Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.Br[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1>C1COCC1>[CH3:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:2][C:1]#[N:3])=[N:11][CH:12]=1
Reactant: CC#N
Reactant: Cc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(CC#N)nc1
Temperature: 78 °C
Reaction time: 1 h
Yield: 234.3 %

Procedure:
To a solution of anhydrous acetonitrile (10.1 mL, 191.83 mmol, 3.3 equiv.) in dry THF (500 mL) was added dropwise n-butyl lithium (2.5 M in hexane, 69.8 mL, 174.39 mmol, 3 equiv.) at minus 78° C. under a nitrogen atmosphere. The resulting white suspension was stirred at minus 78° C. for 1 hour, and then a solution of 2-bromo-5-methylpyridine (10.0 g, 58.13 mmol, 1 equiv.) in dry THF (30 mL) was added. The reaction mixture was kept at minus 78° C. for 1 hour and then warmed up slowly to room temperature and stirred for another hour. Ice/water was added and the layer was separated. The organic layer was washed with water and brine, dried over MgSO4, filtered, and evaporated to give 18 g of crude product, which was used for next step reaction without further purification.
Reaction SMILES: O[Li].O.O.O.O.O.O.[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]([C:36]([O:38]CC)=[O:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([Br:35])[CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]=2[NH:11]1>O.C1COCC1>[O:9]=[C:10]1[N:16]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C@@H:26]([C:36]([OH:38])=[O:37])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[C:30]([Br:35])[CH:29]=3)=[O:24])[CH2:19][CH2:18]2)[CH2:15][CH2:14][C:13]2[CH:41]=[CH:42][CH:43]=[CH:44][C:12]=2[NH:11]1
Reactant: CCOC(=O)[C@@H](Cc1ccc(Br)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](Cc1ccc(Br)c(Br)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of 210 mg (9 mmol) LiOH.6H2O in 40 mL water was added at RT to a solution of 3.64 g (5.83 mmol) of (R)-2-(3,4-dibromo-phenyl)-1-ethoxycarbonylethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 70 mL THF and the reaction mixture was stirred for 7 h at RT. The mixture was evaporated down i.vac., the residue was taken up in 100 mL water, 1 M HCl was added until an acid reaction was obtained, the precipitate was filtered off and dried in the vacuum drying chamber at 50° C. The product was reacted further without purification.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:31])=[C:25]([O:39][CH3:40])[C:24]([Cl:41])=[C:23]([CH3:42])[C:22]=1[C:43](=[O:45])[CH3:44].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Cl:41][C:24]1[C:23]([CH3:42])=[C:22]([C:43](=[O:45])[CH3:44])[C:21]([O:20][CH2:19][CH2:18][CH2:1][N:8]2[CH2:9][CH2:10][S:11](=[O:14])(=[O:15])[CH2:12][CH2:13]2)=[C:26]([O:27][CH2:28][CH2:29][CH:30]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH3:31])[C:25]=1[O:39][CH3:40].[Cl:41][C:24]1[C:23]([CH3:42])=[C:22]([C:43](=[O:45])[CH3:44])[C:21]([O:20][CH2:19][CH2:18][CH2:17][N:8]2[CH2:13][CH2:12][S:11](=[O:14])[CH2:10][CH2:9]2)=[C:26]([O:27][CH2:28][CH2:29][CH:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH3:31])[C:25]=1[O:39][CH3:40]
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCCBr)c1OCCC(C)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCCN2CCS(=O)(=O)CC2)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCCN2CCS(=O)CC2)c1OCCC(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 13 %
Yield: 14 %

Procedure:
A solution of N—BOC-1,1-dioxothiomorpholine (85 mg, 0.365 mmol) in a mixture of DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 0.1 h before concentrating under vacuum and drying the TFA salt of 1,1-dioxothiomorpholine on the high vacuum pump for 3 h. The salt was dissolved in dry DMF (1 mL) and reacted with Example 22a (92 mg, 0.18 mmol) and K2CO3 (2.16 eq.) under General Procedure L. The crude mixture was purified by flash chromatography (silica gel, hexane/Et2O 1:4→MeOH/DCM 1:19) to afford 23 (14 mg, 14%) and 24 (13 mg, 13%) as clear colourless oils.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1.[Br:21]N1C(=O)CCC1=O>CO>[NH2:1][C:2]1[S:3][C:4]([Br:21])=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])/[C:8]([OH:10])=[O:9])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1csc(N)n1
Solvent: CO
Product: CC(C)(C)OC(=O)CO/N=C(\C(=O)O)c1nc(N)sc1Br
