Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](NC(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H]([O:49][C@@H:50]2[O:55][C@@H:54](CO)[C@H:53]([OH:58])[C@@H:52]([OH:59])[C@@H:51]2[NH:60][CH3:61])[C@@]1(O)C=O.C(=O)=O>>[CH2:61]1[NH:60][C@H:51]([CH2:50][OH:49])[C@@H:52]([OH:59])[C@H:53]([OH:58])[C@H:54]1[OH:55]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: O=C=O
Agent: [K+]
Product: OC[C@H]1NC[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
Cells and viruses. BVDV-free MDBK cells (CCL 22) were obtained from the American Type Culture Collection and propagated in DMEM/F12 essential medium supplemented with penicillin (500 U/ml), streptomycin (500 U/ml), and 10% heat inactivated horse serum (Invitrogen). Cells were maintained in a humidified incubator at 37° C. with 5% CO2. BVDV (NADL strain). For infections, virus inoculum was added in complete medium and adsorbed for 1 hour at 37° C., the inoculum was then removed, the cells washed once with medium and fresh medium containing compounds added. Virus stocks were prepared by freeze-thawing the infected cells and culture supernatant three times followed by centrifugation at 1,000 g for 5 min. Stock titers were determined, and stocks were aliquoted and stored at −80° C. WNV was obtained from a cDNA clone of a human 2002 isolate from Texas; virus obtained from BHK cells electroporated with the in vitro synthesized RNA from this cDNA clone was passaged in Vero cells before use in antiviral assays. Dengue virus (DV) serotype 2 was a New Guinea C virus that had been passaged 28 times in suckling mouse brain, twice in Vero cells, and once in C6/36 mosquito cells.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH2:17][C:11]2([C:15](=[O:16])[NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][CH3:28])[CH:21]=1.CN(C)CCN.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I.CCOC(C)=O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[CH2:13][CH2:12]2)[CH2:17][CH2:18]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(Br)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Agent: [Cu]I
Agent: CN(C)CCN
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)ccc1Cl
Temperature: 110 °C

