Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[O:40]([C:47]1[CH:52]=[CH:51][C:50]([N:53]=[C:54]=[O:55])=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[O:40]([C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54]([O:1][CH:2]2[CH2:20][CH:19]3[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]4[C:16]([C:22]([NH:24][S:25]([CH:28]5[CH2:29][CH2:30]5)(=[O:26])=[O:27])=[O:23])([NH:17][C:18]3=[O:21])[CH2:15]4)[CH2:3]2)=[O:55])=[CH:51][CH:52]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Product: CC(C)(C)OC(=O)NC1COCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)Nc3ccc(Oc4ccccc4)cc3)CN2C1=O
Yield: 38 %

Procedure:
Prepared by way of method III using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.175 mmol) and 4-phenoxyphenyl isocyanate (111 mg, 0.53 mmol). The final trituration (diethyl ether/hexane) and filtration gave 52 mg (38%) of 18-(4-phenoxyphenylaminocabonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diaza-12-oxatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.0% pure (HPLC), MS m/z 780 (M−H)−, HRMS: calcd. 799.3337 and found 799.3316 (M+NH4)+, mp 163-165° C.
Reaction SMILES: [CH2:1]([N:4]([C:11]1[CH:12]=[N:13][C:14]([Cl:18])=[C:15]([Cl:17])[CH:16]=1)[CH2:5][CH:6](OC)[O:7]C)[CH:2]=[CH2:3].Cl.ClCCl>O1CCCC1.O>[CH2:1]([N:4]([CH2:5][CH:6]=[O:7])[C:11]1[CH:12]=[N:13][C:14]([Cl:18])=[C:15]([Cl:17])[CH:16]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC(OC)OC)c1cnc(Cl)c(Cl)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCN(CC=O)c1cnc(Cl)c(Cl)c1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
A solution of allyl-(5,6-dichloro-pyridin-3-yl)-(2,2-dimethoxy-ethyl)-amine (57.2 g) in tetrahydrofuran (443 g) was cooled to 10° C. A solution of concentrated hydrochloric acid (136 g) in water (114 g) was slowly added, maintaining the temperature below 20° C. The reaction was then stirred at 15° C. for about 4 hours. Then dichloromethane (570 g) and water (430 g) were added and the layers separated. The organic layer was washed with 5% aqueous sodium bicarbonate (453 g), and then washed twice with water (430 g). The organic layer was concentrated and the residue dissolved in dichloromethane (580 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.C[Al](C)C.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:44]=[CH:43][C:38]([C:39](OC)=[O:40])=[CH:37][CH:36]=2)[O:31][CH2:30]1)[CH3:27]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C@@:25]([OH:51])([CH2:45][N:46]1[CH:50]=[N:49][CH:48]=[N:47]1)[C@H:26]([S:28][C@@H:29]1[CH2:34][O:33][C@@H:32]([C:35]2[CH:36]=[CH:37][C:38]([C:39]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([S:3][C:2]([F:11])([F:1])[F:12])=[CH:5][CH:6]=3)=[O:40])=[CH:43][CH:44]=2)[O:31][CH2:30]1)[CH3:27]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: Nc1ccc(SC(F)(F)F)cc1
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(SC(F)(F)F)cc3)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-(trifluoromethylthio)aniline (230 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (184 mg, yield 93%) as a colorless oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[O:34][C:33](B(O)O)=[CH:32][CH:31]=1.CC(C)([O-])C.[K+]>COCCOC.O.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>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[O:34][C:30]([CH3:29])=[CH:31][CH:32]=4)=[CH:3][C:4]=3[F:28])(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: Cc1ccc(B(O)O)o1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)cc1F
