Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][NH2:14])[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[N:22]=[C:21](S(C)(=O)=O)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([CH:5]1[CH2:16][CH2:15][C:8]2([O:12][CH:11]([CH2:13][NH:14][C:21]3[N:22]=[C:23]([O:25][CH3:26])[CH:24]=[C:19]([O:18][CH3:17])[N:20]=3)[CH2:10][O:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CN)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(OC)nc(NCC2COC3(CCC(C(C)(C)C)CC3)O2)n1
Yield: 66 %

Procedure:
8-t-butyl-2-aminomethyl-1,4-dioxaspiro(4,5)decane (3.3 g, 14.5 mmol), 4,6-dimethoxy-2-methylsulfonyl-pyrimidine (3.16 g, 14.5 mmol) and potassium carbonate (2.76 g, 20 mmol) were heated to 160° C. for 1 hour. The reaction mixture was then extracted with toluene and the concentrated extracts purified by flash chromatography using a 3:1 mixture of toluene and ethylacetate. 3.5 g of a faint yellow oil was obtained which crystallised on standing. NMR analysis indicated the product being a mixture of diastereoisomers. M.p.: 76°-106° C.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=2)[CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][C:6]=1[O:32][CH3:33].Cl.NO.C([N:45](CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:17]1([S:14]([NH:13][CH2:12][CH:11]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH2:45])=[NH:31])=[CH:28][CH:29]=2)[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:3]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:2][Cl:1])=[C:6]([O:32][CH3:33])[CH:7]=2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: COc1cc(C(CNS(=O)(=O)c2ccccc2)Nc2ccc(C#N)cc2)ccc1OC(CCl)c1ccccc1
Agent: Cl
Agent: NO
Agent: O=C([O-])[O-]
Solvent: CCO
Product: COc1cc(C(CNS(=O)(=O)c2ccccc2)Nc2ccc(C(=N)N)cc2)ccc1OC(CCl)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
N-[2-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-2-(4-cyano-phenylamino)-ethyl]-benzenesulfonamide (100 mg 0.18 mmoles) was dissolved in ethanol (3 ml) and hydroxylaminehydrochloride (62 mg, 0.89 mmoles) added. To this was added triethylamine (90 mg, 0.89 mmoles) and later potassium carbonate (62 mg). The reaction was heated to 80° C. for 48 hours. The reaction was cooled and the solvent removed in vacuo. The residue was taken up in ethyl acetate and washed twice with water and once with brine. The solution was dried over sodium sulfate and the solvent removed. The crude intermediate was dissolved in methanol (4 ml) and a few drops of acetic acid added. Approximately 50-100 mg of Raney nickel suspended in sodium hydroxide (Aldrich) was added and the reaction placed under an atmosphere of hydrogen. The suspension was stirred vigorously for 8 hours, the catalyst filtered off and the solvent removed in vacuo. The crude product was purified by reverse-phase chromatography to yield 4-{2-benzenesulfonylamino-1-[4-(2-chloro-1-phenyl-ethoxy)-3-methoxy-phenyl]-ethylamino}-benzamidine (32 mg). MS(M+H)=579.
Reaction SMILES: [O:1]1[CH2:5]/[C:4](=[N:6]\O)/[C:3](=[N:8]/[OH:9])/[C:2]1=[O:10].S(Cl)(Cl)=O>O1CCOCC1>[N:6]1[O:9][N:8]=[C:3]2[C:2](=[O:10])[O:1][CH2:5][C:4]=12
Reactant: O=C1OCC(=N\O)/C1=N/O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: O=C1OCc2nonc21
Reaction time: 8 h

