Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[N:11]([C:18]2[CH:23]=[CH:22]N=CC=2)[CH:12]=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32]Cl)[CH:28]=[C:29]([Cl:31])[CH:30]=1.[CH2:34]([N:36](CC)[CH2:37]C)[CH3:35].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:18][C:23]2[CH:22]=[CH:37][N:36]=[CH:34][CH:35]=2)[C:12]([S:32][C:27]2[CH:26]=[C:25]([Cl:24])[CH:30]=[C:29]([Cl:31])[CH:28]=2)=[C:13]([CH:15]([CH3:16])[CH3:17])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClSc1cc(Cl)cc(Cl)c1
Reactant: CC(C)c1cn(-c2ccncc2)c(COCc2ccccc2)n1
Reactant: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(COCc2ccccc2)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
2-Benzyloxymethyl-4-isopropyl-1-(pyridin-4-yl)-1H-imidazole (5) (10.0 g, 31.1 mmol) was dissolved in toluene (50 ml). The solution was added dropwise to a solution of 3,5-dichlorobenzenesulfenyl chloride (3) (8.0 g, 37.05 mmol) in toluene (24.7 g) under ice-cooling for 30 minutes. To the mixture was added dropwise triethylamine (3.5 g, 34.6 mmol) under ice-cooling for 1 hour and the mixture was stirred at the same temperature for 1.5 hours. To the mixture was added water (25 ml) and toluene layer was separated. The toluene layer was washed with water (25 ml) and each aqueous layer was extracted with toluene (10 ml). The toluene layer was collected, concentrated under reduced pressure to give oily product, which was crystallized with diisopropyl ether 50 ml, filtered and dried to yield the objective (6) (12.6 g) as a pale yellow crystal. Yield 81.3%.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:43]([Cl:45])[Cl:44]>C(O)(=O)C>[NH3:1].[CH2:43]([Cl:45])[Cl:44].[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1OCCCN1CCCCC1
Reactant: Nc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc(NCc2ccccc2OCCCN2CCCCC2)cc1
Product: N
Reaction time: 16 h

Procedure:
A solution of 2-(3-piperidin-1-yl-propoxy)-benzaldehyde (266 mg), 4-chloroaniline (146 mg), and acetic acid (0.07 mL) in DCM (5 mL) was treated with sodium triacetoxyborohydride (400 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (6 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (sodium sulfate) and evaporated. Chromatography of the residue (1–5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (246 mg). 1H NMR (400 MHz, CDCl3): 7.28–7.20 (m, 2H), 7.09 (d, J=8.9 Hz, 2H), 6.89 (m, 2H), 6.55 (d, J=8.9 Hz, 2H), 4.30 (d, J=5.6, 2H), 4.18 (m, 1H), 4.05 (t, J=6.3 Hz, 2H), 2.47 (m, 2H), 2.37 (br, 4H), 1.96 (m, 2H), 1.62–1.56 (m, 4H), 1.49–1.42 (m, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][S:5][C:6]([CH3:16])([CH3:15])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:14])[CH2:11][CH:12]=O.CN(C)[CH:19]=[O:20]>>[CH3:4][S:5][C:6]([CH3:16])([CH3:15])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:14])[CH2:11]/[CH:12]=[CH:15]/[C:6]([CH3:16])=[CH:7][C:1]([O:20][CH3:19])=[O:2]
Reactant: CN(C)C=O
Reactant: CSC(C)(C)CCCC(C)CC=O
Reactant: C[O-]
Agent: [Na+]
Product: COC(=O)C=C(C)/C=C/CC(C)CCCC(C)(C)SC
Reaction time: 3 h

Procedure:
Sodium methoxide (1.2 g. of sodium and 30 ml. of methanol) is added slowly to a mixture of 6.4 g. of 7-methylthio-3,7-dimethyloctan-1-al and 10 g. of diethyl 3-methoxycarbonyl-2-methylprop-2-enyl phosphonate (about 77% trans) in 50 ml. of dimethylformamide, under nitrogen and at about 0°, with stirring. After addition is complete, the reaction is left 3 hours at room temperature and worked up by extraction with hexane/ether to yield cis/trans methyl 11-methylthio-3,7,11-trimethyldodeca-2,4-dienoate mostly the trans, trans isomer.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[N:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8].IC.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[N:11]=[CH:10][N:9]([CH3:15])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2[nH]cnc2c(F)c1Br
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc2c(ncn2C)c(F)c1Br
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-7-fluoro-5-methyl-3H-imidazo[4,5-b]pyridine (1.00 equivalent) in DMF is added iodomethane (1.20 equivalents) and K2CO3 (1.50 equivalents) at room temperature. The resulting mixture is stirred at 75° C. for 1 hour. The reaction mixture is diluted with EtOAc and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][C:12]=3[S:13][CH2:14][C:5]=2[C:4]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])=[N:3]1.OO.[OH2:28].C(O)(=[O:31])C>>[CH3:1][N:2]1[C:6]2[C:7]3[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[CH:11][C:12]=3[S:13](=[O:31])(=[O:28])[CH2:14][C:5]=2[C:4]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])=[N:3]1
Reactant: CC(=O)O
Reactant: Cn1nc(C(=O)N2CCOCC2)c2c1-c1cc([N+](=O)[O-])ccc1SC2
Reactant: O
Agent: OO
Product: Cn1nc(C(=O)N2CCOCC2)c2c1-c1cc([N+](=O)[O-])ccc1S(=O)(=O)C2
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-3-(morpholin-4-ylcarbonyl)-8-nitro-1,4-dihydrothiochromeno[4,3-c]pyrazole (0.084 g, 0.23 mmol) in acetic acid is heated at 100° C. under nitrogen. Hydrogen peroxide 30% in water (0.5 mL, 3.6 mmol, 15 Eq) is added and the reaction mixture is heated for 30 minutes. After 30 minutes, the solvent is removed under reduced pressure. 10% aqueous NaHCO3 is added to the residue. The mixture is stirred for few minutes and then extracted with DCM. The organic layer is concentrated and purified by column chromatography to afford the title compound as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.66 (s, 1H), 8.48 (dd, J=8.5 Hz, J=2.3 Hz, 1H), 8.28 (J=11.8 Hz, 1H), 4.96 (s, 2H), 4.33 (s, 3H), 3.94 (brs, 2H), 3.66-3.63 (m, 6H). MS (ESI+): 393.0. HPLC (max plot) 90.8%; Rt 3.08 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].COCCOC.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C.O>[N:37]1([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][C:9]3[C:10]([O:12][CH3:13])=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=3)[C:4]([O:6][CH3:7])=[O:5])=[CH:32][CH:33]=2)[CH:41]=[CH:40][CH:39]=[N:38]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(OC)cc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)cc1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
To a solution of methyl 2-hydroxy-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.80 g) in a mixed solvent of DME (12.0 mL)-water (4.00 mL) were added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.62 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g) and sodium carbonate (0.55 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.48 g).
Reaction SMILES: [CH:1]([Li])([CH2:3][CH3:4])[CH3:2].[CH2:6]=[CH:7][C:8](=[CH2:10])[CH3:9]>C1C=CC=CC=1>[CH2:6]=[CH:7][C:8](=[CH2:9])[CH3:10].[CH2:2]=[CH:1][CH:3]=[CH2:4]
Reactant: [Li]C(C)CC
Solvent: C=CC(=C)C
Solvent: c1ccccc1
Product: C=CC=C

Procedure:
A 3-arm star isoprene/butadiene block copolymer was synthesized using standard high vacuum techniques, M. Morton et al., J. Rubber Chem. and Technol., 48, 359 (1975). A brief summary of the polymerization procedure is as follows: Ampules containing sec-butyl lithium solution (in benzene) and benzene were released into a 250 ml all-glass high-vacuum apparatus, magnetic stirring was commenced, and sufficient isoprene was added from an ampule to form oligomeric chains five (5) units long. After stirring for 40 hours at 25° C., the mixture was frozen, and an amount of butadiene was distilled into the reaction mixture to add a block of 95 units to the living isoprene oligomers. The reaction mass was then thawed and stirred for 60 hours at room temperature. During this time, a slight increase in viscosity was noted, but the mixture remained clear and water-white. At this point, the living chains were linked with a stoichiometric amount of trichloromethyl silane, followed by precipitation into methanol. Work-up was completed by redissolution of the polymer into hexanes, washing the solution three times with water, drying the solution over MgSO4, and finally removal of the solvent using a Rotovap.
Reaction SMILES: Br[C:2]([CH3:4])=[CH2:3].[CH3:5][C:6]([OH:10])([CH:8]=[CH2:9])[CH3:7].[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:5][C:6]([OH:10])([CH2:8][CH:9]=[C:2]([CH3:4])[CH2:3][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:7]
Reactant: C=C(C)Br
Reactant: C=CC(C)(C)O
Reactant: C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=CCC(C)(C)O)CN1CCCCC1
Temperature: 100 °C
Yield: 80 %

Procedure:
A mixture of 10 mmoles 2-bromopropene, 12.5 mmoles 2-methyl-3-buten-2-ol, 30 mmoles piperidine, 0.10 mmole palladium acetate and 0.20 mmole triphenylphosphine were heated together at 100° C. for 20 hrs. From the reaction mixture there was isolated an 80% yield of 2,5-dimethyl-6-piperidinohex-4-en-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@@H:14]2[CH2:19][CH2:18][C@H:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[CH3:36][O:37][NH2:38]>>[F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:21])[NH:38][O:37][CH3:36])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.[F:1][C:2]1[CH:35]=[CH:34][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:23][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:21])[NH:10][C:11]([CH3:26])([CH3:12])[CH2:36][OH:37])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CON
Reactant: O=C(/N=c1\[nH]c2ccc(CN3CCOCC3)cc2n1[C@H]1CC[C@@H](C(=O)Cl)CC1)c1ccc(F)cc1
Product: CC(C)(CO)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCOCC4)cc32)CC1
Product: CONC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCOCC4)cc32)CC1
Yield: 54 %

Procedure:
The title compound was prepared from cis-4-((E)-2-(4-fluorobenzoylimino)-6-(morpholinomethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarbonyl chloride and O-methylhydroxylamine using a method analogous to that used in the preparation of (E)-4-fluoro-N-(1-(cis-4-(1-hydroxy-2-methylpropan-2-ylcarbamoyl)cyclohexyl)-6-(morpholinomethyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (27.4 mg, 54% yield). MS, m/z (C27H32FN5O4): calcd, 509.2. found, 510.2 [M+H].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.O=[O+][O-].[NH2:9][CH2:10][C:11]([F:38])([F:37])[CH2:12][NH:13][C:14](=[O:36])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][C:24]2[S:28][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:26][CH:25]=2)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[F:38][C:11]([F:37])([CH2:10][N:9]1[CH2:4][CH2:5][O:1][CH2:2][CH2:3]1)[CH2:12][NH:13][C:14](=[O:36])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][C:24]2[S:28][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:26][CH:25]=2)[CH:16]=1
Reactant: NCC(F)(F)CNC(=O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Reactant: C1=COCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NCC(F)(F)CN1CCOCC1)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
A solution of dihydrofuran (35 mg, 0.5 mmol) in MeOH (1.5 mL) was treated with ozone at −78° C. until the solution turned blue. Argon was streamed through the solution to remove excess ozone. The solution was warmed to 0° C., and N-(3-Amino-2,2-difluoro-propyl)-4-fluoro-3-{[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzamide (Example 107) (12 mg, 0.027 mmol)) followed by NaBH(OAc)3 (84 mg) were added over a period of 3 h. The mixture was diluted with CH2Cl2, washed with sat. NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography [silica gel, 1% (NH3/MeOH(2M) in EtOAc] to afford the title compound (7 mg, 51%) as a white solid. LC/MS; (M+H)+=507. 1HNMR (CD3OD): δ 2.47 (m, 4H); 2.66 (t, 2H, J=13.7 Hz); 3.53 (m, 4H); 3.80 (t, 2H, J=14.3 Hz); 4.48 (s, 2H); 6.78 (m, 1H); 6.86 (d, 1H, J=8.25 Hz); 7.0 (m, 2H); 7.15 (s, 1H); 7.23 (m, 1H); 7.54 (m, 1H), 8.15 (d, 1H, J=4.4 Hz).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:16][CH:17]([CH3:23])[CH2:18][S:19](Cl)(=[O:21])=[O:20].[CH:24]1([CH2:27][O:28][C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:26][CH2:25]1>>[CH:24]1([CH2:27][O:28][C:29]2[CH:30]=[CH:31][C:32]([N:33]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([S:19]([CH2:18][CH:17]([CH3:23])[CH3:16])(=[O:21])=[O:20])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:34][CH:35]=2)[CH2:25][CH2:26]1
Reactant: Nc1ccc(OCC2CC2)cc1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CC(C)CS(=O)(=O)N1CCC2(CCN(c3ccc(OCC4CC4)cc3)C2=O)CC1

Procedure:
Grey solid. MS (ESI): 421.21 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-methyl-propane-1-sulfonyl chloride, 4-cyclopropylmethoxy-aniline.
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5](Cl)([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[C:6](Cl)=[N:7][C:8]=1[C:9]#[N:10])#[N:2].[CH2:20]([NH2:22])[CH3:21]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:22][CH2:20][CH3:21])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#CC1=C(C#N)NC(Cl)(c2cccc(F)c2)C(Cl)=N1
Reactant: CCN
Solvent: Cc1ccccc1
Product: CCNc1nc(C#N)c(C#N)nc1-c1cccc(F)c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
2,3-Dicyano-5-chloro-6-chloro-6-(m-fluorophenyl)pyrazine (1.00 g; 0.0039 mole) was dissolved in 30 ml of toluene. The solution was cooled to -5° C., and 0.65 g of a 70% aqueous solution of ethylamine was added dropwise. The mixture was stirred at -5° to 0° C. for 30 minutes. The reaction mixture was worked up in the same way as in Example 13, and recrystallized from ethanol to afford 0.63 g (yield 61%) of 2,3-dicyano-5-ethylamino-6-(m-fluorophenyl)pyrazine.
Reaction SMILES: [CH2:1]([N:19]1[C:28](=[O:29])[C:27]2[N:26]([CH3:30])[CH:25]=[N:24][C:23]=2[N:22]([CH3:31])[C:20]1=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[N+]1([O-])CC[O:36]CC1.S([O-])([O-])=O.[Na+].[Na+].[OH2:46]>CC(C)=O>[OH:46][CH:9]([CH:10]([OH:36])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:19]1[C:28](=[O:29])[C:27]2[N:26]([CH3:30])[CH:25]=[N:24][C:23]=2[N:22]([CH3:31])[C:20]1=[O:21]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: CCCCCCCCC=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCCCCCCC(O)C(O)CCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.5 h
Yield: 40.4 %

Procedure:
A solution of 1-(9-octadecenyl)-3,7-dimethylxanthine (0.15 g, 0.35 mmol), 4-methylmorpholine-N-oxide (49 mg, 0.42 mmol, 1.2 equivalents.) and potassium osmate dihydrate (1 mg) in acetone (4 ml) and water (1 ml) was stirred for 6 hours. A solution of 20% aqueous sodium sulphite (2 ml) was added and stirred for 30 minutes. The reaction mixture was extracted with four 10 ml aliquots of 25% ethanol/dichloromethane. The combined organic extracts were dried over anhydrous magnesium sulfate, the solvent evaporated under reduced pressure and a residue purified by flash chromatography over silica gel using a methanol(5%)/dichloromethane eluant, yielding 0.65 g of 1-(9,10-dihydroxyoctadecyl)-3,7-dimethylxanthine (40.4% yield).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[NH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].I[CH3:31]>>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([C:23]5[C:24](=[O:29])[N:25]([CH3:31])[CH:26]=[CH:27][CH:28]=5)=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccn(C)c3=O)cc1-2
Yield: 20 %

Procedure:
Following the procedure for 477, compound 330 and iodomethane were reacted to give 502 (0.039 g, 20%). 1H NMR (500 MHz, DMSO) δ 9.05 (d, J=2.3, 1H), 8.09 (s, 1H), 7.73 (dd, J=6.7, 1.9, 1H), 7.66 (ddd, J=10.7, 7.7, 2.1, 2H), 7.07 (d, J=8.4, 1H), 6.34 (t, J=6.8, 1H), 5.94 (dt, J=13.2, 6.6, 1H), 4.40 (t, J=4.9, 2H), 3.53 (s, 3H), 3.46 (t, J=5.0, 2H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 420.2 (M+H).
Reaction SMILES: [Li]CCCC.CCCCCC.CC1(C)CCCC(C)(C)N1.C[Si](C)(C)[N:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:31].Cl[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>C1COCC1>[CH3:42][O:41][C:36]1[CH:35]=[C:40]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][NH:24][C:25]2=[O:31])[CH:39]=[CH:38][CH:37]=1
Reactant: C[Si](C)(C)N1CCCCCC1=O
Reactant: COc1ccccc1Cl
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(C2CCCCNC2=O)c1
Reaction time: 0.17 h

Procedure:
To 1.6 M n-BuLi in hexane (31.3 mL, 50 mmol) at 0° C. was added a solution of 2,2,6,6-tetramethyl piperidine (8.43 mL, 50 mmol) in anhydrous THF (100 mL) over 5 min. 1-Trimethylsilanyl-azepan-2-one (as described in Step A above) (9.26 g, 50 mmol) in anhydrous THF (20 mL) was added. After stirring the reaction mixture for 10 min a further portion of 1.6M n-BuLi in hexane (31.3 mL, 50 mmol) was added, the mixture stirred for 10 min, and 2-chloroanisole (6.34 mL, 50 mmol) was added. After stirring for 30 min under Ar, the reaction was quenched with H2O, stirred for 30 min, concentrated in vacuo, diluted with EtOAc, washed with 5N HCl (100 mL) and brine. The organic layer was dried (MgSO4), concentrated and purified using SiO2 chromatography (0.5% MeOH/CH2Cl2) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Br[CH2:13][CH2:14][CH2:15][C:16]#N.C[O:19]CCO>O>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[N:1]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:19])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: N#CCCCBr
Reactant: COCCO
Solvent: O
Product: O=C1CCCN1c1cccc2cccnc12

Procedure:
8-Aminoquinoline (2.0 g, 13.9 mmol) and 4-bromobutyronitrile (2.0 g, 13.9 mmol) were refluxed in 2-methoxyethanol (20 ml) for 24 hours under a nitrogen atmosphere. A few drops of water were added to hydrolyze the 1-(8-quinolyl)-2-iminopyrrolidinone produced, and the mixture was evaporated under vacuum. The residual oil was triturated with diethyl ether (50 ml) and decanted. Upon standing at ambient temperature the ether solution deposited 0.65 g of 1-(8-quinolyl)-2-pyrrolidinone, (m.p. 119°-121°). The ether insoluble oil was dissolved in acetone, filtered and combined with the ether liquor. The solvents were evaporated; the residue was dissolved in methylene chloride, washed with 30% aqueous sodium hydroxide and with water. The water layer was back-extracted with methylene chloride, and the combined methylene chloride layers were dried, filtered, and evaporated. The semi-solid residue was triturated with ether and the mixture filtered to yield 0.40 g of 1-(8-quinolyl)-2-pyrrolidinone, (m.p. 118°-120°). The ether mother-liquor upon standing gave a second crop of 0.50 g, (m.p. 119°-120°). The combined yield was 1.55 g or 52%.
Reaction SMILES: [OH-].[K+:2].O.[NH:4]1[C:8]([C:9]([O:11]CC)=[O:10])=[N:7][N:6]=[N:5]1.CCO>>[NH:4]1[C:8]([C:9]([O-:11])=[O:10])=[N:7][N:6]=[N:5]1.[K+:2].[K+:2].[NH:4]1[C:8]([C:9]([O-:11])=[O:10])=[N:7][N:6]=[N:5]1
Reactant: CCOC(=O)c1nnn[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C([O-])c1nnn[nH]1
Yield: 128 %

Procedure:
A solution of potassium hydroxide (1.3 g, 23.2 mmol) in water (4.2 mL, 230 mmol) was added to a solution of ethyl tetrazole-5-carboxylate (1.1 g, 7.7 mmol) in EtOH (24 mL, 410 mmol). A solid product formed immediately and was collected and washed with cold EtOH to yield the title compound (1.5 g).