Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>>[CH:5]1[CH:6]=[CH:7][C:2]([CH:1]([C:10]2[NH:9][CH:13]=[CH:12][CH:11]=2)[C:13]2[NH:9][CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:4]=1
Reactant: c1cc[nH]c1
Reactant: O=Cc1ccccc1
Product: c1ccc(C(c2ccc[nH]2)c2ccc[nH]2)cc1

Procedure:
Conclusion. The one-flask solventless reaction of an aldehyde with excess pyrrole provides a simple means of preparing the corresponding dipyrromethane. A wide variety of Brønsted or Lewis acids can be employed as catalyst. The Brønsted acids that afford product also give a dark reaction mixture, while the Lewis acids give less discoloration. Excellent results were obtained with InCl3 (for benzaldehyde and other aryl aldehydes) and MgBr2 (for mesitaldehyde). The workup procedure entails quenching with NaOH, filtration, removal of pyrrole, and crystallization. The simplicity of this procedure (no aqueous/organic extraction, distillation, or chromatography) minimizes waste and enables scalability. The absence of any reaction solvent other than pyrrole enables facile recovery of the excess pyrrole from the crude reaction mixture; the recovered pyrrole can be reused. Indeed, the reaction of 0.75 mmol of benzaldehyde in 5.2 L of pyrrole gave 116 g of 5-phenyldipyrromethane and recovery of 90% of the excess pyrrole in a form suitable for reuse. Characterization of the purity of dipyrromethanes is best accomplished using a combination of analytical techniques, including gas chromatography. Given that the N-confused dipyrromethane(s) and the tripyrrane(s) are dominant byproducts of the reaction, and the former is an isomer while the latter is an oligomer of the dipyrromethane, a satisfactory elemental analysis is a necessary but insufficient criterion of purity.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:14][CH2:15]1
Reactant: Oc1cccc2ccc(Cl)nc12
Reactant: C1COCCN1
Solvent: O
Product: Oc1cccc2ccc(N3CCOCC3)nc12
Yield: 80 %

Procedure:
To a stirred mixture of 2-chloroquinolin-8-ol (1.7 g crude, 9.5 mmol) was added morpholine (5 mL). The mixture was heated at reflux for 16 hours. After cooling, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was used directly for the next step. (1.6 g, Yield 80%). LCMS (m/z): 231.1 (M+1).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.[OH-].[Na+]>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH:34][CH:31]3[CH2:33][CH2:32]3)=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCC1CC(n2c(NC3CC3)nc3cc(Cl)c(Cl)cc32)C(O)C1O
Yield: 25.9 %

Procedure:
(±)(1R*, 2S*, 3R*, 5R*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (Example 39, 1.00 g, 1.87 mmol), cyclopropylamine (Aldrich, 1.7 mL, 24 mmol) and absolute ethanol (10 mL) were refluxed under nitrogen for 48 hours. The reaction was cooled and 1 N sodium hydroxide (1.2 mL) was added. Volatiles were evaporated in vacuo and the residual oily solid was chromatographed on silica gel. Elution with 5% methanol--ethyl acetate gave fractions containing white powder (200 mg). Recrystallization from 1:1 water-ethanol gave (±)-(1R*, 2S*, 3R*, 5R*)-5-[5,6-dichloro-2-(cyclopropylamino)-1H-benzimidazol-1-yl]-3-(hydroxymethyl)-1,2-cyclopentanediol as white crystals (180 mg, 40%); m.p. >250° C.; 1H-NMR(DMSO-d6)δ 7.70 (m, 1, NH), 7.62 and 7.39 (both s, 1 each, 2 benzimidazole CH), 5.77 (br s, 1, OH), 5.13 (d, J=5.3 Hz, 1, OH), 4.95-4.80 (m, 1, CHN), 4.48 (t, J=4.7 Hz, 1, CH2OH), 4.2-4.0 (m, 2, 2 OCH), 3.7-4.0 (m, 2, OCH2), 2.9-2.65 (m, 1, OCH), 2.2-1.8 (m, 3, CH2 and CH); mass spectrum (CI): 372(M+1). [See Examples 10-14]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>C1(C)C=CC=CC=1>[CH:23]1([NH:29][C:30]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CCCCC4)cc3)c2cc1OC
Temperature: 85 °C
Yield: 73.8 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (200 mg) was dissolved in toluene (5 ml) with heat, cyclohexyl isocyanate (340 mg) was added, and the admixture was stirred with heat at 80-90° C. for 30 minutes. After the addition of water, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 210 mg of the title compound (yield: 74%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[N:4]=1.I[C:23]1[C:31]2[S:30][N:29]=[C:28]([NH2:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[CH3:33].C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:32][C:28]1[C:27]2[CH:26]=[CH:25][C:24]([CH3:33])=[C:23]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[N:4]=[C:3]([NH:2][CH3:1])[N:12]=[CH:11]4)[C:31]=2[S:30][N:29]=1
Reactant: Cc1ccc2c(N)nsc2c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(N)nsc34)ccc2n1
Temperature: 150 °C

Procedure:
N-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.42 g, 1.5 mmol), 7-iodo-6-methylbenzo[d]isothiazol-3-amine (0.39 g, 1.3 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (0.047 g, 0.067 mmol) and sodium carbonate (0.14 g, 1.3 mmol) were all placed in a clear microwave vial along with 5 ml of 9:1 DMF:water. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with water and extracted with EtAOc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 50 to 100% EtOAc in hexanes. The clean fractions were triturated with warm ether and the solid collected by suction filtration and dried to give 6-(3-amino-6-methylbenzo[d]isothiazol-7-yl)-N-methylquinazolin-2-amine as a tan solid. MS (M+H)+ 322.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[C:7]([O:10][C:11]1[CH:19]=[CH:18]C(C(O)=O)=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>C(Cl)Cl.CN(C=O)C>[C:7]([O:10][C:11]1[CH:19]=[CH:18][C:1]([C:2]([Cl:4])=[O:3])=[CH:13][CH:12]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (0.35 ml) was added to a stirred suspension of 4-acetoxybenzoic acid (0.57 g) in methylene chloride (15 ml) which had been cooled to 0° C. DMF (2 drops) was added and the mixture was stirred at ambient temperature for 4 hours. The mixture was evaporated to give 4-acetoxybenzoyl chloride which was used without further purification. A mixture of the acid chloride so obtained, N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.813 g) and pyridine (15 ml) was stirred and heated at 100° C. for 16 hours. The mixture was cooled to ambient temperature and poured into 2N aqueous hydrochloric acid solution (175 ml). The precipitate was isolated, washed with water and dried. The material so obtained was purified by column chromatography on silica using a 7:3 mixture of isohexane and ethyl acetate as eluent. There was thus obtained the title compound (0.74 g); m.p. 195-196° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12]1([O:18][CH2:19][CH2:20]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>>[O:18]([CH2:19][CH2:20][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCCOc1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1CCCN(CCOc2ccccc2)C1

Procedure:
A mixture of ethyl 3-piperidinecarboxylate (20.58 g), 2-bromoethyl phenyl ether (26.31 g), sodium bicarbonate (10.99 g) and IMS (100 ml) was boiled under reflux for 16 hours. The mixture was evaporated to dryness then diluted with water (100 ml) and 2M sodium hydroxide solution (20 ml). This mixture was extracted with dichloromethane and the combined dichloromethane extracts were extracted with 2M hydrochloric acid. The acidic extracts were washed with dichloromethane and then basified with 2M sodium hydroxide solution. This mixture was extracted with dichloromethane to give ethyl N-(2-phenoxyethyl)piperidine-3-carboxylate as an oil. A sample of the oil was dissolved in ether and ethereal oxalic acid was added. The precipitate was filtered off and recrystallised from aqueous propan-2-ol to give ethyl N-(2-phenoxyethyl)piperidine-3-carboxylate oxalate hemihydrate, m.p. 131°-132° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1>>[N:9]1([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:2]3[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=3)=[CH:21][CH:22]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1cc(Cl)ncn1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Product: Nc1cc(Nc2ccc(OCCN3CCCC3)cc2)ncn1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 152A but using 6-chloro-pyrimidin-4-ylamine, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (Example 148B), and stirring the reaction mixture for 2 h at 150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.[OH:20][CH2:21][C:22]([NH:24][NH2:25])=O>C(O)CCC>[OH:20][CH2:21][C:22]1[N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]2=[N:25][N:24]=1
Reactant: S=C1CN=C(c2ccccc2Cl)c2ccccc2N1
Reactant: NNC(=O)CO
Solvent: CCCCO
Product: OCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Preparation 1, a solution of 1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol is refluxed to give 1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 6 8-Fluoro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:13](O)=[C:12]([Cl:19])[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:13]([O:4][CH3:1])=[C:12]([Cl:19])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(Br)cc(Cl)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cc(Br)cc(Cl)c1OC
Reaction time: 20 h
Yield: 90.5 %

Procedure:
Potassium carbonate (3.9 g, 28 mmol) followed by methyl iodide (0.58 mL, 9.3 mmol) were added to a solution of 4-bromo-2-chloro-6-ethyl-phenol (2.2 g, 9.3 mmol) in DMF (10 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (0% to 3% EtOAc in hexanes) to give the desired product (2.1 g, 91%) 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3H), 2.66 (q, J=7.6 Hz, 2H), 3.82 (s, 3H), 7.22 (s, 1H), 7.37 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].[CH3:32]I>C1COCC1>[CH:1]1([CH2:4][CH2:5][N:6]([CH3:32])[C:7]([C:9]2[N:10]=[N:11][C:12]([N:15]3[CH2:16][CH2:17][CH:18]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:19][CH2:20]3)=[CH:13][CH:14]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCC1CC1)C(=O)c1ccc(N2CCC(C(=O)c3ccc(F)cc3)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of 6-[4-(4-fluorobenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.075 g, 0.189 mmol) and sodium hydride (0.009 g, 60% in mineral oil) in THF (15 mL) was added methyl iodide (0.134 g, 0.945 mmol) at 0° C. The reaction mixture was stirred at ambient temperature overnight, then concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The organic layer was dried, concentrated and purified by column chromatography to yield the title compound in 52% yield (0.040 g). 1H NMR (300 MHz, CDCl3) δ 8.0-7.96 (m, 2H), 7.69-7.6 (m, 1H), 7.18-7.07 (m, 2H), 6.98-6.94 (m, 1H), 5.54-4.45 (m, 2H), 3.8-3.73 (m, 1H), 3.65-3.47 (m, 2H), 3.32-3.07 (m, 4H), 2.06-1.7 (m, 5H), 1.6-1.47 (m, 2H), 0.79-0.67 (m, 1H), 0.52-0.41 (m, 1H), 0.36-0.28 (m, 1H), 0.12-0.07 (m, 1H), 0.1-−0.06 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 200.1, 167.5, 167.2, 166.3, 164.1, 158.8, 148.6, 148.5, 132.1, 132.07, 131.0, 130.9, 129.2, 128.9, 116.1, 115.8, 112.3, 112.2, 51.6, 49.2, 44.5, 43.2, 38.2, 34.4, 33.6, 32.0, 27.9, 8.6, 8.3, 4.3, 4.26. MS (ES+) m/z 411 (M+1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[CH3:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([Cl:22])[N:16]=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19]1[CH:18]=[C:17]([Cl:22])[N:16]=[C:15]([Cl:14])[N:20]=1)[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A solution of (R)-4-((R)-1-tert-butoxyethyl)oxazolidin-2-one (0.830 g, 4.43 mmol) and 2,4,6-trichloropyrimidine (0.894 g, 4.88 mmol, 1.10 equiv) in DMF (15 mL) was treated with NaH (60%, 0.248 g, 6.21 mmol, 1.40 equiv), then the resulting mixture (yellow) was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and quenched with saturated aqueous NaCl (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 0 to 40%) provided (R)-4-((R)-1-tert-butoxyethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1.0 g, white solid) in 69% yield. 1H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 4.70-4.66 (m, 2H), 4.45-4.40 (m, 2H), 1.26 (s, 9H), 1.04 (d, J=6.6 Hz, 3H); MS m/z 334.0 (M+H)+; Rt-1.10 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][CH:12]=1.C(OCC)C.S(=O)(=O)(O)O>C(O)C>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][C:6]([C:5]2[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=2)=[O:7])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCO
Product: O=C(C=Cc1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 3 h

Procedure:
First, 4-hydroxybenzaldehyde (0.488 g, 4 mmole) and 4′-hyroxyacetophenone (0.66 g, 4.84 mmole) are introduced to a 25 mL flask and dissolved completely by adding 10 mL of diethyl ether and 4 mL of ethanol thereto. Next, 4 mL of sulfuric acid is introduced thereto and the reaction mixture is agitated for 3 hours. The reaction mixture is precipitated in water (300 mL) and filtered to obtain a solid, which in turn is washed with distilled water three times, dried under vacuum, and purified by column chromatography using diethyl ether/hexane (1/1, v/v) as eluent to obtain 4,4′-dihydroxychalcone (DHC) having the following structure. The resultant product has a yield and melting point of 30% and 203° C., respectively.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:19]=[CH:18][C:17]3[C:8](=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[CH:12][C:11]([C:20]3NN=[N:22][N:21]=3)=[N:10]4)[N:7]=2)=NN=[N:2]1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[C:26]1([C:25]2[O:32][C:5]([C:6]3[CH:19]=[CH:18][C:17]4[C:8](=[C:9]5[C:14](=[CH:15][CH:16]=4)[CH:13]=[CH:12][C:11]([C:20]4[O:32][C:25]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][N:21]=4)=[N:10]5)[N:7]=3)=[N:1][N:2]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1cc2ccc3ccc(-c4nnn[nH]4)nc3c2nc1-c1nnn[nH]1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: c1ccc(-c2nnc(-c3ccc4ccc5ccc(-c6nnc(-c7ccccc7)o6)nc5c4n3)o2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 17.8 %

Procedure:
Under nitrogen atmosphere, a mixture of 13 g (0.045 mol) 2,9-bis-(1H-tetrazol-5-yl)-[1,10]phenanthroline and 390 ml pyridine was added to a 250 ml three-necked flask. The mixture was then heated to 50° C., and 24.6 g (0.17 mol) benzoyl chloride was then added drop by drop. After the adding, the mixture solution was heated to reflux (110° C.) and stirred overnight. After completion of reaction, the reaction mixture was cooled to room temperature, filtered. Finally, solids were separated, washed by 100 ml methanol, filtered and purified by column chromatography to obtain white products 2,9-bis-(5-phenyl-[1,3,4]oxadiazol-2-yl)-[1,10]phenanthroline 4 g (0.008 mol, yield 17%). MS(m/z, FAB+), 468, 467, 307, 154, 105.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH:13]=O)[CH:9]=2)[C:4](=[O:15])[O:3]1.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:26]3[CH2:25][CH2:24][N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:28][CH2:27]3)[CH:9]=2)[C:4](=[O:15])[O:3]1
Reactant: C[C@@H]1Cc2cc(CC=O)ccc2C(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Reaction time: 8 h

Procedure:
A 1:1 solution of dioxane:3N HCl was added to a flask containing (3R)-6-(1,3-dioxolan-2-ylmethyl)-3-methyl-3,4-dihydro-1H-isochromen-1-one (782 mg, 3.15 mmol). The reaction was then stirred at room temp overnight. The crude reaction mixture was then partitioned between water and DCM. The organic layer was washed with saturated sodium bicarbonate solution, followed by brine. The organic layer was then dried with mag. sulfate, filtered and concentrated to afford [(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]acetaldehyde. The crude aldehyde was redissolved in DCM. To the solution was added Boc-piperazine (671 mg, 3.6 mmol) followed by sodium triacetoxyborohydride (1.91 g, 9.0 mmol). The reaction mixture was allowed to stir overnight before being quenched with 10 mL of MeOH. The excess solvent was removed and the residue was re-redissolved in DCM; washed with water and brine, dried with magnesium sulfate, filtered, concentrated and purified via MPLC (50-100% EtOAc/Hex) to afford tert-butyl 4-{2-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine-1-carboxylate. 1H NMR (500 MHz; CDCl3): 8.02 (d, J=7.8 Hz, 1H), 7.24 (d, J=7.7 Hz, 1H), 7.09 (s, 1H), 4.68 (m, 1H), 3.49 (m, 4H), 2.94 (m, 4H), 2.88 (m, 2H), 2.51 (m, 4H), 1.54 (d, J=6.8 Hz, 3H), 1.48 (s, 9H); LC-MS (IE, m/z): 375 [M+1]+;
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:36][C:35]([F:38])([F:37])[CH2:34]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:36][C:35]([F:37])([F:38])[CH2:34]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCCN4CC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCN4CC(F)(F)C4)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a pale yellow solution of N-tert-butyl-2-(1-(3-(3,3-difluoroazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 57.2 μmol) in dichloromethane (4.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol27), the reaction mixture turned orange and was stirred at 25° C. for 18 h, mixture concentrated and the residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 1 h, then evaporated to a yellow solid, which was dissolved in dichloromethane and purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane and cyclohexane added to allow solid formation, off-white solid was separated by decantation and dried under high vacuum to give N-tert-butyl-2-(1-(3-(3,3-difluoroazetidin-1-yl)propyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (29.5 mg, 55.3 μmol, 96.6%). MS (M+H)+=534; 1H NMR (DMSO-d6) δ: 9.07 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.81-7.96 (m, 2H), 7.40 (d, J=8.3 Hz, 1H), 7.19 (t, J=74.4 Hz, 1H), 4.56 (br. s., 2H), 3.56 (t, J=12.5 Hz, 4H), 2.54 (br. s., 2H), 1.95 (m, J=6.2 Hz, 2H), 1.49 (s, 9H).
Reaction SMILES: [C:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:10]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(=O)CCCBr
Reactant: CCCCCCC(=O)c1c[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12

Procedure:
A mixture of 3-heptanoylindole (1.0 g) obtained in Pre. Ex. 1, ethyl 4-bromobutyrate (0.86 g) and potassium carbonate (1.0 g) in dimethyl formamide (DMF) (25 ml) was stirred at room temperature for 16 hours. The mixture was poured into a mixture of hydrochloric acid (100 ml) and ethyl acetate (AcOEt) (50 ml). The organic layer was washed with water, dried over MgSO 4 and evaporated. The residue was chromatographed on a silica gel column with a mixture of n-hexane and AcOEt (3:1) as eluent to give ethyl 4-(3-heptanoyl-1-indolyl)butyrate as a colorless oil. (1.53 g)