Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:31]([NH2:36])[CH2:32][CH2:33][CH2:34][NH2:35]>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([NH:35][CH2:34][CH2:33][CH2:32][CH2:31][NH2:36])[CH:3]=[CH:4][CH:5]=4)=[N:9][NH:10][C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: NCCCCN
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Product: NCCCCNc1cccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)n1
Yield: 28 %

Procedure:
Following the procedures Example 271, 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and butane-1,4-diamine were reacted and the product was deprotected to give 283 as a yellow solid (20 mg, 28%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.19-9.21 (m, 1H), 9.12-9.13 (m, 2H), 8.53-8.60 (m, 2H), 7.60-7.63 (m, 1H) 7.51-7.54 (m, 1H), 7.44-7.46 (m, 1H), 6.53 (d, J=6.4 Hz, 1H), 3.65 (t, J=1.2 Hz, 2H), 2.93 (t, J=1.2 Hz, 2H), 1.80-1.85 (m, 4H). ESI MS m/z=360 (M+1)
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[CH2:12](OC(OCC)OCC)C>>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[CH:12][O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)OCC
Reactant: NC(=NO)c1ccc(I)cc1
Product: Ic1ccc(-c2ncon2)cc1

Procedure:
A mixture of 4-iodobenzamidoxime (3.93 g) in triethylorthoformate (15 ml) was heated at reflux for 4 hours. The mixture was evaporated and the residue was purified by flash column chromatography on silica gel using 4:1 (v/v) n-pentane/ethyl acetate as eluent to give 3-(4-iodophenyl)-1,2,4-oxadiazole (0.74 g) as a solid; NMR(CDCl3): 7.85(4H,s) and 8.74(1H,s); m/z 272(M).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:9][C:10]1C=C[CH:16]=[CH:15][C:11]=1C([O-])=O)#[N:8].O.[OH-].[Na+].C([O:24][CH2:25][CH3:26])C>>[OH:24][CH2:25][C:26]1[CH:16]=[CH:15][CH:11]=[CH:10][C:9]=1[CH2:7][NH2:8]
Reactant: CCOCC
Reactant: N#CCc1ccccc1C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: NCc1ccccc1CO
Reaction time: 0.17 h

Procedure:
Lithium aluminium hydride (12.4 ml, 1.0M in diethyl ether) was added cautiously to 2-cyanomethylbenzoate (1.00 g, 6.2 mmol) in anhydrous diethyl ether (40 ml) under nitrogen with stirring over 10 min. whilst ensuring the temperature was not greater than 15-25° C. using an ice bath. After the addition was complete the reaction mixture was allowed to warm to 21 C and then heated at reflux for 16 h. The reaction mixture was cooled to approximately −10 C. It was treated cautiously dropwise with water (0.5 ml), 20% aqueous sodium hydroxide (0.37 ml) and water (1.74 ml). The resultant green heterogeous mixture was filtered and the residue was with diethyl ether (150 ml), the combined washings and filtrate were dried (MgSO4) and solvent was removed in vacuo affording the title compound as a green oil (0.807 g). Mass Spectrum m/z 138 (MH+ for C8H12NO).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=O)=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[CH:16][C:15]=2[F:33])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:35][OH:36].N1C=CC=CC=1>O>[C:1]([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[C:25]([CH:26]=[N:35][OH:36])=[C:24]([Br:28])[N:23]=[C:22]3[O:29][CH2:30][CH2:31][CH3:32])=[CH:16][C:15]=2[F:33])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCOc1nc(Br)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCCOc1nc(Br)c(C=NO)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
Compound A (4.7 g, 9.0 mmol), hydroxylamine hydrochloride (943 mg, 13.6 mmol), pyridine (60 mL, 740 mmol), and water (30 mL, 1.7 mol) were combined and stirred at room temperature overnight. Additional water (30 mL) was added, and the solids were filtered, washed with water, and dried to yield compound B (4.4 g) as a white solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[F:10][C:11]1[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:12]=1[C:13](O)=O.[OH-].[Na+]>CCOC(C)=O.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]2[O:9][C:13]([C:12]3[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:19][C:11]=3[F:10])=[N:1][C:2]=2[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(F)c1
Reactant: Nc1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nc3cc(Br)ccc3o2)c(F)c1
Temperature: 195 °C
Yield: 80.5 %