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-fluorobenzenesulfonamide (E103) (200 mg, 0.42 mmol) and (5-methyl-2-furanyl)boronic acid (106 mg, 0.84 mmol) in DME (3 ml) was added potassium tert-butoxide (430 mg, 3.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The solvent was evaporated in vacuo and residue purified using an SCX column followed by mass directed autoprep HPLC (with addition of 0.1 ml of 10% citric acid in water to the DMSO/MeCN sample to help dissolution) to afford the title compound (E309). MS (ES+) m/e 474 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1(=[O:37])[N:27]([CH2:28][C:29](Cl)=[O:30])[C:26](=[O:32])[C:25]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:24]12.C(=O)([O-])O.[Na+]>ClCCCl>[CH2:1]([N:8]1[CH2:14][C@@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[N:11]([C:29](=[O:30])[CH2:28][N:27]2[C:26](=[O:32])[C:25]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:24]3[C:23]2=[O:37])[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1c2ccccc2C(=O)N1CC(=O)N1c2ccccc2N(Cc2ccccc2)C[C@@H]2CCC[C@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 36.9 %

Procedure:
A crude product of (3aR*,10aS*)-9-benzyl-4-1,2,3,3a,4,9,10,10a-octahydrobenzo[b]cyclopenta-[e][1,4]diazepin synthesized from (3aR*,10aS*)-9-benzyl-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta [e][1,4]diazepin-10(1H)-one (2.92 g, 10 mmol) in substantially the same manner as in Working Example 42 was dissolved in 1,2-dichloroethane, to which was added phthalimidoacetyl chloride (2.24 g, 10 mmol). The mixture was stirred for 15 minutes at room temperature, which was refluxed for 15 minutes. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (15 mL). The aqueous layer was separated, and the organic layer was washed with water and, then, dried over magnesium sulfate, which was subject to filtration, followed by concentration under reduced pressure. To the concentrate was added ethanol-diethylether, and the solid matter was collected by filtration and recrystallized from chloroform-ethanol to give 1.72 g (yield 37%) of the titled compound, m.p. 232°-234° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:17]1([C:20]2[CH:21]=[CH:22][C:23]([CH:36]=[O:37])=[N:24][C:25]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:19][CH2:18]1.[Cl-].[NH4+]>O1CCCC1>[CH:17]1([C:20]2[CH:21]=[CH:22][C:23]([CH:36]([C:2]3[CH:7]=[CH:6][C:5]([S:8][CH:9]4[CH2:11][CH2:10]4)=[CH:4][CH:3]=3)[OH:37])=[N:24][C:25]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[CH2:18][CH2:19]1
Reactant: Brc1ccc(SC2CC2)cc1
Reactant: COc1ccc(COc2nc(C=O)ccc2C2CC2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(C(O)c3ccc(SC4CC4)cc3)ccc2C2CC2)cc1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A solution of (4-bromophenyl)(cyclopropyl)sulfane (440 mg) in tetrahydrofuran (10 mL) was cooled to −78° C., and n-butyllithium (2.6 M, 0.74 mL) was slowly added dropwise, followed by stirring for 30 minutes. A solution of 5-cyclopropyl-6-[(4-methoxy benzyl)oxy]pyridine-2-carbaldehyde (417 mg) in tetrahydrofuran (5 mL) was slowly added dropwise, and the mixture was stirred at −78° C. for 4.5 hours. The reaction solution was stirred in an ice bath and a saturated ammonium chloride solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→62:38) to give {5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}[4-(cyclopropylsulfanyl)phenyl]methanol as a yellow oil (469 mg, 73%).
