Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)Cl.Br[CH2:7][C:8]([O:10][CH3:11])=[O:9].[CH:12](=[N:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>C(OC(C)C)(=O)C.[Zn]>[C:20]1([NH:19][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CBr
Reactant: C(=Nc1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: N
Agent: [Zn]
Solvent: CC(=O)OC(C)C
Product: COC(=O)CC(Nc1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under nitrogen protective gas was initially charged with 7.6 g of zinc powder (116 mmol) in 45 ml of isopropyl acetate. After 1.83 ml of trimethylchlorosilane (14.4 mmol) had been added, the mixture was heated to 60° C. for 15 min, then allowed to cool to 55° C. and 16.3 g of undiluted methyl bromoacetate (107 mmol) were subsequently added dropwise within 5 min, and the temperature was maintained at 60° C. by external cooling. The mixture was then stirred at 50° C. for 15 min. After cooling to 5° C., 16.1 g of benzalaniline (89 mmol) dissolved in 10 ml of isopropyl acetate were added and the mixture was heated to 25° C. After the mixture had been stirred at 25° C. for 1 h, it was heated to 40° C. for a further 10 min and then cooled to 5° C. Hydrolysis was then effected using 80 ml of concentrated ammonia solution. After 40 ml of isopropyl acetate had been added, the mixture was heated to 50° C. and precipitate formed went into solution. At this temperature, excess zinc was filtered off and the organic phase removed. The organic phase was then washed at 50° C. with 20 ml of water. After the phase separation, the solvent was distilled off under reduced pressure to give a crude product in a yield of 19.7 g (87% of theory) and a purity of >95% (HPLC). After recrystallization from ethyl acetate, methyl 3-(N-phenylamino)-3-phenylpropionate having a melting point of 110° C. was obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)=[O:9].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.S>CN(C)C=O.CO.[Cu]Br>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:31][CH2:30][CH:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)[CH2:29][CH2:28]2)=[O:9])=[CH:12][CH:13]=1
Reactant: O=C(Nc1ccc(Cl)cc1)c1ccncc1Cl
Reactant: NCC1CCN(c2ccncc2)CC1
Agent: [Cu]Br
Agent: S
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1)c1ccncc1NCC1CCN(c2ccncc2)CC1
Temperature: 110 °C
Reaction time: 18 h
Yield: 14 %

Procedure:
A mixture of 3-chloro-N-(4-chlorophenyl)pyridine-4-carboxamide (130 mg, 0.49 mmol), 1-(4-pyridyl)piperidine-4-methylamine (187 mg, 0.98 mmol), and copper(1) bromide (70 mg) in dimethylformamide (1 mL) was heated at 110° C. After 18 h, the mixture was diluted with MeOH, filtered, and concentrated. The residue was treated with 6:1 chloroform:water (10 mL) followed by MeOH until a homogenoeus solution resulted. The solution was treated with hydrogen sulfide(g), heated at reflux for 0.1 h, and filtered through diatomaceous earth. The filtrate was concentrated and the residue taken up in water, 1 N NaOH, and EtOAc. The aqueous layer was washed with EtOAc (3×), the combined extracts were dried (sodium sulfate), filtered and concentrated. The residue was purified by RPHPLC yielding 29 mg (13%) of the title compound as a hydrochloride salt.
Reaction SMILES: C[O:2][CH:3]1[C:7]([CH2:8][CH2:9][CH:10]=[C:11]([CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:12]=[O:13])=[CH:6][C:5](=[O:25])[O:4]1.[BH4-].[Na+]>CO>[OH:2][CH:3]1[O:4][C:5](=[O:25])[CH:6]=[C:7]1[CH2:8][CH2:9][CH:10]=[C:11]([CH2:12][OH:13])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:24])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:22])[CH3:23]
Reactant: COC1OC(=O)C=C1CCC=C(C=O)CCC=C(C)CCC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)=CCCC(C)=CCCC(=CCCC1=CC(=O)OC1O)CO
Temperature: 35 °C
Reaction time: 4 h
Yield: 58.8 %