Procedure:
2-Amino-4-bromophenol (1.77 g, 9.4 mmol) and 2-fluoro-4-(methylsulfonyl)benzoic acid (2 g, 9.4 mmol) were dissolved in polyposphoric acid (60 g). This mixture was heated at 195° C. for three and half hours. Reaction mixture cooled to rt and diluted with ice water (100 ml). Aqueous layer basified with sodium hydroxide pellets to pH 9. Work up (EtOAc/H2O) followed by evaporation of EtOAc afforded the crude. Crude was purified on combiflash with a gradient mixture of EtOAc and Petether (33:67) to obtain the titled compound (2.8 g) as an off-white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[C-:10]#[N:11].[K+]>CN(C=O)C.CCOC(C)=O.[Cu]I.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.C1OCCOCCOCCOCCOCCOC1>[NH2:9][C:5]1[N:6]=[C:7]([Cl:8])[C:2]([C:10]#[N:11])=[N:3][CH:4]=1
Reactant: Nc1cnc(Br)c(Cl)n1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ncc(N)nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A mixture of 5-bromo-6-chloropyrazin-2-amine (1.00 g, 4.8 mmol), copper (I) iodide (914 mg, 4.8 mmol), 18-crown-6 (95 mg, 0.36 mmol) and tetrakis(triphenylphosphine)palladium (0) (83 mg, 0.072 mmol) was suspended in dry DMF (20 mL) and a stream of nitrogen was passed through for 5 minutes. Potassium cyanide (312 mg, 4.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes, then refluxed at 200° C. for 3 hours. The mixture was cooled, diluted with EtOAc and absorbed onto silica gel (10 g). DMF was removed by evaporation. The product was purified by flash chromatography, eluting with 1:1 EtOAc-hexanes, to yield 5-amino-3-chloropyrazine-2-carbonitrile as a yellow solid (607 mg, 3.93 mmol, 82% yield).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C@H:2]([C:5]([O:7][CH2:8][C:9]([Cl:12])([Cl:11])[Cl:10])=[O:6])[CH2:3][OH:4].Cl[C:31](Cl)(Cl)[C:32](=N)[O:33][C:34]([CH3:38])([CH3:37])[C:35]#[CH:36].[C:42](S(O)(=O)=O)(F)(F)F.ClC(Cl)(Cl)C(=N)[O-]>C(Cl)Cl.CCCCCC>[CH3:31][C:32]([O:33][C:34]([CH3:38])([CH3:37])[C:35]#[CH:36])([CH3:42])[C:2]#[CH:3].[NH:1]([C:13]([O:15][CH2:16][CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C@H:2]([C:5]([O:7][CH2:8][C:9]([Cl:10])([Cl:11])[Cl:12])=[O:6])[CH2:3][OH:4]
Reactant: C#CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: O=S(=O)(O)C(F)(F)F
Agent: N=C([O-])C(Cl)(Cl)Cl
Agent: O=C(N[C@@H](CO)C(=O)OCC(Cl)(Cl)Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCCCCC
Solvent: ClCCl
Product: C#CC(C)(C)OC(C)(C)C#C
Reaction time: 96 h