Reaction SMILES: [Br-].[CH:2]1([C:7](=O)[CH2:8][N+:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3]1>C(=O)(O)[O-].[Na+].O>[CH:2]1([C:7]2[CH:15]=[C:10]3[N:9]([CH:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1cccc[n+]1CC(=O)C1CCCC1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Product: c1ccn2cc(C3CCCC3)cc2c1
Yield: 40.9 %

Procedure:
1-(2-Cyclopentyl-2-oxo-ethyl)-2-methyl-pyridinium bromide salt (3.4 g, 12.0 mmol) was heated at reflux in saturated sodium bicarbonate solution for 3 hrs. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate (×2). The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated to give a residue which was purified by column chromatography using 100-200 mesh silica-gel and 1% ethyl acetate/petroleum-ether as eluent to afford 2-cyclopentyl-indolizine (0.91 g, 41%) as a solid.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14]OS(C)(=O)=O)[S:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[N+:20]([C:23]1[NH:27][N:26]=[CH:25][CH:24]=1)([O-:22])=[O:21].C([O-])([O-])=O.[K+].[K+].[Br-]>CC(C)=O.CC(=O)OCC.O>[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][N:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[N:27]3)[S:12][CH:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2csc(COS(C)(=O)=O)n2)OCCO1
Reactant: O=[N+]([O-])c1ccn[nH]1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2csc(Cn3ccc([N+](=O)[O-])n3)n2)OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl ester (320 mg, 1.15 mmol) in acetone (6.0 mL) was added to a solution of 5-nitro-1H-pyrazole (136 mg, 1.20 mmol) in acetone (6.0 mL). K2CO3 (800 mg, 5.73 mmol) followed by TBA bromide (741 mg, 0.23 mmol) were added and the reaction mixture was stirred at rt overnight. Water (10 mL) and EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (2:1 hept-EA)=0.10. LC-MS-conditions 01: tR=0.81 min, [M+H]+=296.90.
Reaction SMILES: [O:1]1[CH:7]2[CH:2]1[C:3]([CH3:20])([CH3:19])[O:4][C:5]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH3:15])[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:6]=12.Cl([O-])(=O)(=O)=O.[Li+].[C:27]1([CH2:33][CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[CH3:15][O:14][CH2:13][O:12][C:10]1[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:6]2[C@@H:7]([NH:35][CH2:34][CH2:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:2]([OH:1])[C:3]([CH3:20])([CH3:19])[O:4][C:5]=2[CH:11]=1
Reactant: NCCc1ccccc1
Reactant: COCOc1cc2c(cc1[N+](=O)[O-])C1OC1C(C)(C)O2
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1COCCO1
Product: COCOc1cc2c(cc1[N+](=O)[O-])[C@@H](NCCc1ccccc1)[C@H](O)C(C)(C)O2
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 3,4-epoxy-7-methoxymethoxy-2,2-dimethyl-6-nitro-3,4-dihydro-2H-1-benzopyran (332 mg, 1.18 mmol) in dioxane (1.3 mL), lithium perchlorate (126 mg, 1.18 mmol) and 2-phenylethylamine (214 mg, 1.77 mmol) were added at room temperature, and the resulting mixture was stirred for 2 hours. Upon the completion of the reaction, saturated aqueous sodium hydrogencarbonate solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=3/1) and the aimed product was obtained (yield: 73%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]2[O:19][C:20]([CH2:23][CH3:24])=[CH:21][N:22]=2)[O:12]1.C(N(C(C)C)CC)(C)C.Cl.[NH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(O)(C)C>[CH2:23]([C:20]1[O:19][C:18]([C@@H:13]2[C@@H:14]([OH:17])[C@@H:15]([OH:16])[C@H:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[O:12]2)=[N:22][CH:21]=1)[CH3:24]
Reactant: NC1CCOCC1
Reactant: CCc1cnc([C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@H](O)[C@@H]2O)o1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCc1cnc([C@H]2O[C@@H](n3cnc4c(NC5CCOCC5)ncnc43)[C@H](O)[C@@H]2O)o1
Yield: 355.6 %

Procedure:
To a solution of (2R,3R,4S,5S)-2-(6-chloro-purin-9-yl)-5-(5-ethyl-oxazol-2-yl)-tetrahydro-furan-3,4-diol (0.19 g), in isopropanol (15 ml) was added diisopropylethylamine (0.3 ml) and 4-aminotetrahydropyran hydrochloride (0.135 g). After stirring at reflux for 16 h, further diisopropylethylamine (0.2 ml) and 4-aminotetrahydropyran hydrochloride (60 mg) were added. Stirring was continued at reflux for a further 20 h before the mixture was cooled and concentrated in vacuo to give a yellow gum (0.8 g). Purification by chromatography on silica gel (Merck 7734) with dichloromethane:ethanol:ammonia (250:8:1)-(100:8:1), gave the title compound, as a white foam (0.182 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:25][C@H:24]3[C@@H:14]([CH2:15][C:16]4[C:26]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]3=5)[N:18]([CH:27]([CH3:29])[CH3:28])[CH:17]=4)[N:13]([CH3:30])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:38](Cl)(=[O:40])[CH3:39]>O1CCCC1>[C:38]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C@@H:11]2[CH2:25][C@H:24]3[C@@H:14]([CH2:15][C:16]4[C:26]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]3=5)[N:18]([CH:27]([CH3:28])[CH3:29])[CH:17]=4)[N:13]([CH3:30])[CH2:12]2)=[O:10])[CH2:6][CH2:7]1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)N[C@H]3CC[C@H](N)CC3)CN(C)[C@@H]1C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@@H]3c4cccc5c4c(cn5C(C)C)C[C@H]3N(C)C2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 620 mg of (8β)-N-(trans-4-aminocyclohexyl)-1-isopropyl-6-methylergoline-8-carboxamide in 100 ml of dry tetrahydrofuran were added 222 μl of triethylamine. The solution was cooled by means of an external ice bath and 118 μl of acetyl chloride were added in dropwise fashion. The mixture was stirred at room temperature under a nitrogen atmosphere for 2.5 hours. The reaction mixture was concentrated in vacuo and ethyl acetate, water, and 2N sodium hydroxide were added. The layers were separated and the aqueous layer extracted an additional three times with ethyl acetate and six times with methylene chloride. The combined organic layers were washed twice with water, once with a saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to provide 690 mg of a pale yellow solid. This material was crystallized from tetrahydrofuran/ethanol/hexanes to provide 259 mg of title product as a tan powder, m.p. >280° C. Analytical high pressure liquid chromatography indicated the material was 97.9% pure. NMR, MS
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.[Br:26][CH2:27][CH2:28][CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:7]([C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:29][CH2:28][CH2:27][Br:26])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1
Reactant: BrCCCBr
Reactant: O=C(c1ccc(O)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCCBr)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12

Procedure:
A mixture of 3.2 g. (9.2 mmol.) of 5-chloro-3-(4-hydroxybenzoyl)-2-phenylbenzofuran, 3.5 ml. (0.035mol.) of 1,3-dibromopropane and 4.0 g. (0.029 mol.) of potassium carbonate in 100 ml. of acetone is refluxed for 3 hours. After cooling, the reaction mixture is filtered and the filtrate is concentrated to give 5-chloro-3-[4-(3-bromopropoxy)benzoyl]-2-phenylbenzofuran.
Reaction SMILES: CCCCCC.[H-].[Na+].[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[C:17]#[N:18])=[N:14][CH:15]=1.Br[CH2:28][CH2:29][CH2:30][Cl:31]>CN(C=O)C.CCOCC>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)([CH2:28][CH2:29][CH2:30][Cl:31])[C:17]#[N:18])=[N:14][CH:15]=1
Reactant: ClCCCBr
Reactant: COc1cccc(C(C#N)c2ccc(Br)cn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc(C(C#N)(CCCCl)c2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of hexane washed 60% sodium hydride (0.35 g, 8.6 mmol) in DMF (2 mL) at 0° C. was added a solution of (5-bromo-pyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile (1.75 g, 5.76 mmol) in DMF (5 mL). The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. 1-bromo-3-chloropropane (0.69 mL, 6.91 mmol) was added and the mixture was stirred at room temperature for 4 h. To the reaction mixture was added H20 (5 mL) and Et2O and the organic layer was washed with brine (5x5 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10:1) yielded 1.81 9 of 2-(5-bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phenyl)-pentanenitrile. 1HNMR (400 MHz, CDCl3) 6 8.65 (s, 1H), 7.76 (dd, 1H), 7.36 (d, 1h), 7.27-7.21 (m, 1H), 7.03 (d, 1H), 6.98 (s, 1H), 6.82 (dd,1H), 4.77 (s, 3H), 3.55 (t, 2H), 2.79-2.70 (comp, 1H), 2.62-2.52 (comp, 1H) 1.89-1.79 (comp, 2H); MS (M+1)378.8, 380.8.