Procedure:
4H,6H-Furo[3,4-c][1,2,5]oxadiazol-4-one was synthesized according to literature procedures (Pollet, et al., Synthesis Communications, 1979, 977-979.) To a stirred solution of (3Z,4Z)-furan-2,3,4(5H)-trione 3,4-dioxime (3.0 g, 0.021 mol) in 1,4-dioxane (21 mL) under nitrogen, thionyl chloride (2.1 mL, 0.029 mol) was added dropwise. The resulting yellow solution was stirred overnight and then concentrated in vacuo. The resultant crystalline material was recrystallized once from a minimum amount of ethanol (EtOH) to give the desired compound as an off-white powder. The filtrate was concentrated down and recrystallized again. Combined solids yielded the desired product (2.0 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ: 5.67 (s, 2H). MF=C4H2N2O3; LCMS calculated for C4H3N2O3(M+H)+: m/z=127.014.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](Br)=[C:13]2[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].CCN(C(C)C)C(C)C.CN(C)C=O>O.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:22]=[CH:21]/[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[C:13]2[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCc2c(Br)ccc(OCc3ccccc3)c21
Reactant: C=CC(=O)OCC
Agent: Cl[Pd]Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)c2c1CCC2=O
Temperature: 90 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 7-(benzyloxy)-4-bromo-2,3-dihydro-1H-inden-1-one (520 mg, 1.64 mmol, 1.00 equiv), ethyl prop-2-enoate (825 mg, 8.24 mmol, 5.03 equiv), PdCl2 (58 mg, 0.33 mmol, 0.200 equiv), DIEA (1.06 g, 8.20 mmol, 5.00 equiv), (o-Tol)3P (201 mg, 0.66 mmol, 0.400 equiv), N,N-dimethylformamide (15 mL). The resulting solution was stirred for overnight at 90° C. in an oil bath. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:2). The resulting solution was diluted with 20 mL of H2O. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic extracts were combined. The resulting mixture was washed with 1×15 mL of water and 1×15 mL of aqueous saturated sodium chloride solution. The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied to a silica gel column, eluting with ethyl acetate/petroleum ether (1:4). This resulted in 500 mg (86%) of ethyl (2E)-3-[7-(benzyloxy)-1-oxo-2,3-dihydro-1H-inden-4-yl]prop-2-enoate as a red solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:9])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:10](Cl)(=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:4][C:5]([O:8][C:10](=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:6][CH:7]=1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)Oc1cc(OC(=O)CCCCCCCCCCCCCCCCC)c(Cl)cn1
Yield: 15 %

Procedure:
A 2.00 g quantity of 5-chloro-4-hydroxy-2-pyridone was refluxed in 150 ml of pyridine to obtain a uniform solution. To the solution was added 5.85 g of stearoyl chloride and the mixture was subjected to reaction at room temperature overnight. After completion of the reaction, the pyridine was concentrated and the concentrate was extracted with petroleum ether. The petroleum ether layer was concentrated and subjected to silica gel column chromatography using as an eluent petroleum ether-chloroform (1:9), giving 1.40 g of the title compound in a yield of 15%.
Reaction SMILES: [CH3:1][N:2]([CH2:12][C@@:13]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][C@H:14]1[CH2:16][O:17]CC1C=CC=CC=1)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4]>[Pd].CCOC(C)=O>[OH:17][CH2:16][C@@H:14]1[CH2:15][C@@:13]1([CH2:12][N:2]([CH3:1])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C[C@@]1(c2ccccc2)C[C@H]1COCc1ccccc1)S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(C[C@@]1(c2ccccc2)C[C@H]1CO)S(=O)(=O)c1ccccc1
Yield: 94.4 %