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 12 g of 2-(2-aminothiazol-4-yl)-2(Z)-(tert-butoxycarbonylmethoxyimino)acetic acid and 9.54 g of N-bromosuccinimide in 100 ml of methanol is stirred at 60° C. for 2 hours.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.ClCCl.Cl[S:24]([C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])=[O:31])(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:12][O:11][C:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([NH:2][S:24]([C:27]2[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=2)[C:30]([O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:37])[CH3:38])=[O:31])(=[O:25])=[O:26])[CH2:8][CH2:7]1)=[O:10]
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Reactant: C[Si](C)(C)CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 604 mg of methyl trans-4-aminocyclohexane carboxylate hydrochloride, 0.90 mL of triethylamine, and 10 mL of dichloromethane was stirred at room temperature for 30 minutes, and 10 mL of pyridine and 1.00 g of 2-(trimethylsilyl)ethyl 3-(chlorosulfonyl)benzoate were added thereto in this order, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and to the residue was added an aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 1.27 g of 2-(trimethylsilyl)ethyl 3-{[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoate as a colorless oily substance.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH3:15])[C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.O>ClCCl>[Si:1]([O:8][CH2:9][C@H:10]([CH3:15])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: C[C@H](CO)CO[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
Methyl (S)-(+)-3-(t-butyldimethylsilyloxy)-2-methylpropionate (10.0 g; 43.1 mmol) was dissolved in anhydrous dichloromethane (100 ml), and a hexane solution (100 ml) of 1M diisobutylaluminum hydride was dropwise added thereto at a temperature below 0° C. in an argon stream. After stirring for 30 minutes, water (20 ml) was added thereto, and the resultant mixture was stirred for 1 hour, followed by separation of the organic layer. The aqueous layer was extracted with dichloromethane, and the extracts were combined together with the organic layer. The solvent was distilled under reduced pressure to give (R)-(+)-3-(t-butyldimethylsilyloxy)-2-methyl-1-propanol (7.9 g; yield, 90%) as a colorless oil. A portion of the oil was distilled to give a purified product (bath temperature: 112° C./17 mmHg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[C:8]([C@@H:19]([NH2:21])[CH3:20])=[CH:7]2.C(O)CCC.Br[C:28]1[N:36]=[CH:35][N:34]=[C:33]2[C:29]=1[NH:30][CH:31]=[N:32]2.C(N(CC)C(C)C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=1)[C:8]([C@@H:19]([NH:21][C:28]1[N:36]=[CH:35][N:34]=[C:33]3[C:29]=1[N:30]=[CH:31][NH:32]3)[CH3:20])=[CH:7]2
Reactant: Brc1ncnc2nc[nH]c12
Reactant: Cc1cccc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-c2nc3c(Cl)cccc3cc2[C@H](C)Nc2ncnc3[nH]cnc23)n1
Temperature: 110 °C

Procedure:
To a stirred solution of (1S)-1-(8-chloro-2-(6-methylpyridin-2-yl)quinolin-3-yl)-ethanamine (146 mg, 0.49 mmol) in 1-butanol (5.4 mL, 59 mmol) was added 6-bromopurine (0.107 g, 0.54 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) with heating (110° C.) overnight. solvents were removed and the residue subjected to chromatography, gradient, 89:9:1(DCM:MeOH:NH4OH).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:17]1[CH:21]=[C:20]([C:22]([O:24]C)=O)[N:19]=[CH:18]1)[CH2:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1)[CH3:3].[CH3:26][NH2:27]>O1CCCC1.ClCCl>[CH3:26][NH:27][C:22]([C:20]1[N:19]=[CH:18][N:17]([C@H:4]([CH2:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)[C@@H:2]([OH:1])[CH3:3])[CH:21]=1)=[O:24]
Reactant: CN
Reactant: COC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)O)cn1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)c1cn([C@H](CCc2cccc3ccccc23)[C@H](C)O)cn1
Temperature: 120 °C

Procedure:
A mixture of methyl 1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxylate (obtained in Example 23(7))(25 mg) and methylamine (40% in water; 1 ml) in tetrahydrofuran (3 ml) was heated in a steel sealed tube at 120° C. overnight. The mixture was taken up in dichloromethane, washed with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (30:1) to give a white powder of N-methyl-1-[(2S,3R)-2-hydroxy-5-(1-naphthyl)-3-pentyl]imidazole-4-carboxamide (18.6 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]2[N:7]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:22]=[O:23].C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C.O>[Br:31][C:5]1[C:4]2[C:3]([CH:22]=[O:23])=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[C:8]=2[N:7]([S:12]([C:15]2[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C)cc(C)c32)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(C=O)c(C)cc(C)c32)cc1