Procedure:
A mixture of 1-oxo-2,8-diaza-spiro[4,5]decane-8-carboxylic acid tert-butyl ester (127 mg, 0.5 mmol, 1 equiv), 4-bromo-1-chloro-2-methoxy-benzene (221 mg, 2equiv), N,N-dimethylethylenediamine (14 mg, 0.3 equiv), CuI (29 mg, 0.3 equiv) and Cs2CO3 (325 mg, 2 equiv) in 1 mL of dioxane were heated at 110° C. overnight and then cooled to room temperature, taken up in a 1:1 mixture of methanol and EtOAc, filtered through a thin pad of celite and concentrated. The crude product was purified by flash column to give 2-(4-Chloro-3-methoxy-phenyl)-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[CH:10][S:9][C:8]=1[CH:12]1[O:16]CCO1.[B:17]([O-])([O-:23])[O:18]CCCC.Cl>CCCCCC.CCOCC>[CH:12]([C:8]1[S:9][CH:10]=[CH:11][C:7]=1[B:17]([OH:23])[OH:18])=[O:16]
Reactant: CCCCOB([O-])[O-]
Reactant: Brc1ccsc1C1OCCO1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: O=Cc1sccc1B(O)O
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
A 1.1 N solution of n-butyllithium in hexane (28 ml) was added dropwise (10 mins) to a solution of 2-(3-bromo-2-thienyl)-1,3-dioxalane (3) (6.6 g, 28.1 mmol) in anhydrous ether (30 ml) at −70° C. After stirring for 10 mins, butyl borate (9.1 ml, 33.7 mmol) in anhydrous ether (20 ml) was added in a single portion. The reaction mixture was stirred for 4 hrs at −70° C. and then left to return to room temperature. 1 N hydrochloric acid (20 ml) was added, and the mixture was left for 1 hr with stirring. The aqueous phase was extracted with ether and the combined ether phases were washed with a solution of sodium bicarbonate, dried (Na2SO4), and evaporated under reduced pressure to give the intermediate (4) (2.2 g, 14.1 mmol, 50% yield) as a brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH:22][C:23](=O)[C:24](OCC)([O:26]CC)[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>C(O)(=O)C.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=3[N:22]=[C:23]2[C:24](=[O:26])[CH3:25])[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)(OCC)C(=O)Nc1cc(C)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)c1nc2cc(C)ccc2n1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
4-[2-(2,2-Diethoxy-propionylamino)-4-methyl-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.11 mmol) was dissolved in glacial acetic acid (5 mL), and the mixture was heated at 90° C. overnight. The mixture was cooled, concentrated under reduced pressure. The resulting residue was partitioned between CH2Cl2 (50 mL) and dilute aqueous K2CO3 solution. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×25 mL). The combined organic layers were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to approximately 30 mL, and di-tert-butyldicarbonate (218 mg, 1 mmol) and DMAP (5 mg, 0.04 mmol) were added. The mixture was stirred overnight at rt, washed with saturated aqueous NH4Cl solution and dried over anhydrous Na2SO4. The mixture was concentrated, and the residue was purified by flash chromatography (30% ethyl acetate in hexanes) to give 4-(2-acetyl-5-methyl-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (270 mg, 0.756 mmol, 68%) as a waxy solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1ccc(C(=O)O)c(O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A two-phase mixture of 45.6 g (0.3 mol) 4-methylsalicylic acid, NaOH (36 g, 0.9 mol), benzyl bromide (154 g, 0.9 mol) and tetrabutylammonium bromide (10 g, 30 mmol) in water (200 ml) and CH2Cl2 (200 ml) was stirred at room temperature for 3 hours. The layers were separated and the CH2Cl2 was removed from the organic fraction. The residue was dissolved in a mixture of ethanol (250 ml) and 2N NaOH (50 ml), and the mixture was heated under reflux for 30 min. The ethanol was removed under vacuum and the residue was diluted with water and washed with ethyl acetate. The aqueous layer was separated and acidified with dilute HCl to give a precipitate of 4-methyl-2-phenylmethoxybenzoic acid (65.3 g, 90%) m.p. (MeOH aq) 105°-107° C. Anal (C15H14O3) C,H,O.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][N:6]=[CH:5]2.[H-].[Na+].C([Li])(CC)C.C1CCCCC1.Cl.[C:26](=O)(O)[O-:27].[Na+]>CN(C)C=O.O1CCCC1>[CH3:11][C:9]1[CH:10]=[C:2]([CH:26]=[O:27])[CH:3]=[C:4]2[C:8]=1[NH:7][N:6]=[CH:5]2
Reactant: O=C([O-])O
Reactant: Cc1cc(Br)cc2cn[nH]c12
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
5-Bromo-7-methylindazole (6.10 g, 28.9 mmol) and sodium hydride (60% in mineral oil, 1.27 g, 1.1 equiv) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (30 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to −70° C. and a solution of sec-butyllithium in cyclohexane (1.4M, 45 mL, 2.2 equiv) was added over several minutes. After 1 h at −70° C., dimethylformamide (10 mL) was added over several minutes. The mixture was allowed to warm to room temperature and was stirred overnight. It was then cooled to 0° C. and carefully treated with 1N hydrochloric acid (60 mL). After a few minutes, solid sodium bicarbonate was added to basify the mixture to pH 9-10. The layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic phases were extracted with 0.8M sodium hydrogen sulfate (3×125 mL). The combined aqueous phases were washed with ethyl acetate (100 mL) and then the pH was adjusted to ca. 10 with solid sodium hydroxide. The resulting suspension was extracted with ethyl acetate (3×150 mL). The combined organic phases were washed with brine, dried (magnesium sulfate) and evaporated to give the product as a light-tan solid (3.01 g, 65%). 1H-NMR (CDCl3, 500 MHz) δ 2.63 (3H, s), 7.73 (1H, s), 8.12 (1H, s), 8.25 (1H, s), 10.03 (1H, s). Mass spec.: 161.06 (MH)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]2[CH:22]=1)=[O:11])[CH2:2][CH3:3].[OH-].[Na+]>[Ni].C(O)C>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][N:15]2[CH:22]=1)=[O:11])[CH2:24][CH3:25]
Reactant: CCCN(CCC)CCCCNC(=O)c1cn2cc(C#N)ccc2n1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CN)C2
Yield: 97.4 %

Procedure:
An ethanol solution (20 ml) containing the compound (40.2 mg) obtained in Example 19-2 was added with an ethanol suspension of Raney nickel and a 1 mol/l sodium hydroxide aqueous solution (2.0 ml), and the whole was stirred at room temperature for 14 hours under a hydrogen atmosphere. The catalyst was removed by filtration through Celite. The residue obtained by distilling the solvent off under reduced pressure was dissolved in chloroform, washed with water and a saturated saline solution, and dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (40.1 mg) as a yellow oily substance.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=3[C:10](=[O:18])[N:9]([CH3:19])[CH2:8][C:7]=12)#[CH:2].C([Li])CCC.CN(C)P(=O)(N(C)C)N(C)C.[CH3:36][C:37]([CH3:39])=[O:38]>O1CCCC1.CCCCCC.O>[F:17][C:15]1[CH:14]=[CH:13][C:12]2[N:6]3[CH:5]=[N:4][C:3]([C:1]#[C:2][C:37]([OH:38])([CH3:39])[CH3:36])=[C:7]3[CH2:8][N:9]([CH3:19])[C:10](=[O:18])[C:11]=2[CH:16]=1
Reactant: CC(C)=O
Reactant: C#Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN1Cc2c(C#CC(C)(C)O)ncn2-c2ccc(F)cc2C1=O
Reaction time: 2 h

Procedure:
1.27 g (5 mmol) of 3-ethynyl-8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was suspended in 10 ml of tetrahydrofuran and treated dropwise within 20 minutes at a maximum of -5° with 6.4 ml (10 mmol) of 1.6M butyllithium in hexane. After stirring in an ice-bath for 2 hours the mixture was cooled to -70° and there was added thereto in succession 1.7 ml of hexamethylphosphoric acid triamide and 0.6 g (10 mmol) of acetone. The mixture was left to come to room temperature within 4.5 hours, left to stand overnight and poured into about 120 ml of water. After acidification with 4N hydrochloric acid the mixture was extracted four times with ether and six times with ethyl acetate, the combined extracts were dried over magnesium sulphate and evaporated. After chromatography of the residue on silica gel while eluting with ethyl acetate and after crystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-3-(3-hydroxy-3-methyl-1-butynyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 163°-164°.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH2:1]([C:10]1([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=[CH:13][CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C1=CCC=C1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C1=CC(Cc2ccccc2)(Cc2ccccc2)C=C1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
A 1.0 L double-walled reactor, provided with baffles, condenser, top stirrer, thermometer and dropping funnel equipped with a nitrogen inlet was charged with ALIQUAT 336 (8.1 g, 20 mmol), benzylbromide (62.9 g, 0.37 mol) and freshly cracked cyclopentadiene (11.9 g, 0.18 mol). A 50 wt. % NaOH aqueous solution (149 g) was then added via the dropping funnel to the turbulently stirred reaction mixture. The reaction mixture was cooled with water during the addition of the base. After 0.5 hour, the reaction mixture was heated 40° C. After 4 hours, stirring was stopped and the phases separated, the aqueous basic solution was isolated, removed and replaced with a fresh 50 wt. % NaOH solution (146 g). After 0.5 hours of stirring at 40° C., the stirring was stopped, the layers separated and the product was distilled at reduced pressure. After vacuum distillation, 45.0 g of di-(benzyl)cyclopentadiene were obtained. Characterization of the product took place with the aid of GC, GC-MS, 13C- and 1H-NMR.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[O:10]=[C:9]1[C:5]2=[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:2](=[O:1])[C:6]2=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1nc(-c2ccccc2)c2c(=O)nc(-c3ccccc3)c1=2
Reactant: O=C(Cl)c1ccccc1
Product: O=C1C2=C(c3ccccc3)N(C(=O)c3ccccc3)C(=O)C2=C(c2ccccc2)N1C(=O)c1ccccc1

Procedure:
5.8 parts of 1,4-diketo-3,6-diphenylpyrrolo-[3,4-c]-pyrrole are stirred with 50 parts of benzoyl chloride at 190° C. for 22 hours. The starting material dissolves in the course of the reaction. On cooling of the reaction mixture, most of the reaction product precipitates. The reaction mixture is introduced into 320 parts of methanol, with stirring, and the mixture is stirred for 2 hours, without heating. The precipitated product is filtered off, washed with methanol and dried. 4.9 parts of ochre-coloured crude product which is purified by crystallisation from 50 parts of dimethylformamide, with addition of a filtration assistant, are obtained. 3.8 parts of 1,4-diketo-2,5-dibenzoyl-3,6-diphenylpyrrolo-[3,4-c]-pyrrole are obtained in the form of brownish-yellow crystals (formula XVIII). ##STR22##
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)Br)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)N1CCC(O)CC1
Reactant: Fc1ccc(C(Br)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)N1CCC(OC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 140 °C