Procedure:
Fmoc-Ser-OTce (0.83 g, 1.8 mmol) was dissolved in CH2Cl2-Hexane (2:1, 4 mL), and 1,1-dimethylpropinyl trichloroacetimidate (0.41 g, 1.8 mmol, 1 equiv) and CF3SO3H (40 μl) were added under N2 atmosphere. The reaction mixture was allowed to stir for 4 days adding the same quantities of the trichloroacetimidate and CF3SO3H every 24 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo, dissolved in EtOAc (10 mL) and washed with saturated aqueous NaHCO3 (2×10 mL), H2O (2×10 mL) and brine (2×10 mL). The organic solution was dried (MgSO4) and concentrate in vacuo to obtain the 1,1-dimethylpropinyl ether of Fmoc-Ser-OTce (0.95 g), which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:23])[N:6]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[N:7]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH2:16][CH2:15][C:14]=3[CH:18]=2)[CH:9]=1)(O)=[O:2].C(N(CC)CC)C.C(=O)([O-])OCCCl.[BH4-].[Na+].Cl>C1COCC1.O>[CH:20]1([CH2:19][N:6]2[C:5](=[O:23])[C:4]([CH2:1][OH:2])=[CH:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]4[O:17][CH2:16][CH2:15][C:14]=4[CH:18]=3)=[N:7]2)[CH2:22][CH2:21]1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Agent: Cl
Agent: O=C([O-])OCCCl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1CC1CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4-carboxy-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one (1.8 g, 5.76 mmol) in THF (25 mL), triethylamine (641 mg, 6.34 mmol) was added, and a solution of chloroethyl carbonate (688 mg, 6.34 mmol) in THF (1 mL) was added dropwise to the resultant mixture under cooling with ice, followed by stirring for 30 minutes. The formed triethylamine hydrochloride was removed through filtration, and a solution of sodium borohydride (327 mg, 8.64 mmol) in water (2 mL) was added to the filtrate under cooling with ice, followed by stirring for 15 minutes at room temperature. Aqueous hydrochloric acid (2 mol/L) was added to the reaction mixture, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate anhydrate. The solvent was removed under reduced pressure, and the residue was subjected to a separation/purification step through silica gel column chromatography [silica gel 60 g, chloroform/methanol (100/1)], to thereby yield 566 mg of the title compound as pale yellow powder (32.9%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Li]CCCC.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C1COCC1>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1
Reactant: Cc1cc(C)c2c(n1)N(C)CC2
Reactant: CCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cc(C)c2c(n1)N(C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 181 mg (1.12 mmol) of 1,4,6-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 3 mL of THF was added 1.19 mL (1.90 mmol, 1.6 M in hexanes) of n-BuLi followed by 255 μL (1.34 mmol) of 1-bromononane at −78° C. The reaction mixture was slowly warmed to room temperature and stirred for another 16 h. The reaction mixture was quenched by the addition of 10 mL of sat aq NH4Cl at 0° C. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (25 3.2 cm). Elution with 10:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 210 mg (66%); silica gel TLC Rf 0.18 (8:1:1 hexanes/ethyl acetate/MeOH); 1H NMR (CDCl3) δ 0.86 (t, 3H, J=6.8 Hz), 1.24-1.30 (m, 16H), 1.65 (quint, 2H, J=7.6 Hz), 2.08 (s, 3H), 2.54 (t, 2H, J=8.0 Hz), 2.81 (t, 2H, J=8.0 Hz), 2.90 (s, 3H), 3.38 (t, 2H, J=8.0 Hz) and 6.13 (s, 1H); 13C NMR (CDCl3) δ 14.2, 18.1, 22.8, 24.5, 29.5, 29.68, 29.73, 29.75, 29.77, 30.1, 32.1, 33.4, 38.2, 52.6, 112.6, 118.4, 141.3, 159.3 and 163.9; mass spectrum, m/z 288.3 (M+) (theoretical 288.3); mass spectrum (APCI), m/z 289.2653 (M+H)+ (C19H33N2 requires 289.2644).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[K+].Br[CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>C(C(C)=O)C(C)C.O>[C:22]([C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[CH2:19][N:3]1[CH2:4][CH2:5][S:1][C:2]1=[O:6])#[N:23]
Reactant: O=C1NCCS1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: N#Cc1ccccc1CN1CCSC1=O
Reaction time: 0.5 h

Procedure:
A mixture containing 3.09 g (0.03 mol) of 2-thiazolidinone, 11.2 g (0.081 mol) of potassium carbonate, 1.8 g (0.018 mol) of potassium hydrogen carbonate, 0.5 ml (0.027 mol) of water and 6.47 g (0.033 mol) of 2-bromomethylbenzonitrile in 30 ml of methyl isobutyl ketone is refluxed for 5 hours, then cooled down. After adding 30 ml of water the mixture is stirred for 30 minutes, the insoluble precipitate is filtered off, washed twice with 10 ml of water each and dried. After recrystallizing 4.71 g of crude product from 20 ml of ethanol under simultaneous clarification with activated carbon 3.39 g (51.8%) of white, crystalline title compound are obtained, m.p.: 116°-117° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][C:8]([CH3:11])=[CH:7]2.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[CH3:11][C:8]1[CH2:9][C:10]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1=Cc2cccc(Cl)c2C1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: CC1=Cc2cccc(-c3ccccc3)c2C1

Procedure:
A 5 L round bottom flask was equipped with mechanical stirring, a reflux condenser and ice bath. 488.2 g distilled 7-chloro-2-methylindene (2.97 mol) was added, dissolved in 2 L ether and 32.2 g Ni(dpp) (0.059 mol, 2 mol %) slurried in the solution, and stirred to cool to 0°-2° C. 1.05 L of 3.1M phenylmagnesium bromide in ether (3.25 mol, 10% excess) was added slowly from an addition funnel so that the temperature remained below 5° C. Once complete, the ice bath was removed, and the reaction stirred up to room temperature. The reaction was refluxed for 8 hours, and checked for completion by GC. The reaction flask was cooled with an ice bath, and 250 mL water added, then 1 L 10% HCl. The aqueous and organic layers are separated, and the organic layer dried over anhydrous Na2SO4. Ether was distilled, and the residual oil placed on a column of 100 g silica gel. Elution with hexane was performed, the hexane distilled under reduced pressure to a temperature of 90° C. 2-methyl-7-phenylindene (Spaleck compound 13a) was obtained by distillation at <1 mm Hg with a 36 cm Vigreux column at 125° C. A fore-cut containing biphenyl was obtained at 70°-90° C. and discarded. Yield was 507.8 g (2.47 mol) equal to 80%.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[CH:8]=1.[OH-].[Na+].[CH3:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[SH:23]>>[CH3:2][NH:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:16])[CH:8]=1
Reactant: CNCCCc1cccc(Cl)c1
Reactant: Cc1ccccc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CNCCCc1cccc(Sc2ccccc2C)c1

Procedure:
N-Methyl-3-chloro-benzenepropanamine hydrochloride (13.14 g, 0.06 mol), 25%, by weight, sodium hydroxide solution (9.6 g of solution; 0.06 mol of sodium hydroxide), sodium hydroxide pellets (2.0 g, 0.05 mol) and 2-methylbenzenethiol (6.2 g, 0.05 mol) were reacted to provide N-methyl-3-[(2-methylphenyl)thio]benzenepropanamine as an oil. The oil was purified by preparative HPLC and then converted to the hydrochloride salt as in Example 1. Recrystallization from methylene chlorideethyl acetate provided approximately 3.0 g of title compound. m.p. ≈90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.[CH3:17][C:18]1[CH:29]=[CH:28][C:21]([CH2:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:25]1[CH2:26][CH2:27][CH:23]([CH2:22][C:21]2[CH:20]=[CH:19][C:18]([CH3:17])=[CH:29][CH:28]=2)[CH2:24]1)=[O:15]
Reactant: Cc1ccc(CC2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: Cl
Product: Cc1ccc(CC2CCN(C(=O)c3cnoc3-c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-methylbenzyl)pyrrolidine hydrochloride (12.7 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (8.4 mg). Calcd for C22H21N2O2: 380.1292, found 380.1296.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30]>>[CH3:13][C:12]1[C:7]([NH:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]2[CH3:23])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Reactant: CC1CCCCC1N
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 2-methylcyclohexanamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (bs, 3H), 1.28-1.42 (m, 6H), 1.62-1.70 (m, 1H), 1.78-1.89 (m, 2H), 1.93 (s, 3H), 2.07 (s, 3H), 2.95-3.04 (m, 1H), 4.43 (bs, 2H), 7.22 (t, J=7.30 Hz, 1H), 7.56 (d, J=7.76 Hz, 1H), 7.68-7.75 (m, 1H), 8.65 (d, J=4.92 Hz, 1H); MS (ESI) m/z 326.4.0 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[CH:20]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]#[N:35])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:20]([O:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:35]
Reactant: N#Cc1ccc(OCc2ccsc2)cc1O
Reactant: CCOC(=O)CCC(Cl)c1ccccc1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C#N)c1ccccc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 5.2 %

Procedure:
2-Hydroxy-4-(3-thienylmethoxy)benzonitrile (2.5 g) is added portionwise to a stirred suspension of sodium hydride (0.44 g, 60% dispersion in mineral oil) in dry dimethyl formamide (30 mL). After stirring at ambient temperature for 30 minutes, ethyl (RS)-4-chloro-4-(2-cyanophenyl)butanoate (2.87 g) is added in one portion and the reaction stirred for 16 hours at 100° C. The reaction is concentrated in vacuo and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase is dried over magnesium sulphate, filtered and concentrated in vacuo. The residual oil is purified by flash chromatography on silica eluting with a mixture of ethyl acetate and pentane (1:2 v/v). Fractions homogeneous in the required product are combined and evaporated to give ethyl (RS)-4-(2-cyanophenyl)-4-[2-cyano-5-(3-thienylmethoxy)phenoxy]butanoate (250 mg) as an orange oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.I[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([OH:23])[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.O.[Cu]I>[OH:23][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:8][CH:9]=2)[CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]1
Reactant: c1c[nH]cn1
Reactant: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(O)(c2ccc(-n3ccnc3)cc2)CC1
Temperature: 190 °C
Reaction time: 0.17 h