Temperature: 60 °C
Reaction time: 18.5 h

Procedure:
To a solution of 5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (Example 46-D) (2 g, 6.11 mmol) in DMF (10 mL) was added NBS (2.39 g, 13.44 mmol), and then the mixture was stirred at 60° C. for 18.5 h. The reaction mixture was cooled to room temperature. The mixture was diluted with H2O, the layers were separated and the aqueous layer was extracted with EtOAc. The organic phase was washed with H2O and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography to give the title compound. MS (ESI+) m/z 406.0, 408.0 (M+H).
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27].[C:28]([O-:31])([OH:30])=O.[Na+].ClCCl>O>[C:28]([CH2:3][C@H:4]1[CH2:27][C@@H:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[Cl:12])[O:10][C:8]1=[O:9])([OH:31])=[O:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C([O-])O
Reactant: C=CCCCCCCc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(O)C[C@H]1C[C@@H](CCCCCCc2ccc(Cl)cc2Cl)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
m-Chloroperbenzoic acid (50% grade, 1.38 g, 4.01 mmol) was added in portions to a vigorously stirred mixture of 8-(2,4-dichlorophenyl)-1-octene (687 mg, 2.67 mmol), saturated aqueous NaHCO3 (15 ml), and dichloromethane (10 ml) at 0° C. The mixture was stirred for 5 min at 0° C., at room temperature for 1 h, then poured into water, and extracted with ether. The extracts were washed with aqueous Na2SO3 /NaHCO3, water, saturated aqueous NaCl, and dried (MgSO4). The solvent was removed under vacuum and the residue purified by chromatography on silica gel (5-20% ether/petroleum ether 40°-60° C.) to give the title compound (265 mg, 25%, 3 steps) as an oil.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CI.[OH-].[K+].O1CCOC[CH2:14]1>O>[CH3:1][C:2]1([CH3:14])[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: C1COCCO1
Reactant: CC1C(=O)CCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
Synthesized according to Agosta and Smith, J. Org. Chem. 35: 3856 (1970) A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in water (25 mL)/dioxane (75 mL) was heated at reflux. After 5 hours, a solution of KOH (2 g) and MeI (2.4 mL) in water (5 mL)/dioxane (15 mL) was added and after another 3 hours at reflux, the solution was stirred at room temperature overnight. A solution of KOH (2 g) and MeI (2.4 mL) in water (5 mL)/dioxane (15 mL) was added to the overnight reaction and heating at reflux. After 4 hours, the mixture was cooled to room temperature and extracted with ether (1×100 mL, 3×75 mL). The combined ether extracts were evaporated, the residue combined with 10% HCl (50 mL), and the resulting mixture placed in a 120° C. oil bath until it began boiling (ca. 15 minutes). The mixture was cooled to room temperature, neutralized by addition of saturated NaHCO3 solution (150 mL) and the resulting mixture extracted with CH2Cl2 (4×75 mL). The combined CH2Cl2 solution was dried (MgSO4), filtered and evaporated to leave a brown oil (10.474 g, 83 mmol, 93%) which was used directly in the next step.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27]([OH:29])=O)[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:62][N:63]([CH3:67])[CH2:64][CH2:65][NH2:66]>ClCCl>[CH2:1]([O:8][NH:9][C:10](=[O:31])[CH2:11][C@H:12]([C:22]1[O:23][C:24]([CH3:30])=[C:25]([C:27]([NH:66][CH2:65][CH2:64][N:63]([CH3:67])[CH3:62])=[O:29])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1oc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)nc1C(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A solution 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-5-methyl-1,3-oxazole-4-carboxylic acid (Preparation 72) (200 mg, 0.47 mmol), N-methylmorpholine (77 □1,0.70 mmol), 1-hydroxybenzotriazole hydrate (63 mg, 0.47 mmol)and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydochloride (134 mg, 0.70 mmol) in dichloromethane (10 ml) was treated with N,N-dimethylethylenediamine (56 □1,0.51 mmol) and stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a system of 94:4:0.4 (dichloromethane:methanol:ammonia) to afford the title compound as a white solid (216 mg).