Procedure:
A mixture of 21.5 parts of ethyl 4-hydroxy-1-piperidinecarboxylate, 35.2 parts of bis(4-fluorophenyl)bromomethane and 8.6 parts of potassium carbonate is stirred and heated in an oil-bath at 140° C. for 3 hours. The reaction mixture is allowed to cool to room temperature and water is added. The product is extracted with methylbenzene. The extract is washed successively with water, a diluted hydrochloric acid solution and a sodium bicarbonate solution, dried, filtered and evaporated. The forerun is distilled off (bp. till 143° C. at 0.5-1 mm. pressure), yielding ethyl 4-[bis(4-fluorophenyl)methoxy]-1-piperidinecarboxylate as an oily residue.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][C:15](OC)=[O:16])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[BH4-].[Na+]>CO>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH2:14][CH2:15][OH:16])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNC(CCO)C1
Reaction time: 8 h

Procedure:
Methyl 4-boc-piperazine-2-acetate (CAS number: 183742-33-8, Chemfinder) (1.0 g, 4 mmol) was dissolved in 10 mL of MeOH, then NaBH4 (1.5 g, 40 mmol) was added portion wise and stirred overnight. The solvent was removed in vacuo and the residue was partitioned between EtOAC and water. The organic layer was separated, and then dried over Na2SO4 and concentrated to give 3-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butyl ester as crude oil (compound E), which was used directly without further purification.
Reaction SMILES: C([Li])CCC.CCOCC.[CH:11](=[C:15]1[C:23]2[CH:22]=[CH:21][O:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14].[C:24](=[O:26])=[O:25]>C(Cl)(Cl)(Cl)Cl>[CH:11](=[C:15]1[C:23]2[CH:22]=[C:21]([C:24]([OH:26])=[O:25])[O:20][C:19]=2[CH2:18][CH2:17][CH2:16]1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC=C1CCCc2occc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCCC=C1CCCc2oc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.66 N n-butyl lithium (nBuLi) (328 m in n-hexane solution) and Et2O (100 ml) was added a mixture of 4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]furan (9.60 g) and Et2O (50 ml) dropwise over 5 minutes while maintaining -30~-20° C. by dry ice--carbon tetrachloride (CCl4) cooling. The reaction mixture was stirred at r.t. for 1 hour, and was bubbled by carbon dioxide (CO2) gas for 1 hour. The whole mixture was stirred at r.t. overnight and poured into a mixture of water and Et2O. The separated aqueous layer was adjusted to pH 1.4 with 10% HCl, and extracted by AcOEt. The organic layer was washed with brine, dried over MgSO4, and evaporated to give 4-n-butylidene-4,5,6,7-tetrahydrobenzo[b]-furan-2-carboxylic acid (3.91 g) as a reddish oil, which was used in the next reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH2:11])[C:4]=2[CH:5]=[N:6][CH:7]=1.[C:12](O)(=[O:15])[CH2:13][CH3:14].CCN=C=NCCCN(C)C.OP([O-])(O)=O.[K+]>C(Cl)Cl>[Br:1][C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])[C:4]=2[CH:5]=[N:6][CH:7]=1
Reactant: CCC(=O)O
Reactant: NC1CCc2c(Br)cncc21
Agent: CCN=C=NCCCN(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Product: CCC(=O)NC1CCc2c(Br)cncc21
Temperature: 25 °C
Yield: 39 %

Procedure:
To a stirred black solution of (rac)-4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-amine (intermediate A-4 [C]) (213 mg, 1 mmol) and propionic acid (82.1 μL, 1.1 mmol) in CH2Cl2 (5.0 mL) at 0° C. was added EDCI (230 mg, 1.2 mmol), stirring was continued over night and the reaction mixture was allowed to warm up to RT. The reaction mixture was poured on aq. 10% KH2PO4 solution followed by extraction with AcOEt (3×). The organic phases were washed once with aq. 10% KH2PO4, aq. sat. NaHCO3 and aq. sat. NaCl solution. The combined organic phases were dried over Na2SO4, filtered, evaporated and purified by flash chromatography (75 g SiO2, Telos-cartridge, CH2Cl2/MeOH (2%)) to afford the title compound (105 mg, 39%) as a dark grey solid. MS: 269.0 (M+H+, 1 Br).
Reaction SMILES: [CH2:1]([S:3][CH:4]([CH3:8])[CH2:5][CH2:6][OH:7])[CH3:2].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl>[CH3:9][S:10]([O:7][CH2:6][CH2:5][CH:4]([S:3][CH2:1][CH3:2])[CH3:8])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CCSC(C)CCO
Solvent: ClCCl
Product: CCSC(C)CCOS(C)(=O)=O
Reaction time: 2.5 h

