Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([S:20][NH2:21])[N:3]=1.O.CC(C)=[O:25].ClC1C=C(C=CC=1)C(OO)=O>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])=[C:4]([S:20]([NH2:21])=[O:25])[N:3]=1
Reactant: CC(C)=O
Reactant: NSc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Solvent: O
Product: Nc1nc(S(N)=O)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 0 °C

Procedure:
A mixture of 2-amino-9-β-D-ribofuranosyl-9H-purine-6-sulfenamide (18) (1.57 g, 0.005 mol), ethanol (700 mL) and water (50 mL) was vigorously stirred and cooled in an ice bath. After the temperature of the suspension had decreased to <10° C., acetone was added to the ice bath to obtain a temperature of <0° C. With continual stirring a solution of commercially available (Aldrich Chem Co.) 3-chloroperoxybenzoic acid (80-85%, 1.0 g, 0.0046-0.0049 mol) in ethanol (40 mL) was added dropwise over a period of approx. 15 min. The reaction flask was stoppered, the mixture was allowed to stir and warm as the ice melted, and then stirred at ambient temperature for a total reaction time of 19 hr. The reaction mixture was filtered (Whatman GF/A glass microfiber filter) to remove a trace of undissolved solid and then the filtrate was evaporated in vacuo and at a temperature of >25° C. to near dryness. The product was washed from the evaporation flask with acetone (50-100 mL) and the solid was collected by filtration, suspended in diethyl ether (50 mL), refiltered, dried under vacuum at ambient temperature: (1.3 g, 0.0042 mol, 85%), m.p. 183°-185° C. dec. with prior sintering and darkening. IR (KBr): 1040 (vs, S=O), 3000-3600 (NH2, OH)cm-1 : UV: λmax (pH 1) 333 nm (ε2,900): λmax (pH 7) 326 nm (ε10,700): λmax (pH 11) 325 nm (ε8,700): 1H NMR (DMSO-d6): δ 5.85 (d, 1, J =5.52 Hz, C1'H), 6.49 (s, 2, SONH2, exchanged with D2O), 6.98 (s, 2, NH2, exchanged with D2O), 8.45 (s, 1, C8 e,uns/H/ ), and other sugar protons. Anal. Calcd. for C10H14N6O5S.1/2C2H5OH (353.32): C, 37.39: H, 4.82: N, 23.80: S, 9.07. Found: C, 37.29: H, 4.56: N, 23.78: S, 8.92.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[C:11]3[N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]4([CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][S:18](=[O:21])(=[O:22])[CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCS(=O)(=O)CC2)c2ccc(N3CCOCC3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S1(=O)CCC2(CC1)CNc1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl 6-(4-morpholinyl)-2′,3′,5′,6′-tetrahydrospiro-[indole-3,4′-thiopyran]-1(2H)-carboxylate 1′,1′-dioxide (60 mg, 0.142 mmol) in DCM (1 mL) was added TFA (438 μL, 5.68 mmol) and the reaction was stirred at rt for 1 h. After this time the reaction was evaporated in vacuo and dried on the vacuum pump overnight. The resulting residue was then partitioned between DCM (40 mL) and NaHCO3 (10 mL, sat. aqueous solution). The separated organic layer was dried over MgSO4, filtered and evaporated in vacuo to give 6-morpholin-4-yl-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]1′,1′-dioxide. Mass Spectrum (ESI) m/e=323.2 (M+1).
Reaction SMILES: [OH:1][NH:2][C:3]([NH2:5])=[O:4].CO.CO[CH:10](OC)[CH2:11][C:12](=O)[CH2:13][CH3:14].C(O)C.[ClH:21]>>[ClH:21].[CH2:13]([C:12]1[N:5]=[C:3]([OH:4])[N+:2]([O-:1])=[CH:10][CH:11]=1)[CH3:14]
Reactant: NC(=O)NO
Reactant: CCC(=O)CC(OC)OC
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CCc1cc[n+]([O-])c(O)n1
Temperature: -6.5 °C
Reaction time: 1 h

Procedure:
0.388 mol (25.9 g) hydroxy urea were dissolved in 195 ml 2 M HCl, 80 ml of methanol were added and 0.388 mol (56.7 g) of 1,1-dimethoxypentane-3-on (62% content in product mixture) were added dropwise under cooling with the internal temperature being maintained at −6 to −7° C. The solution was thawed to room temperature in an ice bath and stirred for 1 h, then evaporated until dryness. The residue was suspended with 100 ml of acetone, the mixture was cooled to below 0° C. in an ice/ethanol bath, the solid filtered off and washed with little ice-cold acetone. After drying 32.6 g crude product were obtained. The crude product was heated until boiling with 200 ml ethanol, hot filtered and slowly cooled to −18° C. The precipitated solid was filtered off, washed with a little amount of ethanol and dried. 11.7 g of the title compound were obtained.
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([C:9]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH:17]([C:19](=[S:21])[NH2:20])N.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:5]1([C:9]2([C:13]3[S:21][C:19]([NH2:20])=[N:17][N:14]=3)[CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=1
Reactant: N#CC1(c2cccc(C(F)(F)F)c2)CCC1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Nc1nnc(C2(c3ccccc3)CCC2)s1
Temperature: 60 °C

Procedure:
To a T-vial containing 1-[3-(trifluoromethyl)phenyl]cyclobutanecarbonitrile (1 eq) and hydrazinecarbothioamide (1 eq) was added TFA (1 eq) dropwise at rt. Then the mixture was heated to 60° C. for 2 hrs and cooled to rt. Ethyl acetate and aq. NaHCO3 were added and extracted with ethyl acetate twice, the organic layers combined, dried with MgSO4, and concentrated to give the desired product which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:18][CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=1.C=O.[BH3-][C:23]#N.[Na+].C(O)(=O)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([N:18]([CH3:23])[CH3:19])[CH:5]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: [BH3-]C#N
Reactant: CNc1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN(C)c1cc(Br)cc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
0.34 g (0.001 mol) of [3-bromo-5-(4-nitrophenylsulphanyl)-phenyl]-methylamine was dissolved in 10 ml of acetonitrile, treated with 1.52 ml (0.020 mol) of formaldehyde, 0.74 g (0.010 mol) of NaBH3CN and 1.76 ml of acetic acid and stirred at room temperature for 1 hr. Thereafter, the solvent was removed, the residue was partitioned in ethyl acetate/water and the organic phase was washed with sat. sodium chloride solution, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane 1:19. There was obtained 0.35 g (99%) of [3-bromo-5-(4-nitro-phenylsulphanyl)-phenyl]-dimethylamine as yellow crystals; m.p.: 102-104° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:11][C:12](=[S:22])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:33])=[O:32])=[CH:27][CH:26]=1>C1COCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:11][C:12]([S:22][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:33])=[O:32])=[CH:27][CH:26]=3)=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1
Reactant: CS(=O)c1ccc(CCl)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1ccc(CSc2nc(-c3ccc(F)cc3)c(-c3ccnc(Cl)c3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH (55-65%; 0.1 g; about 2 mmol) was introduced into a solution of 24a (0.31 g; 1.0 mmol) in absolute THF (15 ml). The initial charge was stirred at room temperature for 5 min, and 4-methylsulfinylbenzyl chloride (3, 0.19 g; 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The yellow-brown solution was diluted with H2O and neutralized with 10% strength citric acid. The THF was removed and the aqueous solution was extracted with ethyl acetate (2×). The combined organic extract was washed with saturated NaCl solution (2×), dried over Na2SO4 and concentrated. The solids residue was purified by column chromatography (SiO2 60, CH2Cl2/EtOH 9.5+0.5). M.p. 179° C.
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]=[CH:5][N:6]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH:7]=1.[Br:17][CH2:18][CH2:19][CH2:20]Br.C(OCC)(=O)C>CS(C)=O>[Br:17][CH2:18][CH2:19][CH2:20][N:8]([N:6]1[CH:5]=[N:4][N:3]=[CH:7]1)[C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1
Reactant: BrCCCBr
Reactant: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N(CCCBr)n2cnnc2)cc1
Reaction time: 8 h

Procedure:
Sodium hydride (60%, 240 mg, 6.0 mmol) was added to a solution of 4-([1,2,4]triazol-4-ylamino)-benzonitrile (926 mg, 5.0 mmol) in DMSO (25 mL) at r.t. The mixture was stirred for 1 hour at this temperature and 1,3dibromopropane (5 mL) was added. The reaction mixture was stirred overnight and ethyl acetate (100 mL) was added. The mixture was transferred into a separation funnel and extracted with water (twice 100 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure (water bath temperature <30° C.). The resulting orange oil was mixed with diethyl ether (100 mL) and filtered through a layer of silica (ca. 5 cm). The silica was washed with more diethyl ether (ca. 100 mL) to remove the excess of 1,3-dibromopropane, the crude product was washed from the silica with acetone (120 mL). The acetone solution was concentrated under reduced pressure and the residue was purified by column-chromatography (eluent: ethyl acetate) to give the title compound as a white solid. Yield: 792 mg (52%). 1H-NMR (400 MHz, d6-DMSO) δ=2.01 (tt, J=7.0, 6.6 Hz, 2H), 3.64 (t, J=6.6 Hz, 2H), 3.95 (t, J=7.0 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 9.02 (s, 2H). 13C-NMR (100 MHz, d6-DMSO) δ=30.38, 32.13, 52.72, 103.17, 113.83, 119.74, 134.63, 144.14, 151.65. LRMS (FAB+): 306.0 (100, [M+H]+).
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=[C:4](/[CH:8]=[CH:9]/[C:10]2[CH:14]=[CH:13][S:12][CH:11]=2)[O:3]1.[SH:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][S:21][CH:9]([C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[CH2:8][C:4]1[O:3][C:2]([CH3:1])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6](=[O:7])[CH:5]=1
Reactant: OCCCCS
Reactant: CC1(c2ccccc2)OC(/C=C/c2ccsc2)=CC1=O
Product: CC1(c2ccccc2)OC(CC(SCCCCO)c2ccsc2)=CC1=O

Procedure:
According to the procedure of Method A, Example 1, (E)-2-methyl-2-phenyl-5-[2-(3-thienyl)ethenyl]-3(2H)-furanone was reacted with 4-mercapto-1-butanol to provide 5-[2-[(4-hydroxybutyl)thio]-2-(3-thienyl)ethyl]-2-methyl-2-phenylfuran-3(2H)-one: 1H NMR (CDCl3) δ1.52-1.70 (broad s with fine structure, ˜5H) and 1.65 and 1.67 (singlets, 3H), 2.41 (m, 2H), 3.08-3.24 (m, 2H), 3.60 (m, 2H), 4.40 (m, 1H), 5.37 and 5.39 (singlets, 1H), 7.05-7.16 (m, 2H), 7.25-7.40 (m, 6H); MS (HR-EI) m/z 388.1161 (M+ calcd. for C21H24O3S2 388.1167).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][O:21][Si](C(C)C)(C(C)C)C(C)C)=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Agent: Cl
Solvent: CO
Product: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-(4-[(triisopropylsilyl)oxy]methyl-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one (1.7 g, 3.7 mmol) was dissolved in anhydrous MeOH (MeOH) (110 mL) followed by addition of 2 M of hydrogen chloride in MeOH (9.2 mL). Reaction was stirred at 70° C. for 4 hrs. After concentration in vacuo the sample was loaded onto 120 g ISCO cartridge eluting with EtOAc/hexane. Fractions were combined and evaporated to yield desired product as an off-white powder. (1.12 g, 97%). 1H NMR (400 MHz, DMSO-d6) δ: 7.96 (dd, J=6.8, 2.3 Hz, 1H), 7.66 (m, 1H), 7.64 (m, 1H), 5.95 (s, 1H), 4.85 (s, 2H); MF═C11H6ClFN4O4; LCMS calculated for C11H7ClFN4O4(M+H)+: m/z=313.014.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7]2>C1COCC1.[Ni]>[Br:1][C:2]1[CH:11]=[C:10]([NH2:12])[C:9]([NH2:15])=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7]2
Reactant: Nc1c([N+](=O)[O-])cc(Br)c2c1CN(CCc1ccccc1)CC2
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cc(Br)c2c(c1N)CN(CCc1ccccc1)CC2
Yield: 97.8 %

Procedure:
A solution of the product from Example 9 (0.6 g, 1. mmol) in THF (50 mL) was stirred over RaNi under a hydrogen balloon for 40 mins. The catalyst was filtered off and concentrated under vacuum to give the title compound (0.54 g, 98% yield) as a pink solid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[O:10]1[CH2:15][CH2:14][N:13]([C:16]([CH2:18][N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:17])[CH2:12][CH2:11]1.C1CCC(N=C=NC2CCCCC2)CC1>C(#N)C>[O:10]1[CH2:15][CH2:14][N:13]([C:16]([CH2:18][N:19]2[CH2:20][CH2:21][N:22]([C:7]([CH:2]3[NH:1][C:5](=[O:6])[CH2:4][CH2:3]3)=[O:9])[CH2:23][CH2:24]2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C1CCC(C(=O)N2CCN(CC(=O)N3CCOCC3)CC2)N1
Yield: 93.9 %