Reaction SMILES: C([Mg]Br)C.[C:5]1([S:11][CH2:12][C:13]#[CH:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21]>CCOCC.O1CCCC1>[C:5]1([S:11][CH2:12][C:13]#[C:14][CH2:16][C:17]#[C:18][CH2:19][C:20]#[CH:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C#CCC#CCBr
Reactant: C#CCSc1ccccc1
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CCC#CCC#CCSc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
24.64 ml (12.48 g, 0.0936 mol) of a 3.8N solution of ethylmagnesium bromide in ether was added dropwise, under argon to a cold solution of 13.2 g (0.089 mol) of 3-phenylthio-1-propyne (G. Pourcelot et al, vide supra) in 70 ml of anhydrous tetrahydrofuran. The temperature was maintained at 0°-5° C. Thereafter, the reaction mixture was stirred for 1 hour further at room temperature. Then, 440 mg of cuprous cyanide were added and the solution stirred for 20 minutes more. Then a solution of 7 g (0.0445 mol) of 1-bromo-2,5-hexadiyne in 20 ml of anhydrous tetrahydrofuran was added dropwise, maintaining the temperature between 0°-5° C. After the addition, the reaction mixture was stirred at room temperature for 3 additional hours, and then quenched with 150 ml of 1N sulfuric acid and ice. After extraction with ether (3×150 ml) the combined organic extracts were concentrated in vacuo to a small volume, and washed several times with EDTA and then with water,dried over sodium sulfate and evaporated. The crude material was purified by column chromatography on 150 g of silica gel, using hexane as eluant, to produce 9-phenylthio-1,4,7-nonatriyne, as an oil. The product was stored in dry ice.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[OH:11].C([Li])CCC.Cl[CH2:18][Si:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[O:11][CH2:18][Si:19]([O:20][CH2:21][CH3:22])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25]
Reactant: Oc1c(F)c(F)cc(F)c1F
Reactant: CCO[Si](CCl)(OCC)OCC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CCO[Si](COc1c(F)c(F)cc(F)c1F)(OCC)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.32 g (20 mmol) of 2,3,5,6-tetrafluorophenol are dissolved in 50 ml of toluene, and 8 ml of n-butyllithium (2.5 M in hexane) are added at 0° C. After warming to room temperature, the solution is stirred for a further 2 hours. Then 4.3 g of (chloromethyl)triethoxysilane (20 mmol) are added dropwise and the reaction mixture is boiled under reflux for 6 hours. The resulting suspension is filtered and the solvent is stripped off in vacuo. The pale yellow liquid which remains is subjected to fractional distillation.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[S:13].[CH3:15][I:16]>CO>[I-:16].[CH3:15][S:13][C:12]([NH2:14])=[NH+:11][CH2:10][CH2:9][S:8][CH2:7][C:3]1[N:4]=[CH:5][NH:6][C:2]=1[CH3:1]
Reactant: CI
Reactant: Cc1[nH]cnc1CSCCNC(N)=S
Solvent: CO
Product: CSC(N)=[NH+]CCSCc1nc[nH]c1C
Product: [I-]
Yield: 62.1 %

Procedure:
a solution of N-[2-((5-methyl-4-imidazoly)methylthio) ethyl]thiourea (2.29g) and methyl iodide (1.56 g) in methanol (5 ml) was kept at room temperature for 18 hours affording S-methyl-N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]thiouronium iodide (2.3 g), m.p. 128°-131°. The iodide was converted into the corresponding sulphate by ion-exchange on an ion-exchange resin (IRA 401) in the sulphate form.