Procedure:
To a solution of imidazole (102 mg, 1.5 mmol) and 8-(4-iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (316 mg, 1 mmol) in DMF (1 mL) was added CuI (19 mg, 0.1 mmol) and Cs2CO3 (488 mg, 1.5 mmol) and the mixture was stirred at 190° C. under microwave for 10 min. The mixture was diluted with ethyl acetate (50 mL) and water (10 mL). The organic layer was filtered through celite and the filtrate was washed with saline solution (2×10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was dissolve in THF (1 mL) and was treated with 5% HCl (9 mL) at rt for 14 h. The mixture was neutralized with 1N NaOH to pH 7, concentrated on rotvap, and then extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The resulting residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (100/0 to 0/100), to provide the desired compound (180 mg, 70% for the two steps). LCMS: 257.2 (M+H+, 100%); 1H NMR: (CDCl3) δ 7.82 (s, 1H), 7.64 (d, 2H), 7.40 (s, 1H), 7.28 (s, 1H), 7.21 (s, 1H), 2.99-2.91 (m, 2H), 2.43-2.28 (m 4H), 2.23-2.18 (m, 2H).
Reaction SMILES: [C:1]([O:4][C@:5]1([O:21][C@H:20]([C@@H:22]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:23][C:24](=[O:26])[CH3:25])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[CH2:9]1)C(O)=O)(=[O:3])[CH3:2].OSN1C=CC=CC1=O.N#N>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C.N1C=CC=CC=1.[W]>[C:1]([O:4][C@@H:5]1[O:21][C@H:20]([C@@H:22]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:23][C:24](=[O:26])[CH3:25])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H]1O[C@@](OC(C)=O)(C(=O)O)C[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [W]
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC[C@@H](OC(C)=O)[C@H]1O[C@@H](OC(C)=O)C[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
To a solution of acid chloride prepared from 20a (30 mg, 0.067 mmol) in toluene was added dropwise a solution of N-hydroxythiopyridone 22 (11 mg, 0.09 mmol) and DMAP (2 mg) in toluene (0.5 mL) and pyridine (0.3 mL) at room temperature under N2 in the dark. After stirring for 10 min, t-butylmercaptane (0.5 mL) was added and the mixture was irradiated with white light (tungsten lamp, 100 W) at room temperature. After stirring for 10 min, N2 was introduced to the mixture under a slightly reduced pressure to remove residual t-butylmercaptane for 30 min. Usual workup and purification by silica gel preparative TLC [developed with hexane-Et2O (1:1)] afforded 21 (18.5 mg, 68%) as an oil, [α]22D+36.8° (c 1.85, CHCl3); 1H NMR (CDCl3) δ2.000-2.150 (2H, m, H-2ax, H-2eq), 2.010 (6H, s, acetyl), 2.082 (3H, s, acetyl), 2.119 (3H, s, acetyl), 2.137 (3H, s, acetyl), 3.882 (1H, dd, J5,4=1.5, J5,6=10.0 Hz, H-5), 4.115 (1H, dd, J7′,6=4.5, J7′,7=12.5 H, H-7′), 4.437 (1H, dd J7,6=2.5, J7,7′=12.5 Hz, H-7), 5.073 (1H, ddd, J3,4=3.0, J3,2eq=5.0, J3,2ax=12.5 Hz, H-3), 5.165 (1H, ddd, J6,7=2.5, J6,7′=4.5, J6,5=10.0 Hz, H-6), 5.303 (1H ,dd, J4,5=1.5, J4,3=3.0 Hz, H-4), 5.748 (1H, dd, J1,2eq=3.0, J1,2ax=10.0 Hz, H-1); 13C NMR (CDCl3) δ20.59, 20.59, 20.65, 20.65, 20.84, 30.35, 62.26, 63.84, 67.32, 67.90, 71.62, 91.67, 168.60, 169.60, 169.83, 170.30, 170.54. HRMS (M+Cs+) calcd C17H24O11Cs 537.0373, found 537.0359.