Procedure:
A solution of 100 mg of 2-[3-(2,5-dihydro-2-methoxy-5-oxo-3-furanyl)propylidene]-6,10-dimethyl-5,9-undecadienal (Example 15G) and 10.9 mg of sodium borohydride in 30 ml of dry methanol under an argon atmosphere was stirred for four hours at room temperature followed by four hours of stirring at 35° C. The reaction was quenched by the slow addition of water and the mixture was extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 3 ml of tetrahydrofuran and 0.34 ml of 0.1N sodium hydroxide at room temperature and under argon. The solution was brought to reflux for two hours, cooled, and adjusted to pH 4 with the slow addition of 0.1N hydrochloric acid. Extraction with ether provided an organic solution which was washed with 0.01N hydrochloric acid and a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The resulting oil was purified by medium pressure liquid chromatography over silica gel eluting with 1:2 hexane/ethyl acetate to afford 56.8 mg of the title product as an oil. Proton NMR, 13C NMR, and mass spectra were consistent with the desired structure.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:16])=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[CH:21]2)=[O:16]
Reactant: [H][H]
Reactant: O=C(CCCNC(=O)OCc1ccccc1)Nc1ccc2[nH]ccc2c1
Agent: [Pd]
Solvent: CO
Product: NCCCC(=O)Nc1ccc2[nH]ccc2c1

Procedure:
4.56 of 4-(Benzyloxycarbonylamino)-N-(1H-indol-5-yl)butanamide, 1.1 g palladium (10%) on charcoal and 100 ml methanol are added together at room temperature in the presence of hydrogen until about 90% of theoretical hydrogen uptake is obtained (maximum uptake). The suspension is filtered through talc and the solvent evaporated off giving an oily residue of 4-amino-N-(1H-indol-5-yl)butanamide which is recrystallised from methanol/ether (M.P. 124°-136°).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([CH3:17])=[CH:4][C:3]=1[OH:18].Br[CH2:20][CH2:21][CH2:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:28][C:23]([CH3:29])([CH2:22][CH2:21][CH2:20][O:18][C:3]1[CH:4]=[C:5]([CH3:17])[C:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(C)(C)CCCBr
Reactant: Cc1cc(O)c(C)c(C)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(OCc2ccccc2)c(C)c1C
Yield: 1007.8 %

Procedure:
A 2-1, 3 neck, round bottom flask equipped with an overhead stirrer is charged with 29.4 g (12mmol) of 2,3,5-trimethyl-4-(phenylmethoxy)phenol (Example C), 29.8 g (1.1×12.1 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226), 20.1 g (1.2×121 mmol) of anhydrous potassium carbonate and 300 mL of acetonitrile. The heterogeneous mixture is stirred at reflux for 96 hours. The solid is removed and the reaction flask and filtered solids are washed with fresh acetonitrile, the solvent removed and the residue taken up in 500 mL of hexane. On standing the product crystallizes partially and a seed crystal is retained. The solution is diluted to 700 mL with hexane and warmed to dissolve the product. After washing with 2×75 mL of 2N potassium hydroxide solution, and brine the solution is dried and evaporated leaving 46.5 g of a pale yellow solid. This crystallizes from 500 mL of hexane in the presence of charcoal and the solution is cooled to 0° C. and seeded to afford 41.4 g of the title compound as a colorless solid; mp 67°-68° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH:14]1([C:17](=[O:24])[CH2:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH2:16][CH2:15]1.N1CCCCC1>C(O)(=O)C>[CH:21]1([C:19](=[O:20])[C:18](=[CH:5][C:4]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=2)[C:17]([CH:14]2[CH2:15][CH2:16]2)=[O:24])[CH2:22][CH2:23]1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)C1CC1)C1CC1

Procedure:
A mixture containing 2.75 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 3.8 g of 1,3-dicyclopropyl-l,3-propanedione, 0.2 ml of piperidine and 0.4 ml of acetic acid was refluxed for 1 h with a Dean-Stark separator. After cooling the product was filtered and recrystallized from acetic acid. Yield 2.85 g, mp 159°-162° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:34]1[C:38]2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.Cl.CN>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:34][CH3:38])=[O:27])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Reactant: On1nnc2ccccc21
Agent: CN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(F)c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1F
Reaction time: 0.17 h
Yield: 82.7 %