Reaction SMILES: [O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:9])[NH2:8])[CH3:6])[OH:3].[NH:10]1[C:14](=[O:15])[CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17].C(O)C>C(OCC)(=O)C>[NH:10]1[C:14](=[O:15])[CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=[O:17].[O:1]=[C:2]([CH2:4][N:5]([C:7](=[NH:8])[NH2:9])[CH3:6])[OH:3]
Reactant: O=C1CCC(C(=O)O)N1
Agent: CN(CC(=O)O)C(=N)N
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CC[C@@H](C(=O)O)N1

Procedure:
According to a preferred embodiment, the aforementioned salt can be prepared by reacting creatine with an equimolar amount of D,L-pyroglutamic acid in ethyl acetate (or in a mixture of equal parts ethyl acetate and ethanol) until complete formation of the salt. The solution can be optionally concentrated and, upon cooling, the crystallized salts are filtered and washed with ethyl acetate (or a mixture of ethyl acetate and ethanol). Alternatively, the procedure can be carried on by reacting excess D,L-pyroglutamic acid with creatine in ethyl acetate (or a mixture of ethyl acetate and ethanol).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[N:14]1([S:20](Cl)(=[O:22])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C.CC(=O)OCC>[CH3:1][C:2]1[N:3]([S:20]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:22])=[O:21])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: CCOC(=O)c1cc[nH]c1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(S(=O)(=O)N2CCCCC2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (3.06 g, 20 mmol) in dry DMF (40 mL) was added NaH (0.96 mg, 24 mmol) in portions and the mixture was stirred at rt for 30 min. Then a solution of piperidine-1-sulfonyl chloride (4.4 g, 24 mmol) in dry DMF (10 mL) was added and the resulting mixture was stirred overnight, diluted with EA, washed with water and brine, dried over Na2SO4, concentrated and purified by CC (PE/EA=1/0 to 10/1) to give compound 4a (4.77 g, 78%).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:14][C:15](=[O:39])[CH2:16][C:17]1([CH2:20][CH2:21][CH:22]([CH2:37][OH:38])[CH2:23][C:24]2[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)[CH3:13]>ClCCl>[CH2:12]([O:14][C:15](=[O:39])[CH2:16][C:17]1([CH2:20][CH2:21][CH:22]([CH:37]=[O:38])[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])=[CH:35][CH:36]=2)[CH2:19][CH2:18]1)[CH3:13]
Reactant: CCOC(=O)CC1(CCC(CO)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)CC1(CCC(C=O)Cc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
846 mg (3.93 mmol) of pyridinium chlorochromate (PCC) are added to a solution of 1278 mg (3.27 mmol) of tert-butyl 4-{4-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]-2-(hydroxymethyl)-butyl}benzoate in 60 ml of dichloromethane, and the mixture is stirred at room temperature for 12 hours. After complete conversion, 5 g of silica gel are added and the solvent is carefully removed to dryness under reduced pressure. The residue is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 3:1). This gives 1080 mg (85% of theory) of a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl.[OH-].[Na+].C(O)CCC>CO>[NH:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:15][CH2:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3ccccc3[nH]2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Solvent: C1COCCO1
Product: c1ccc2[nH]c(NCC3CCNCC3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
After dissolving 4-[(1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (4.33 g, 13.1 mmol) in methanol (10 mL), a 4N hydrogen chloride-1,4-dioxane solution (33 mL, 131 mmol) was added in small portions at a time in an ice bath, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled on ice, 2N aqueous sodium hydroxide was added to adjust the pH to approximately 11. Salt was added to the aqueous solution to saturation, and the organic layer obtained by extraction with 1-butanol (100 mL×3 times) was washed with saturated brine and then dried over anhydrous sodium sulfate. The dried 1-butanol was concentrated under reduced pressure to obtain (1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine.