]1CCCN1)CN1CCCC1
Temperature: 80 °C

Procedure:
A mixture of 7.0 g of (R)-2-[3-(1- pyrrolidinyl)-1-propynyl]-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester, 61 ml of ethanol and 61 ml of 2N hydrochloric acid is heated at 80° C. for one hour. The reaction is concentrated in vacuo and the residue is extracted with methylene chloride. The aqueous layer is concentrated in vacuo, made basic with 10N sodium hydroxide and extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is dissolved in methanol, treated with an excess of methanolic hydrogen chloride and precipitated with the addition of diethyl ether. The dihydrochloride is recrystallized from hot methanol to give pure product, mp 198°-200° C. with decomposition, [α]D26° =+21°±1 (C=1.012%, methanol).
Reaction SMILES: [NH2:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([NH:5][C@@H:6]1[C:11]2[CH:12]=[C:13]([C:16]#[N:17])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH3:19])([CH3:18])[C@H:7]1[OH:20])=[O:4].[O:27]1CC[CH2:29][CH2:28]1>>[C:16]([C:13]1[CH:14]=[CH:15][C:10]2[O:9][C:8]([CH3:19])([CH3:18])[C@@H:7]([OH:20])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([NH:1][C:28](=[O:27])[CH3:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:11]=2[CH:12]=1)#[N:17]
Reactant: C1CCOC1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C(N)c2ccccc2)[C@@H]1O
Product: CC(=O)NC(C(=O)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O)c1ccccc1

Procedure:
To a solution containing (3S-trans)-α-amino-N-(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)benzeneacetamide (600 mg, 1.7 mmol; isomer B of the title compound of Example 2)in tetrahydrofuran (7 mL) at room temperature was slowly added excess acetyl chloride while maintaining the reaction at pH ~8.5 by simultaneous addition of 7% sodium carbonate solution. After the completion of the reaction, it was diluted with ethyl acetate and washed with water and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to provide a colorless gum (518 mg, 77.2%) which was stirred with ether to give (3S-trans)-N-[2-[(6-cyano-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl)amino]-2-oxo-1-phenylethyl]acetamide, mp 133°-145° C. (starts shrinking@124° C). Analysis calculated for C22H23N3O4.0.4H2O: C, 65.95; H, 5.99; N, 10.49. Found: C, 66.09; H, 5.92; N, 10.30. [α]D =+62.4° (c=0.5, MeOH).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)[C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([CH:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:35])=[O:5])=[CH:12][CH:11]=2)[C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=2)=[CH:30][CH:29]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccc(NC(C(=O)Nc2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(C(Nc2ccc(C(=O)O)cc2)C(=O)Nc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
4-{[(4-tert-Butyl-phenyl)-(4-iodo-phenylcarbamoyl)-methyl]-amino}-benzoic acid tert-butyl ester (430 mg, 0.74 mmol) was taken up in 10 mL of dichloromethane followed by addition of 1 mL of TFA and stirred for 16 h at RT. Removal of the organic layer under reduced pressure followed by addition of water to the precipitate. The solids were filtered to give 340 mg (87%) of white solids. 1H NMR showed the compound to be very clean and sufficient for the following step. LCMS (M+1=529.6).
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.[NH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: Nc1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccncc1)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 50 °C

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (51.5 mg, 0.186 mmol) in dry dichloromethane (5 mL) was added triethylamine (0.065 mL, 0.466 mmol), 2-chloro-1-methylpyridinium iodide (63.4 mg, 0.248 mmol), and 4-aminopyridine (19.2 mg, 0.204 mmol) sequentially at room temperature under nitrogen. The reaction was then heated to 50° C. for 1.5 hours. LC/MS showed reaction complete. The reaction mixture was concentrated and purified by HPLC on a 30×100 mm Waters Sunfire column to afford the title compound as an orange solid after lyophilization.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:21]([O-])=O)[CH:18]=3)[CH2:13]2)[C:11](=[O:24])[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[NH2:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[CH2:13][C:12]1([C:11](=[O:24])[NH:10][C:9](=[O:25])[N:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:20]2
Reactant: O=C1NC(=O)C2(Cc3ccc([N+](=O)[O-])cc3C2)N1Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)CC1(C2)C(=O)NC(=O)N1Cc1ccccc1
Reaction time: 18 h

Procedure:
To a solution of (±)-3-benzyl-5′-nitro-spiro[imidazolidine-4,2′-indane]-2,5-dione from Step C (80 mg, 0.24 mmol) in EtOAc (1.5 mL) and MeOH (1.5 mL) was added 10% Pd/C (5 mg) and the reaction mixture was stirred vigorously under hydrogen (ca. 1 atm). After 18 h, the catalyst was filtered off and the filtrate was concentrated to yield the title compound as a pale brown solid. MS: m/z=308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][CH2:26][CH2:25][NH:24]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 12.3 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[(2S)-pyrrolidin-2-ylmethoxy]phenyl}-1H-indole-3-carboxylate (40 mg, 0.22 mmol) in methanol (8 mL) was added 1.0 M aqueous NaOH (2.0 mL, 2.0 mL). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by reverse phase HPLC to give the title compound (10 mg, 11% yield) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:10][C:11]([NH2:15])=[C:12]([NH2:14])[CH:13]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:26](Cl)=[O:27]>N1C=CC=CC=1>[NH2:15][C:11]1[N:10]=[C:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[F:1])=[CH:13][C:12]=1[NH:14][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([CH3:32])=[C:23]([F:22])[CH:24]=1
Reactant: Nc1cc(-c2ccncc2F)c(-c2cccnc2)nc1N
Reactant: Cc1ccc(C(=O)Cl)cc1F
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2cc(-c3ccncc3F)c(-c3cccnc3)nc2N)cc1F
Temperature: 40 °C
Yield: 99.5 %

Procedure:
To a solution of 3″-fluoro-3,2′:3′,4″-terpyridine-5′,6′-diamine (Intermediate 1, 0.2 g, 0.71 mmol) in pyridine (2 mL), 0.071 mL (0.78 mmol) of 3-fluoro-4-methylbenzoyl chloride were added. The mixture was heated at 40° C. for 4 h and the solvent was evaporated. The crude mixture was extracted between ethyl acetate and water, the organic layer was dried (MgSO4) and evaporated to give the title compound (0.295 g, 88% of yield) which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][CH2:11][CH:12]2[CH2:14][O:13]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[Br:15][C:16]1[N:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.O>[Br:15][C:16]1[N:21]=[CH:20][C:19]([O:22][CH2:14][CH:12]([OH:13])[CH2:11][CH2:10][N:3]2[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=[C:2]2[Cl:1])=[CH:18][CH:17]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=[N+]([O-])c1cn(CCC2CO2)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: O=[N+]([O-])c1cn(CCC(O)COc2ccc(Br)nc2)c(Cl)n1
Temperature: 83.5 °C
Reaction time: 28 h
Yield: 36.9 %

Procedure:
A mixture of epoxide 129 (see Example 2AA) (1.004 g, 4.61 mmol), 6-bromo-3-pyridinol (4.015 g, 23.1 mmol) and powdered K2CO3 (3.319 g, 24.0 mmol) in anhydrous 2-butanone (10 mL) under N2 was stirred at 82-85° C. for 28 h. The resulting cooled mixture was diluted with water (100 mL) and extracted with 25% EtOAc/CH2Cl2 (3×100 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-40% EtOAc/petroleum ether firstly gave foreruns, and then further elution with 40% EtOAc/petroleum ether gave 1-[(6-bromo-3-pyridinyl)oxy]-4-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-butanol (137) (667 mg, 37%) as a cream solid: mp (MeOH/CH2Cl2/pentane) 112-114° C.; 1H NMR [(CD3)2SO] δ 8.56 (s, 1H), 8.12 (d, J=3.1 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.39 (dd, J=8.8, 3.2 Hz, 1H), 5.28 (br d, J=4.5 Hz, 1H), 4.24 (dd, J=14.0, 5.8 Hz, 1H), 4.18 (dd, J=14.2, 7.3 Hz, 1H), 3.99 (dd, J=10.0, 4.9 Hz, 1H), 3.96 (dd, J=10.0, 5.5 Hz, 1H), 3.82 (m, 1H), 2.06 (dtd, J=13.9, 7.7, 3.4 Hz, 1H), 1.90 (ddt, J=13.7, 9.2, 6.7 Hz, 1H); HRESIMS calcd for C12H13BrClN4O4 m/z [M+H]+ 394.9754, 392.9782, 390.9803. found 394.9753, 392.9777, 390.9797.
Reaction SMILES: [C:1]([O:4][C:5]12[CH2:9][C:7]([NH2:10])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2].C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:18])[CH3:17]>CN(C=O)C>[C:1]([O:4][C:5]12[CH2:9][C:7]([NH:10][C:16](=[O:18])[CH3:17])([CH2:8]1)[CH2:6]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC12CC(N)(C1)C2
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NC12CC(OC(C)=O)(C1)C2
Temperature: 25 °C

Procedure:
To a DMF (2 mL) solution of 3-aminobicyclo[1.1.1]pentan-1-yl acetate (1 mmol) is added sodium bicarbonate (3 mmol) and then acetyl chloride (1 mmol) by syringe at 0° C. The reaction is allowed to warm up to r.t. and monitored by LCMS. After LCMS analysis indicated consumption of starting material, the reaction is diluted with water and extracted with EtOAc (3×). The organic layers are combined, washed with brine, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to give 3-acetamidobicyclo[1.1.1]pentan-1-yl acetate (3).
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:19]1([CH2:25][CH2:26][NH2:27])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[N:19]1([CH2:25][CH2:26][NH:27]/[C:1](/[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:9]2\[C:10](=[O:18])[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13]\2)[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: NCCN1CCOCC1
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Product: O=C1/C(=C(\NCCN2CCOCC2)c2ccccc2)Sc2ccccc21
Yield: 62 %

Procedure:
Prepared as in Example 35 from 2-benzoyl-benzo[b]thiophen-3-ol and 2-(4-morpholinyl)-ethylamine instead of ammonium acetate with a yield of 62% of theory.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1>ClCCl>[Br:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(CBr)N1CCOCC1
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
A solution of bromoacetyl bromide (3.0 mL, 0.034 mol) in dichloromethane (240 mL) was cooled to −25° C. A solution of morpholine (9.0 mL, 0.10 mol) in dichloromethane (20 mL) was slowly added over a period of one hour. After the addition was complete, the reaction was stirred at −25° C. for 15 minutes and allowed to warm to ambient temperature. Dichloromethane was added, and the resulting solution was washed with water, 1N aqueous hydrogen chloride, and brine; dried over magnesium sulfate; filtered; and concentrated under reduced pressure to provide 4-(2-bromoacetyl)morpholine as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([NH:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][N:5]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1CCC(N2Cc3c(NCc4ccccc4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.1 %

Procedure:
A stirred mixture of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (518 mg, 2.0 mmol) and benzaldehyde (0.21 ml, 2.0 mmol) in methanol (20 ml) was heated to reflux for 5 h. The solvent was removed in vacuo to give a solid. The solid was re-dissolved in acetic acid (20 ml). The stirred solution was heated to reflux for 1 h, and was then allowed to cool to room temperature. To the stirred solution was added sodium borohydride (90 mg, 2.3 mmol) and stirring continued at room temperature for 18 h. The resulting suspension was filtered and washed with acetic acid (10 ml) and ether (20 ml) to give 3-{1-oxo-4-[benzylamino]isoindolin-2-yl}piperidine-2,6-dione as an off-white solid (420 mg, 60% yield): mp, 257–259° C.; 1H NMR (DMSO-d6) δ 2.01–2.07 (m, 1H, CHH), 2.23–2.30 (m, 1H, CHH), 2.49–2.65 (m, 1H, CHH), 2.85–3.00 (m, 1H, CHH), 4.19 (d, J=17 Hz, 1H, CHH), 4.31 (d, J=17 Hz, 1H, CHH), 4.39 (d, J=5.7 Hz, 2H, CH2), 5.12 (dd, J=5.1, 13 Hz, 1H, NCH), 6.37 (t, J=5.9 Hz, 1H, NH), 6.62 (d, J=8.0 Hz, 1H, Ar), 6.91 (d, J=7.3 Hz, 1H, Ar), 7.19–7.40 (m, 6H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.79, 31.25, 45.79, 46.09, 51.56, 110.32, 112.34, 126.72, 127.05, 128.32, 129.07, 132.08, 139.72, 143.33, 168.82, 171.22, 172.90; Anal Calcd for C20H19N3O3: C, 68.75; H, 5.48; N, 12.03. Found C, 68.73; H, 5.41; N, 12.04.
Reaction SMILES: [BH4-].[Na+].C[C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[C:15](=[O:26])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[CH3:27]N(C)C=O.O>CO>[OH:26][CH:15]([C:5]1[N:6]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:27])[CH:12]=[CH:11][CH:10]=2)[O:8][CH:4]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: CN(C)C=O
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2nc(C(O)COc3ccc(C#N)cc3)co2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
Sodium borohydride (0.654 mg) was added to a suspension of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]benzonitrile (5.5 g) in methanol (100 ml)-N,N-dimethylformamide (50 ml), followed by stirring at room temperature for 1 hour. The reaction solution was poured into water and the crystals which separated out were collected by filtration to give 4-[2-hydroxy-2-(5-methyl-phenyl-4-oxazolyl)ethoxy]benzonitrile (5.1 g, 92.7%). Recrystallization from acetone afforded colorless neddles, m.p. 176°-177° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][C:27]=1[O:38][CH:39]([CH3:41])[CH3:40].[Cl:42][C:43]1[C:44]([C:53]([F:56])([F:55])[F:54])=[N:45][N:46]([CH2:49][C:50](O)=[O:51])[C:47]=1[CH3:48]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:33][CH2:34][N:35]([C:50](=[O:51])[CH2:49][N:46]3[C:47]([CH3:48])=[C:43]([Cl:42])[C:44]([C:53]([F:56])([F:55])[F:54])=[N:45]3)[CH2:36][CH2:37]2)=[CH:28][C:27]=1[O:38][CH:39]([CH3:41])[CH3:40]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: CC(C)Oc1cc(N2CCNCC2)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)c(OC(C)C)c2)CC1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Chloro-3-isopropoxy-phenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.21 (d, 1H), 6.71 (s,1H), 6.53 (d, 1H), 5.38 (s, 2H), 4.66 (m, 1H), 3.58 (m, 4H), 3.25 (m, 2H), 3.15 (m, 2H), 2.18 (s, 3H), 1.26 (d, 6H) ppm; MS (ES) M+H expected=479.1, found=479.0.
Reaction SMILES: [Br:1]Br.[C:3]1([N:9]2[C:13]3[NH:14][C:15](=[O:18])[CH:16]=[CH:17][C:12]=3[CH:11]=[N:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.O>[Br:1][C:16]1[C:15](=[O:18])[NH:14][C:13]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:10]=[CH:11][C:12]=2[CH:17]=1
Reactant: BrBr
Reactant: O=c1ccc2cnn(-c3ccccc3)c2[nH]1
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c2c(cnn2-c2ccccc2)cc1Br
Reaction time: 0.5 h
Yield: 68 %

Procedure:
Bromine (76 μl, 1.47 mmol) was added to a solution of 1-phenyl-1,7-dihydropyrazolo[3,4-b]pyridin-6-one (0.31 g, 1.47 mmol) in acetic acid (7 ml) and the mixture was stirred for 30 min. The suspension was diluted with water, stirred for 10 min and then the precipitate filtered off, washing with water. The product was dried in a desiccator at 40° C. under vacuum for 17 h to give 5-bromo-1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.29 g, 68%) as a brown solid. δH (400 MHz; DMSO) 7.32-7.37 (1H, m), 7.52-7.58 (2H, m), 8.12-8.24 (3H, m), 8.50 (1H, s); m/z (ES+) 290 (M+H+), 292 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C(B(CC)[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)C.C([O-])([O-])=O.[Na+].[Na+]>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.C(COC)OC>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:12][CH2:13][N:14]([C:17]5[C:22]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:15][CH2:16]4)[NH:7][C:6]=3[CH:5]=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=2)[CH:35]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2cccnc2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reaction time: 0.67 h

Procedure:
A mixture of 4-bromo6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (99 mg, 0.2 mmol, Example 7), diethyl(3-pyridyl)borane (37 mg, 0.25 mmol, Aldrich), Pd(PPh3)4 (23 mg, 0.02 mmol, Aldrich), Na2CO3 (32 mg, 0.3 mmol) and dimethoxyethane (1 mL) was subjected to microwave irradiation at 200° C. with stirring for 40 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexane, to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 493 (M+1).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11]I)=[O:8])(=[O:4])=[O:3].[N-:17]=[N+:18]=[N-:19].[Na+]>C(O)C>[NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][N:17]=[N+:18]=[N-:19])=[O:8])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: NS(=O)(=O)c1ccccc1C(=O)OCCI
Agent: [Na+]
Solvent: CCO
Product: [N-]=[N+]=NCCOC(=O)c1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 41.1 %

Procedure:
A mixture of 1.6 g of the product from Example 2 and 0.3 g of sodium azide in 10 mL absolute ethanol was heated at reflux temperature for 24 hours. Additional sodium azide (0.3 g) was added and the suspension was heated for another 24 hours. The reaction mixture was cooled to room temperature and the ethanol was removed in vacuo. The resultant crude oil was purified by careful chromatography on silica gel. Elution with 1:1 hexane/ethyl acetate gave 0.5 g of the desired product as a colorless, viscous oil; IR (film): 1720, 2100 cm-1 ; NMR (CDCl3): δ 3.67 (t, 2H, J=4 Hz), 4.55 (t, 2H, J=4 Hz), 5.77 (br s, 2H), 7.65 (m, 2H), 7.9 (m, 1H), 8.15 (m, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])=[N:6][C:7]=1[Br:8].N([O-])=O.[Na+].[ClH:18]>O.Cl[Cu]>[Br:8][C:7]1[N:6]=[C:5]([NH:9][C:10](=[O:13])[O:11][CH3:12])[CH:4]=[CH:3][C:2]=1[Cl:18]
Reactant: COC(=O)Nc1ccc(N)c(Br)n1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1ccc(Cl)c(Br)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a mixture of methyl 5-amino-6-bromopyridin-2-ylcarbamate (100 mg, 0.41 mmol) and CuCl (120 mg, 1.6 mmol) in HCl (28%, 10 mL) was added and NaNO2 (29 mg, 0.41 mmol) at 0° C. The mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give methyl 6-bromo-5-chloropyridin-2-ylcarbamate (80 mg, 75%). 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.38 (brs, 1H), 3.82 (s, 3H).