Procedure:
To a mixture of 0.0696 g (0.154 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0339 g (0.251 mmole) of 1-hydroxybenzotriazole, 0.0906 g (0.239 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1629 g (1.263 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0224 g (0.328 mmole) of methylamine hydrochloride was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0594 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-N-methyl-benzamide (I-238) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[NH:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CC(O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH:4]2[O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:19][CH2:18]1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: O=C1NCC(CCCl)O1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Product: O=C1NCC(CCN2CCN(c3ccccc3Cl)CC2)O1
Yield: 24.3 %

Procedure:
A stirred mixture of 8.3 g (0.056 mol) of 5-(2-chloroethyl)-2-oxazolidinone, 11 g (0.056 mol) of 1-(2-chlorophenyl)piperazine and 7.7 g (0.056 mol) of potassium carbonate in 150 ml of 2-propanol was heated at reflux temperature for 18 h. The mixture was filtered and the filtrate concentrated at reduced pressure. The residue was dissolved in 2-propanol and treated with a solution of 6.9 g (0.0595 mol) of maleic acid in warm methanol. The resulting maleic acid salt was collected and recrystallized several times from a 2-butanone/methanol mixture to obtain 5.8 g (25%) of solid, mp 166°-168.5° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22]([O:24]C)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[NH4+:28]>CO.C(OCC)(=O)C>[C:1]1([CH2:7][N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([OH:21])[C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][C:13]=3[C:22](=[O:24])[NH2:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1
Yield: 26 %

Procedure:
A solution of the 9-[(phenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (200 mg, 0.6 mM) in 4 mL MeOH and 40 mL concentrated aqueous ammonium hydroxide was sonicated for 30 h at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 50 mg (26%) of the 9-[(phenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.85 (dd, 1H, J=1 and 8 Hz), 7.5-7.1 (m, 9H), 6.6 (d, 1H, J=8 Hz), and 5.8 (s, 2H). IR (KBr, cm−1) 3428, 3198, 3063, 1631, 1599, 1579, 1562, 1496, 1442, 1330, 1261, 1215, 775, and 697. MS (ES) m/e 315, 317.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.C(N(CC)CC)C.[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C>[CH2:29]([N:15]1[C:14](=[O:20])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:12]=2)[C:17](=[O:18])[N:16]1[CH3:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]n(C)c2=O)cn1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)n(C)n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 20.4 %

Procedure:
4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-methyl-1,2,4-triazolidine-3,5-dione (example 10-64) (785 mg, 2.7 mmol) was dissolved in acetonitrile (50 mL). Triethylamine (1 g, 10 mmol) and benzyl bromide (510 mg, 3 mmol) were added and the reaction was stirred at ambient temperature for 12 hours. The mixture was then concentrated on the rotovap, dissolved in methanol (5 mL) and purified by reversed phase HPLC (5-95% acetonitrile in H2O: 25 minute gradient). The pure fractions were pooled and concentrated and the product was recrystallized form ethanol to afford 1-benzyl-4-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-2-methyl-1,2,4-triazolidine-3,5-dione (210 mg, 20%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.13 (s, 3H), 2.39 (s, 3H), 3.09 (s, 3H), 4.81 (s, 2H), 5.18 (s, 2H), 7.30-7.35 (m, 5H), 7.76 (s, 1H), 8.18 (s, 1H). MS M+H calculated 381.1. Found 381.1. Melting point: 124-126° C. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13](=[NH:22])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[CH:5]=1.[O-]Cl.[Na+].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:22]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[Cl:21])[NH:12][C:6]=2[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)=[O:23]
Reactant: COC(=O)c1ccc(OC)c(NC(=N)c2ccc(F)cc2Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]Cl
Solvent: CO
Product: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(F)cc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52 %