Procedure:
Pyroglutamic acid (1.6 g), 2.1 g of 1-(morpholinocarbonylmethyl)piperazine, 2.47 g of DCC and 130 ml of acetonitrile were heated to reflux for 48 hours with stirring. The insoluble matter was removed by filtering the reaction mixture and the solvent was evaporated from the filtrate in vacuo. The residue was subjected to a silica gel column chromatography to give 3.0 g of the product. This was recrystallized from a mixture of ethyl acetate, isopropanol and n-hexane to give 2.6 g of desired product, m.p. 167°-169° C.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:29])[C:14]=2[NH:18][C:19](=[O:28])[CH2:20][CH:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:9]1=[O:30])[CH3:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[CH:21]1([CH2:20][C:19]([NH:18][C:14]2[C:13]([CH3:29])=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[CH:17][N:8]([C@H:6]([CH3:7])[CH2:5][OH:4])[C:9]3=[O:30])=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)OC[C@@H](C)n1ccc2c(NC(=O)CC3CCCCCC3)c(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(=O)n([C@H](C)CO)ccc2c1NC(=O)CC1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with (R)-2-(5-(2-cycloheptylacetamido)-6-methyl-1-oxoisoquinolin-2(1H)-yl)propyl acetate (180.0 mg, 0.0004363 mol), potassium carbonate (180 mg, 0.0013 mol), methanol (15 mL, 0.37 mol) and few drops of water. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water was added to the residue and extracted with (chloroform:IPA, 3:1) and the solvent removed under reduced pressure and the residue purified by reverse phase prep BPLC to afford the product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.Cl>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[N:12]1([CH2:11][CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: OC(CCCN1CCCCC1)c1ccc(F)cc1
Agent: [Mn+4]
Agent: Cl
Agent: [O-2]
Solvent: c1ccccc1
Product: O=C(CCCN1CCCCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
A mixture of 2 g of 1-(p-fluorophenyl)-4-piperidino-1-butanol liberated from the hydrochloride, 20 ml of benzene, and 4 g of a fine powder of manganese dioxide was stirred for 8 hours at room temperature. After filtration, the precipitate was washed with 20 ml of benzene. The benzene washings and filtrate were combined and concentrated under reduced pressure to obtain oily γ-piperidino-p-fluorobutyrophenone (2 g in weight; infrared absorption spectrum, ν C=0 1678 cm-1). The said oily product was dissolved in 20 ml of ether, and gaseous hydrogen chloride was introduced therein to saturation. The precipitate formed was recrystallized from ethanol-ether to yield the hydrochloride melting at 180° - 181°C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.C1COCC1.[Pd]>[N:10]1([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:14]=[CH:13][N:12]=[N:11]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(-n2ccnn2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cccc(-n2ccnn2)c1
Yield: 101.6 %

Procedure:
1-(3-Nitro-phenyl)-1H-[1,2,3]triazole (9.66 g, 51 mmol) were dissolved in 300 ml methanol and 70 ml THF. Palladium on charcoal (10%, 500 mg) were added and the reaction mixture was stirred with a hydrogen balloon for 36 h. Palladium on charcoal was filtered off and washed with methanol. The solvent was evaporated off to yield the title compound (8.3 g, 100%) as an off-white solid, mp 71-73° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([N:12]3[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13]3)=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:17][CH:14]1[CH2:15][CH2:16][N:12]([C:11]2[C:6]([CH:4]3[CH2:5][N:2]([C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)[CH2:3]3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:13]1
Reactant: Clc1ccc2ccccc2n1
Reactant: CC1CCN(c2nccnc2C2CNC2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCN(c2nccnc2C2CN(c3ccc4ccccc4n3)C2)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 2-Azetidin-3-yl-3-(3-methyl-pyrrolidin-1-yl)-pyrazine hydrochloride (44) (127 mg, 0.5 mmol, PREPARATION 13) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs2CO3 (325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was diluted with water, extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (15 mL) and brine (15 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography on silica gel to give (rac)-2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline (127.65 mg, 0.37 mmol, yield 74%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][C:20]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([NH2:26])=[N:24][CH:25]=1>>[Br:19][C:20]1[CH:21]=[C:22]([O:27][CH3:28])[C:23]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:24][CH:25]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: COc1cc(Br)cnc1N
Product: COc1cc(Br)cnc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 5-bromo-3-methoxypyridine-2-amine as the starting materials.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:30])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[O:19]1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:28]2[CH:29]=[C:25]([B:20]3[O:19][C:18]([CH3:30])([CH3:17])[C:22]([CH3:24])([CH3:23])[O:21]3)[CH:26]=[N:27]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(Cc3ccc(OCc4ccccc4)cc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 4A (0.54 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.377 g) in N,N-dimethylformamide (5 mL) was cooled to 0° C. To this solution was added 60% sodium hydride (0.096 g). The solution was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 25% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C)C=O>[C:11]1(=[O:21])[N:15]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCOCCOCCCl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOCCOCCO

Procedure:
188 g of 2-[2-(2-Chloroethoxy)ethoxy]ethanol and 146 g of potassium phtalimide in 700 ml of dimethylformamide are brought to 95° C. for 17 hours.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([NH:9][CH2:10][CH2:11][NH2:12])[CH3:8].O>C(O)(C)C.[Cu].[Cu]Cl>[CH2:7]([N:9]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:10][CH2:11][NH2:12])[CH3:8]
Reactant: CCNCCN
Reactant: Brc1nccs1
Agent: Cl[Cu]
Agent: [Cu]
Solvent: O
Solvent: CC(C)O
Product: CCN(CCN)c1nccs1
Temperature: 70 °C
Yield: 8 %

Procedure:
47 mg (0.74 mmol) of copper and 225 mg (2.27 mmol) of copper(I) chloride were added to a solution of 1.35 g (15.0 mmol) of 2-bromothiazole and 9.48 ml (90.0 mmol) of N-ethylethylenediamine in isopropanol (7.5 ml). The mixture was then heated to 70° C. for 1 h. After cooling to RT, the reaction solution was poured into water and extracted with EA. The organic phase was dried over MgSO4, filtered and evaporated under a vacuum. 200 mg (1.2 mmol, 8%) of N1-ethyl-N1-(thiazol-2-yl)ethane-1,2-diamine were obtained by carrying out CC twice (i. DCE/EtOH 5:1; ii. DCE/EtOH/conc. aq. NH4OH soln. 5:1:0.06) with the residue.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][NH:16][CH2:15]1)=[N:10][C:9]([C:19]1[NH:23][C:22](=[O:24])[NH:21][N:20]=1)=[CH:8]2.CC1C=CC=C(C)N=1.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C(Cl)Cl>[C:33]([N:16]1[CH2:17][CH2:18][C@H:14]([NH:13][C:11]2[C:12]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[Cl:2])[CH:8]=[C:9]([C:19]3[NH:23][C:22](=[O:24])[NH:21][N:20]=3)[N:10]=2)[CH2:15]1)(=[O:36])[CH:34]=[CH2:35]
Reactant: O=c1[nH]nc(-c2cc3cccc(Cl)c3c(N[C@H]3CCNC3)n2)[nH]1
Reactant: C=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=CC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
To a mixture of (S)-3-(8-chloro-1-(pyrrolidin-3-ylamino)isoquinolin-3-yl)-1H-1,2,4-triazol-5(4H)-one hydrochloride (100 mg, 0.3 mmol) in DCM (20 mL) was added 2,6-dimethylpyridine (97 mg, 0.91 mmol). The resulting mixture was cooled to −40° C. Acryloyl chloride (51 mg, 0.6 mmol, 10 mg/mL in dry DCM) was added dropwise and the mixture was stirred at −40° C. for 30 minutes. The reaction was subsequently quenched with MeOH (5 mL) and the mixture was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound (57 mg, 52%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.91 (s, 1H), 11.80 (s, 1H), 7.85-7.83 (m, 1H), 7.61-7.59 (m, 3H), 7.49-7.47 (m, 1H), 6.6-6.5 (m, 1H), 6.17-6.13 (m, 1H), 5.67-5.63 (m, 1H), 5.18-5.16 (m, 1H), 4.18-4.17 (m, 0.5H), 3.69-3.65 (m, 0.5H), 3.42 (m, 0.5H), 3.32-3.31 (m, 1.5H), 2.31-2.29 (m, 1H), 2.04-2.01 (m, 1H); ESI-MS m/z [M+H]+ 385.1.