Procedure:
N-methyl-N-[((1S,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)methyl]benzenesulfonamide (1.57 g, 3.74 mmol), accessed via the method of preparation 6A, was combined with 10% palladium on activated carbon (0.35 g) in EtOAc and hydrogenated under 1 atm H2(g) for 4 h at ambient temperature. The catalyst was filtered off through celite and the filtrate concentrated to give the title product (1.17 g, 3.53 mmol, 95%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.68-7.18 (m, 10H), 4.07-4.03 (m, 1H), 3.72-3.66 (m, 1H), 3.55 (d, J=14.1 Hz, 1H), 3.25 (d, J=14.1 Hz, 1H), 2.36 (s, 3H), 1.59 (m, 1H), 1.18-1.15 (m, 1H), 0.79 (m, 1H). ES-LCMS m/z 354.3 (M+Na).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]([OH:8])[C:6]([CH3:10])([CH3:9])[CH:5]([OH:11])[C:4]([CH3:13])([CH3:12])[CH:3]1[OH:14].[C:16]([C:20]1[CH:21]=[C:22]([CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1>[C:16]([C:20]1[CH:21]=[C:22]([CH2:31][CH2:32][C:33]([O:14][CH:3]2[C:2]([CH3:15])([CH3:1])[CH:7]([O:8][C:33](=[O:34])[CH2:32][CH2:31][C:22]3[CH:23]=[C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])[C:25]([OH:26])=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[CH:21]=3)[C:6]([CH3:9])([CH3:10])[CH:5]([O:11][C:33](=[O:34])[CH2:32][CH2:31][C:22]3[CH:23]=[C:24]([C:27]([CH3:28])([CH3:30])[CH3:29])[C:25]([OH:26])=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:21]=3)[C:4]2([CH3:13])[CH3:12])=[O:34])[CH:23]=[C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:25]=1[OH:26])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1cc(CCC(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CC1(C)C(O)C(C)(C)C(O)C(C)(C)C1O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(CCC(=O)OC2C(C)(C)C(OC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C(C)(C)C(OC(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)C2(C)C)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred cooled solution of 2.16 g (0.010 mole) of 2,2,4,4,6,6-hexamethyl cyclohexane-1,3,5-triol in 50 ml of pyridine is added in several portions over a 20 minute period, 10.69 g (0.036 mole) of 3-(3,5-di-t-butyl-4hydroxyphenyl)propionyl chloride. This mixture is stirred for 30 minutes at 0° to 5°C and then for 15 hours at 45° to 50°C. The mixture is cooled to room temperature and poured into ice water. This mixture is then extracted several times with ethyl ether and these extracts are in turn washed with 2N sulfuric acid, water, 5% aqueous sodium carbonate solution, water and finally saturated sodium chloride solution. The ethereal extracts are then dried over sodium sulfate and evaporated to yield the product. Further purification is achieved by means of chromatography through silica gel, eluting successively with heptane and benzene. Removal of solvent and drying to constant weight at 100°/0.1 mm affords the product, m.p. 105°-115°C.
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CS(O[CH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1)(=O)=O>CN(C)C=O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:4]=2[N:3]=1
Reactant: CS(=O)(=O)OCCC1CC1
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCC1CC1
Yield: 49.1 %

Procedure:
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.64 mmol), sodium carbonate (844 mg, 7.9 mmol) and 2-cyclopropylethyl methanesulfonate (1.19 g, 7.3 mmol) were stirred in dimethylformamide (25 ml, dry) for two days at 80° C. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with hydrochloric acid (2N), brine, dried (MgSO4) and then evaporated to dryness. The crude product was triturated with ether and the solid collected by filtration to afford the title compound as a white solid (0.96 g, 49%). m/z 295 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19]CC2C=CC=CC=2)=[CH:8][CH:7]=1>CO.CN(C)C=O.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(NC(=O)CCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(NC(=O)CCCCCO)cc1
Reaction time: 24 h
Yield: 24.4 %

Procedure:
[4-(6-Benzyloxyhexanoylamino)-phenoxy]-acetic acid methyl ester 57 (24 grms, 62.33 mmol) was dissolved in a mixture of methanol (200 ml) and dimethyl form-amide (50 ml) in a pressure vessel. Palladium on carbon (5%, 15 g) was added and the mixture stirred under an atmosphere of hydrogen (4 kg) for 24 hours. Catalyst was removed by filtration, and the solvents distilled off under vacuum. Crude 58 was purified by column chromatography on silica gel using chloroform as eluant to get pure 58 (4.5 g, 24.4%) as a white powder with an m.p. between 87.5-90.4° C.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([NH2:23])([C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.C1COCC1.[Li+].[OH-].Cl>CO.O>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][C:4]([NH2:23])([C:15]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[C:3]([OH:24])=[O:2])=[CH:7]1
Reactant: COC(=O)C(N)(Cc1c[nH]c2ccccc12)C(=O)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: NC(Cc1c[nH]c2ccccc12)(C(=O)O)C(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 3(1H-indol-3-yl)-2-[pyridine-3-carbonyl]-amino-propionic acid methylester (0.5 g, 1.6 mmol), in methanol (5 mL), THF (9 mL) was added LiOH (0.39 g, 7.70 mmol), dissolved in water (3 mL), The mixture was allowed to stir at room temperature (25° C.) over 2 h. Stripped off solvent, acidified reaction mass with 1.5N HCl, extracted with ethylacetate (100 mL) dried over sodium sulphate and concentrated to obtain product as colorless solid (0.48 g, 99%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([NH:12][C:13]1[C:18]([CH:19]=[O:20])=[C:17](Cl)[N:16]=[C:15]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:14]=1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:32]([OH:35])[CH:33]=[CH2:34].[OH-].[Na+]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH2:32]([O:35][C:17]1[C:18]([CH:19]=[O:20])=[C:13]([NH:12][C@H:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[N:14]=[C:15]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:25]=2[F:31])[N:16]=1)[CH:33]=[CH2:34]
Reactant: C=CCO
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1nc(SCc2cccc(F)c2F)nc(Cl)c1C=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOc1nc(SCc2cccc(F)c2F)nc(N[C@H](C)CO[Si](C)(C)C(C)(C)C)c1C=O

Procedure:
To the subtitle product of step ii) (1.0 g) in toluene was added allyl alcohol (0.23 g), sodium hydroxide (0.16 g) and benzyltriethylammonium chloride (10 mg). The mixture was stirred at room temperature for 2 h before sodium hydroxide solution (10 ml, 1M) was added the organics extracted with EtOAc (2×50 ml). The combined organics were washed with brine (20 ml) and dried (MgSO4). The solid was filtered and the filtrate evaporated to dryness to yield the subtitle compound as a white solid. Yield 1.0 g
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19](S(C)(=O)=O)=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[O:10][CH:9]=1.[CH3:26][NH2:27].O1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[C:14]([C:17]3[O:18][C:19]([NH:27][CH3:26])=[N:20][N:21]=3)[CH:15]=[CH:16][C:11]=2[O:10][CH:9]=1
Reactant: CS(=O)(=O)c1nnc(-c2ccc3occ(-c4ccccc4Cl)c3c2)o1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nnc(-c2ccc3occ(-c4ccccc4Cl)c3c2)o1
Yield: 65 %

Procedure:
In the same manner as in Example 110 and using 2-[3-(2-chlorophenyl)-1-benzofuran-5-yl]-5-(methylsulfonyl)-1,3,4-oxadiazole instead of 2-(2,3-dihydro-1-benzofuran-5-yl)-5-(methylsulfonyl)-1,3,4-oxadiazole and using 2M methylamine-tetrahydrofuran solution instead of 3-fluorobenzylalcohol, the title compound (yield 65%) was obtained as colorless crystals.
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C([N:28](CC)CC)C.ClC(OC)=O.N>O1CCCC1>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][CH2:18][CH2:19][C:20]([NH2:28])=[O:21])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCN(CC)CC
Reactant: O=C(O)CCCOc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Agent: COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)CCCOc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 4-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]butyric acid (0.24 g) was stirred in dry tetrahydrofuran (5 ml) at ambient temperature and triethylamine (0.20 ml) was added. The mixture was stirred at ambient temperature for 15 minutes then cooled in an ice bath and then methyl chloroformate (0.2 ml) was added. The mixture was stirred at ice bath temperature for 1 hour and then concentrated ammonia solution (SG 0.880, 5 ml) was added dropwise by pipette. The mixture was stirred at 0° C. for 5 minutes and then evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica using dichloromethane/IMS/triethylamine (8:1:1) as the mobile phase. Appropriate fractions were combined and evaporated to give 4-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]butyramide, m.p. 200-202° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]([O:24]C)=[O:23])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18]2)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].CO.[OH-].[Na+].Cl>C1COCC1>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][C:4]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[C:19]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:18]2)([CH2:3][C:1]#[N:2])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)c1cn(C2(CC#N)CCN(C(=O)OC(C)(C)C)CC2)nc1Nc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(C(=O)O)c(Nc3ccccc3)n2)CC1
Temperature: 50 °C

Procedure:
To a solution of tert-butyl 4-(cyanomethyl)-4-[4-(methoxycarbonyl)-3-(phenylamino)-1H-pyrazol-1-yl]piperidine-1-carboxylate (0.12 g, 0.27 mmol) in THF (1.8 mL) was added MeOH (1 mL), and 1M aqueous NaOH (0.82 mL, 0.82 mmol). The mixture was heated to 50° C. for 2 hours. The mixture was then cooled to ambient temperature and acidified to pH 3-4 with 1N aqueous HCl. The mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@@H:12]3[CH2:23][C@@H:15]4[CH2:16][N:17]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:18][C@@H:14]4[C@H:13]3[CH3:24])=[C:9]([C:25]([NH2:27])=[O:26])[CH:8]=[N:7][N:6]2[CH:28]=1)#[N:2].[N:29]([Sn](CCCC)(CCCC)CCCC)=[N+:30]=[N-:31]>CN1CCCC1=O>[CH3:24][C@@H:13]1[C@@H:14]2[C@@H:15]([CH2:16][N:17]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:18]2)[CH2:23][C@H:12]1[NH:11][C:10]1[C:5]2[N:6]([CH:28]=[C:3]([C:1]3[N:29]=[N:30][NH:31][N:2]=3)[CH:4]=2)[N:7]=[CH:8][C:9]=1[C:25]([NH2:27])=[O:26]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(C#N)cc12
Solvent: CN1CCCC1=O
Product: C[C@@H]1[C@H]2CN(S(C)(=O)=O)C[C@H]2C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nn[nH]n3)cc12

Procedure:
A solution of 6-cyano-4-(((3aS,4R,5R,6aS)-4-methyl-2-(methylsulfonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (34 mg, 0.084 mmol) and azidotributyltin (0.028 mL, 0.101 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was heated to 180° C. under microwave for 1 h. LCMS analysis showed that the expected product was observed as the major peak. The reaction mixture was taken to the next step without purification. MS (ES+) m/z: 446.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1>[Pd].CO>[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cnc1N1CCOCC1
Yield: 90.3 %

Procedure:
A methanol (20 ml) solution containing 4-(3-methyl-5-nitropyridin-2-yl)morpholine (67 mg) was prepared and subjected to a hydrogenation reaction (room temperature; 1 bar; flow rate: 1 ml/min; 10% Pd/C) using H-cube™. Then, the solvent was distilled away under reduced pressure, and a purple solid of 5-methyl-6-morpholinopyridin-3-amine (52.4 mg) was thus obtained.
Reaction SMILES: [CH2:1]1[O:21][C:4]2=[CH:5][C:6]3[O:11][CH:10]=[C:9]([C:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=4)[C:8](=[O:19])[C:7]=3[CH:20]=[C:3]2[O:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][O:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35].O>CN(C)C=O>[CH2:1]1[O:21][C:4]2=[CH:5][C:6]3[O:11][CH:10]=[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH:33]([C:32]([O:31][CH2:30][CH3:29])=[O:36])[CH2:34][CH3:35])=[CH:16][CH:17]=4)[C:8](=[O:19])[C:7]=3[CH:20]=[C:3]2[O:2]1
Reactant: CCCC(=O)OCCBr
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC)Oc1ccc(-c2coc3cc4c(cc3c2=O)OCO4)cc1

Procedure:
6,7-Methylenedioxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one [cp. Nippon Kagaku Zasshi 85, 793 (1964), Agr. Biol. Chem. (Tokyo) 32, 740 (1968) and Angew. Chem. 93, 129 (1981)] (2.0 g) is dissolved in dimethylformamide (15 ml) and K2CO3 (2.8 g) is added to the solution. While stirring, 2-bromoethylbutyrate (2.7 g) is dropped into the mixture. The content of the reaction flask is refluxed for 30 min. After cooling, water (50 ml) is added and the mixture is extracted with chloroform (3×30 ml), the extract washed with water (3×15 ml) and dried over Na2SO4. Chloroform is removed under reduced pressure and the residue is recrystallized from methanol. The product is dried in vacuo to constant weight to yield 6,7-methylenedioxy-3-[4-(1-ethoxycarbonyl-1-propyloxy)-phenyl]-4H-1-benzopyran-4-one, m.p. 119°-121°.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[Cl:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:15][C:13]1[CH:12]=[CH:11][C:10]([Cl:16])=[C:9]([CH:14]=1)[O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(O[Si](C)(C)C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc(CBr)ccc1Cl
Temperature: 85 °C
Yield: 33.5 %

Procedure:
A solution containing tert-butyl(2-chloro-5-methylphenoxy)dimethylsilane 80 (6.15 g, 24 mmol), N-bromosuccinimide (4.7 g, 26 mmol), and benzoyl peroxide (0.058 g, 0.24 mmol) in 40 mL of dry CHCl3 was purged with N2 and heated to 85° C. The reaction was exposed to a 60 W lamp and was stirred at reflux for 4 h. The lamp was removed and the reaction was cooled to room temperature. The solution was concentrated and was redissolved in ether. The mixture was filtered and then concentrated again. The crude material was purified by silica gel chromatography using a 5% to 20% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (5-(bromomethyl)-2-chlorophenoxy)(tert-butyl)dimethylsilane 81 (2.7 g, 34% yield). The product was carried forth to the next step as is.