Procedure:
3-[(2-chloro-4-fluoro-benzimidoyl)-amino]-4-methoxy-benzoic acid methyl ester (10 g, 29.76 mmol) obtained in step 1 was dissolved in 50% methanol and 5% NaOCl (53 ml, 35.71 mmol) was added dropwise thereto at room temperature. After 5 min, Na2CO3 (6.31 g, 59.52 mmol) was added dropwise thereto and refluxed for 5 min. The resulting solution was cooled to room temperature, extracted with ethyl acetate, the extract was concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (5.17 g, 15.48 mmol) in a yield of 52%.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]([O:18][CH2:19]C2C=CC=CC=2)[C@@H:7]([CH2:26][O:27]CC2C=CC=CC=2)[O:6][C@@H:5]1[CH2:35][P:36]([O:41][CH2:42][CH3:43])(=[O:40])[O:37][CH2:38][CH3:39])=[N+:2]=[N-:3].C(Cl)Cl>CC(O)=O.CC(OC(C)=O)=O.OS(O)(=O)=O.CC(OC(C)=O)=O>[C:5]([O:27][CH2:26][C@H:7]1[O:6][C@H:5]([CH2:35][P:36]([O:37][CH2:38][CH3:39])(=[O:40])[O:41][CH2:42][CH3:43])[C@@H:4]([N:1]=[N+:2]=[N-:3])[C@@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]1[O:18][CH2:19][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:6])[CH3:4]
Reactant: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CCOP(=O)(C[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1N=[N+]=[N-])OCC
Reaction time: 8 h
Yield: 169.2 %

Procedure:
Compound 3 (3.2 g, 5.2 mmol) was dissolved in HOAc/Ac2O (1:1, 32 mL). Ten drops of 1% H2SO4 in Ac2O was added. After stirring overnight the mixture was poured into a separation funnel containing ice and CH2Cl2. The organic phase was separated, filtered through a plug of silica and concentrated. The residue was purified by column chromatography to give 4 (2.48 g, 4.4 mmol, 84%). 13C-NMR (CDCl3) 170.41, 137.41, 136.95, 128.34-127.75, 77.77, 77.60, 74.01, 73.39, 72.17, 71.89, 69.26, 62.47, 61.82, 61.73, 60.50, 60.37, 27.57 (d, J=141 Hz), 20.59, 16.27, 16.19; 31P-NMR (CDCl3) 27.50; [α]D+37 (c 1.0, CHCl3).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[CH2:25][NH2:26].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[CH2:25][NH:26][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1
Reactant: CC1(c2ccc(F)nc2)CCOCC1
Reactant: COc1ccc(CN)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ccc(C3(C)CCOCC3)cn2)c(OC)c1
Temperature: 160 °C
Yield: 51.8 %

Procedure:
To a solution of 2-fluoro-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridine (110 mg, 0.56 mmol) in (2,4-dimethoxyphenyl)methanamine (1016 μL, 6.76 mmol) and DIEA (246 μL, 1.41 mmol) was added potassium carbonate (156 mg, 1.12 mmol). The resulting mixture was heated to 160° C. in an oil bath for 16 h, The reaction mixture was diluted with ethyl acetate, washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silicagel (ISCO) eluting with 0-100% ethyl acetate in heptane to give N-(2,4-dimethoxybenzyl)-5-(4-methyltetrahydro-2H-pyran-4-yl)pyridin-2-amine (100 mg, 0.29 mmol, 51.8% yield) as light yellow color solid. LCMS (m/z): 343 (MH+), 0.63 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C@@H:8]1[CH2:14][CH:13]=[CH:12][CH2:11][O:10][CH2:9]1>CCOC(C)=O.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9]1
Reactant: COCCOCO[C@@H]1CC=CCOC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCOCO[C@@H]1CCCCOC1
Yield: 92.3 %