Procedure:
3-(Ethylthio)-1-butanol (for example, as prepared for Intermediate 27) (247 mg, 1.84 mmol) was dissolved in DCM (10 ml), and the stirred solution was cooled in an external ice-water bath. Methanesulfonyl chloride (commercially available, for example, from Aldrich) (154 μl, 1.99 mmol) was added and stirring was continued under a nitrogen atmosphere for 2.5 h. The reaction mixture was diluted with further DCM (5 ml) and quenched with saturated aqueous sodium hydrogen carbonate. The layers were separated and the aqueous was extracted with further DCM (×2) (hydrophobic frit). The combined organic solutions were concentrated in vacuo to give the title compound as a colourless oil, which later partially solidified (360 mg, 92%): 1H NMR δ (CDCl3) 4.46-4.32 (2H, m), 3.03 (3H, s), 2.98-2.88 (1H, m), 2.57 (2H, q, J=7.5 Hz), 2.03-1.87 (2H, m), 1.35 (3H, d, J=7 Hz), 1.26 (3H, t, J=7 Hz).
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[C:7]([CH2:19][C@@H:20]2[O:22][C@@:21]2([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:8]([O:12][CH3:13])=[CH:9][CH2:10][CH:11]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CCOC(C)=O.CCCCCC>[CH3:4][O:5][C:6]1[C@@:7]2([CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:19][CH:20]3[O:22][C@@:8]2([O:12][CH3:13])[C@H:9]([CH2:10][CH:11]=1)[C@:21]3([CH3:29])[CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28]
Reactant: COC1=CCC=C(OC)C1(CC=C(C)C)C[C@@H]1O[C@@]1(C)CCC=C(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COC1=CC[C@H]2[C@]3(OC)OC(C[C@]13CC=C(C)C)[C@@]2(C)CCC=C(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 90.6 %

Procedure:
A DCM (100 mL) solution of 12 (1.88 g, 5.21 mmol, 1 equiv.) and 2,6-di-tert-butyl-4-methylpyridine (2.14 g, 10.4 mmol, 2 equiv.) was cooled to −78° C. in a 250-mL round-bottom flask, and trimethylsilyl trifluoromethanesulfonate (1.13 mL, 6.26 mmol, 1.2 equiv.) was slowly added. Immediately upon this addition, the solution turned bright yellow. After stirring at −78° C. for 45 min, the reaction was quenched with saturated aqueous NaHCO3 and allowed to warm to room temperature. The mixture was then extracted thrice with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to a faintly yellow residue. Flash column chromatography (30 mL SiO2, 99:1 to 19:1 hexane:EtOAc) afforded 1.70 g (4.72 mmol, 90% yield) of 13 as a white, crystalline solid. 1H NMR (600 MHz; CDCl3): δ 5.34 (t, J=7.1 Hz, 1H), 5.03 (t, J=7.1 Hz, 1H), 4.52 (dd, J=5.5, 2.0 Hz, 1H), 3.74 (d, J=5.1 Hz, 1H), 3.48 (s, 3H), 3.46 (s, 3H), 2.36 (dd, J=14.7, 6.9 Hz, 1H), 2.22-2.17 (m, 2H), 2.03 (td, J=8.6, 6.4 Hz, 2H), 2.01-1.94 (m, 1H), 1.82 (d, J=12.4 Hz, 1H), 1.78 (dd, J=12.4, 5.1 Hz, 1H), 1.69 (s, 3H), 1.67 (s, 3H), 1.61 (s, 3H), 1.58 (s, 3H), 1.45 (td, J=13.0, 4.8 Hz, 1H), 1.22 (td, J=13.0, 4.6 Hz, 1H), 1.14 (s, 3H). 13C NMR (125 MHz; CDCl3): δ 158.5, 131.6, 131.2, 124.9, 123.6, 112.7, 90.6, 78.9, 54.6, 51.4, 46.5, 44.4, 42.0, 39.4, 33.6, 32.8, 28.2, 26.4, 25.9, 22.9, 20.1, 18.00, 17.85. HRMS-ESI (m/z): [M+H]+ calculated for C23H36O3, 361.2737. found, 361.2730.