Reaction SMILES: C([O:4][CH2:5][C:6](=O)[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])(=O)C.[OH2:19]>O1CCCC1.[OH-].[K+].C(O)C>[OH:4][CH2:5]/[C:6](/[CH2:7][CH2:8]/[CH:9]=[C:10](\[CH3:17])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:17])=[CH:11]/[CH2:12][OH:19]
Reactant: O
Reactant: CC(=O)OCC(=O)CC/C=C(\C)CCC=C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C/CO)CO
Temperature: -20 °C
Reaction time: 2 h

Procedure:
In 30 ml of anhydrous tetrahydrofuran was suspended 5.4 g of (E)-4-methyl-6-acetoxy-4-hexen-1-yltriphenylphosphonium iodide, and to this suspension was added dropwise two molar equivalents of a n-butyllithium-hexane solution at -20° C. in a stream of nitrogen. The mixture was stirred at -20° C. for 2 hours, and to this was further added 2.5 g of (E)-6,10-dimethyl-2-oxo-5,9-undecadien-1-ol acetate (prepared in Referential example 2) in 10 ml of anhydrous tetrahydrofuran. The resulting mixture was again stirred at room temperature for 3 hours and, after addition of ice-water, extracted with ether, and from the extract was obtained an oil. The so obtained crude oil was dissolved in 25 ml of a 5% potassium hydroxide-ethanol solution under ice-cooling, and allowed to stand for 2 hours. This was, after addition of water, extracted with ether and treated in the usual way. The resultant was then chromatographed on silica gel to yield 0.95 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[C:6]2[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C.[CH2:31]1[O:41][C:40]2[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][C:33]=2[O:32]1>CN(C=O)C.C(Cl)Cl>[O:41]1[C:40]2[CH:39]=[CH:38][C:35]([CH2:36][N:19]3[CH2:20][CH2:21][CH:16]([NH:15][C:6]4[C:5]5[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=4)[CH2:17][CH2:18]3)=[CH:34][C:33]=2[O:32][CH2:31]1
Reactant: COc1ccc2c(c1)c(NC1CCNCC1)cc(=O)n2C
Reactant: ClCc1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(NC1CCN(Cc3ccc4c(c3)OCO4)CC1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 6-methoxy-1-methyl-4-(piperidin-4-ylamino)-1H-quinolin-2-one (300 mg, 0.8 mmol) and diisopropylethlyamine (705 uL, 4 mmol) in DMF (5 mL) was added a solution of 3,4 methylenedioxybenzyl chloride in methylene chloride (231 uL, 0.9 mmol, 50% by weight in CH2Cl2). After stirring at room temperature for 2 hours, the reaction mixture was diluted up with methylene chloride, washed with brine and dried with MgSO4. The residue was purified by flash chromatography through a silica gel column with dichloromethane and methanol (95:5 v/v) to provide the title compound (66.4 mg, 20%): 1H NMR (300 MHz, CDCl3) δ 1.58-1.72 (2H, m), 2.10-2.23 (4H, m), 2.88-2.98 (2H, m), 3.40-3.50 (1H, m), 3.48 (3H, s), 3.64 (3H, s), 4.58 (1H, bd, J=7.5), 5.75 (1H, s), 5.95 (2H, s), 6.77 (2H, s), 6.89 (1H, s), 7.25 (1H, d; J=1.89 Hz), 7.26 (1H, s), 7.40 (1H, dd, j=1.79, 8.75 Hz).
Reaction SMILES: CN(C=O)C.[H-].[Na+].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[SH:18].[NH2:19][C:20]1[N:28]=[C:27](Cl)[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>[Cl-].[Na+].O>[NH2:19][C:20]1[N:28]=[C:27]([S:18][C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Sc1ccc2ccccc2c1
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(Sc2ccc3ccccc3c2)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
To DMF suspension (20 ml) containing sodium hydride (800 mg, 20 mmol, 60% in mineral oil) were added 2-naphthalenethiol (3.8 g, 24 mmol) and 6-amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) in order. The mixture was stirred under heating at 100° C. for 10.5 hours. Brine was added thereto and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate, filtrated and the solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (0.5% methanol/chloroform) to give the subject compound (244 mg, yield 83%).