Procedure:
A mixture of 12 (90 mg, 0.44 mmol) and a catalytic amount of 10% Pd/C in EtOAc (3 mL) was stirred at 23° C. under a hydrogen atmosphere for 3 h. After this time, the catalyst was filtered off through a pad of Celite and the filtrate was concentrated under reduced pressure to afford (R)-3-[(2-methoxyethoxy)methoxy]oxepane (83 mg, 92%) as a colourless oil: 1H NMR (CDCl3) δ 4.70 (d, J=7.2 Hz, 1H), 4.67 (d, J=7.2 Hz, 1H), 3.83-3.58 (m, 7H), 3.50 (t, J=4.6 Hz, 2H), 3.34 (s, 3H), 1.72-1.67 (m, 1H), 1.46-1.44 (m, 4H), 1.22-1.19 (m, 1H); 13C NMR (CDCl3) δ 93.9, 76.5, 73.7, 71.8, 71.6, 66.7, 58.8, 32.6, 30.7, 20.9. A mixture of the above compound (50 mg, 0.24 mmol) and 6 N HCl (0.5 mL) in THF (2 mL) was stirred at 23° C. for 16 h. The solvent was removed and the aqueous phase was extracted with CHCl3. The organic extracts were washed with a saturated solution of NaHCO3, dried (Na2SO4) and the solvent was removed. The residue was purified by flash-chromatography (1:4 EtOAc/CHCl3) to afford 8e (24 mg, 84%) as a colourless oil: [α]D20=−4.2 (c 0.8, CHCl3); 1H NMR (CDCl3) δ 3.87-3.85 (m, 1H), 3.76-3.62 (m, 4H), 2.37 (bs, 1H), 1.78-1.65 (m, 5H), 1.54-1.52 (m, 1H); 13C NMR (CDCl3) δ 73.2, 70.7, 70.4, 36.4, 30.0, 20.2.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([CH2:18][CH:19]=[CH2:20])=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:2]1[O:4][CH2:3]1.C(OO)(=[O:29])C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Na+]>[CH2:1]([O:5][C:6]1[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:8][C:9]([CH2:18][CH:19]2[O:29][CH2:20]2)=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:2]1[O:4][CH2:3]1
Reactant: C=CCc1cc(-c2ccccc2)c(OCC2CO2)c(-c2ccccc2)c1
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc(CC3CO3)cc(-c3ccccc3)c2OCC2CO2)cc1
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A 100 ml sulfurating flask equipped with stirrer, cooler, thermometer and drip funnel is charged with 13.7 g (0.04 mole) of 4-allyl-2,6-diphenylphenyl glycidyl ether in 20 ml of toluene and 0.7 g of sodium acetate. Over 2 hours, 9.13 g (0.048 mole) of 40% peracetic acid are added at a temperature in the range from 30° to 50° C. When the dropwise addition is complete, the reaction mixture is stirred for a further 7 hours. When the reaction is complete, the reaction mixture is diluted with 700 ml of toluene, the resultant aqueous phase is separated and the organic phase is washed with two 150 ml portions of NaHCO3 (5%) and then washed with 150 ml of water. The organic phase is dried over Na2SO4 and made peroxide-free with Na2SO3 and filtered. The filtrate is concentrated, affording 12.46 g (86.5%) of a yellow resin with an epoxide content of 4.99 eq/kg (89.5%) and a viscosity of 6850 mPas/40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([N:15](C(OC(C)(C)C)=O)[NH:16][C:17](OC(C)(C)C)=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:31]1[N:35](C2CCCCO2)[N:34]=[CH:33][CH:32]=1.[CH3:45]C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]3[N:10]([C:17]([CH3:45])=[N:16][N:15]=3)[C:9]=2[CH:8]=[C:7]1[C:31]1[NH:35][N:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(cc(-c3ccnn3C3CCCCO3)n2Cc2cccc(Cl)c2)n1
Reactant: CC(=O)O
Product: Cc1nnc2ccc3c(cc(-c4ccn[nH]4)n3Cc3cccc(Cl)c3)n12

Procedure:
A solution of di-tert-butyl 1-{1-(3-chlorobenzyl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-1H-pyrrolo[3,2-b]pyridin-5-yl}hydrazine-1,2-dicarboxylate (0.50 g, 0.72 mmol, from Step 4) in AcOH (20 mL) and was heated in the microwave to a temperature of 180° C. for 8 minutes. The AcOH was removed in vacuo and the product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Yield (78 mg, 30%).