Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C([O:45][C:46](=[O:53])[CH2:47]CCCCBr)C.COC(C)(C)C>[Cl-].C[N+](C)(C)C.C1C=CC=CC=1>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:47][C:46]([OH:53])=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCOC(=O)CCCCCBr
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: COC(C)(C)C
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 10 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 0.55 g (5 mmol) of tetramethylammonium chloride and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of benzene is cooled to 10° C. At 10° C., 35.7 g (160 mmol) of 6-bromohexanoic acid ethyl ester is added in drops over 10 minutes while being stirred vigorously. It is stirred for 2 hours at 10° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol/50 ml of water. 60 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for four hours. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water, 500 ml of ethyl acetate is added, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n=hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate, and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.C([Li])CCC.[CH3:15][N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2.Cl>C(OCC)C.O1CCCC1.O>[Cl:9][C:4]1[CH:3]=[C:2]([C:19]2([OH:24])[CH2:20][CH:21]3[N:16]([CH3:15])[CH:17]([CH2:23][CH2:22]3)[CH2:18]2)[CH:7]=[CH:6][C:5]=1[Cl:8]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CN1C2CCC1CC(=O)C2
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN1C2CCC1CC(O)(c1ccc(Cl)c(Cl)c1)C2
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 1-bromo-3,4-dichlorobenzene (178.6 g, 0.8 mol) in anhydrous diethyl ether (1430 mL) under an argon atmosphere was cooled to -70° C. A solution of n-butyllithium in hexanes (310 mL 2.5 M; 0.78 mol) was added slowly while the temperature was kept below -65° C. (addition time=1 hour). The resulting solution was stirred for another 30 minutes at -70° C. followed by addition of a solution of 8-methyl-8-azabicyclo[3.2.1]octan-3-one (50 g, 0.36 mol) in anhydrous tetrahydrofuran (360 mL). The temperature was kept below -50° C. during the addition which took approximately one hour. The resulting solution was stirred at -50° C. for two hours followed by a addition of water (215 mL) over 15 minutes and 4M HCl (360 mL) over 25 minutes. The temperature reached -20° C. by the end of the addition. The organic phase was discharged and the aqueous phase was washed once with diethyl ether (500 mL). Concentrated NH4OH (approximately 200 mL) was added to the aqueous phase to pH=10 which resulted in precipitation of the title compound. A crude product was isolated by filtration which was suspended twice in water (2×300 mL) and finally dried under a lamp yielding the title compound as a white solid (88 g, 86%), m.p. 179.3-180.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([Br:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C(O)c1cccc(Br)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)c4cccc(Br)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-benzoic acid.
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[NH:10][CH2:9][CH:8]([NH2:17])[CH2:7]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[NH:10][CH2:9][CH:8]([N:17]([CH2:7][CH2:6][CH3:11])[CH2:13][CH2:4][CH3:5])[CH2:7]2
Reactant: NC1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(CCC)C1CNc2c(cc(Br)cc2[N+](=O)[O-])C1
Temperature: 100 °C
Reaction time: 5 h
Yield: 139.5 %

Procedure:
A mixture of 6-bromo-1,2,3,4-tetrahydro-8-nitro-3-quinolinamine dihydrochloride (11.5 g, 0.033 mol), idopropane (21 g, 0.12 mol) and anhydrous sodium carbonate (20 g, 0.19 mol) in dimethylformamide (100 mL) was stirred at 100° C. for 5 hours. The solution was then evaporated, partitioned between ethyl acetate and water, and the ethyl acetate was evaporated to give a red oil. This was chromatographed on silica gel to give 8.2 g of 6-bromo-1,2,3,4-tetrahydro-8-nitro-N,N-dipropyl-3-quinolinamine. The product was crystallized from ethyl acetate:hexane to give 7.6 g of product, mp 79°-81° C. Anal. Calcd. for C15H22BrN3O2 : C, 50.57; H, 6.23; Br, 22.43; N, 11.79. Found: C, 50.59; H, 6.27; Br, 22.53; N, 11.69.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(O)=O.[CH2:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH3:16].[NH2:21][C@H:22]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH3:23].O=[C:35]([CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:36]([O:38][CH2:39][CH3:40])=[O:37].C([BH3-])#N.[Na+]>C(O)C>[CH2:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH3:16].[CH2:39]([O:38][C:36]([CH:35]([NH:21][C@H:22]([C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])[CH3:23])[CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:37])[CH3:40]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: CCS(N)(=O)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
Powdered activated 4 Å molecular sieve (13.5 g.) followed by triethylamine (11.13 ml.) were added to a stirred solution of L-alanyl-L-proline ethanesulphonamide trifluoroacetate (31.1 g.) in ethanol (450 ml.). Ethyl 2-oxo-4-phenylbutyrate (41.0 g.) was then added and the mixture was stirred at laboratory temperature for 30 minutes. A solution of sodium cyanoborohydride (7.7 g.) in ethanol (225 ml.) was then added during 15 hours and the mixture was stirred for a further 10 hours, filtered through a filter-aid and the filtrate was evaporated to dryness under reduced pressure. The residue was partitioned between saturated aqueous sodium carbonate solution (1000 ml.) and diethyl ether (1000 ml.) and the aqueous layer was separated, acidified to pH 3 with concentrated aqueous hydrochloric acid and extracted with methylene chloride. The extract was dried and evaporated to dryness under reduced pressure and the residue was purified by chromatography on a silica gel column using a 9:1 v/v mixture of methylene chloride and methanol as eluant. There were thus obtained the mixed isomers of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline ethanesulphonamide in a ratio (as shown by high pressure liquid chromatography) of approximately 11:9 by weight. The isomers were separated by chromatography on a silica gel column using a 99:1 v/v mixture of ethyl acetate and acetic acid as eluant, and there were thus separately obtained N-[(1R)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline ethanesulphonamide, and N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl-L-proline ethane-sulphonamide, both of which were oils, the structures of which were confirmed by proton magnetic resonance and mass spectroscopy. The isomer initially present as 45% by weight of the mixture was considerably more active as an inhibitor of ACE than the other isomer.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1>[CH:20]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1)=[O:21]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred solution of 4-bromo-2-methylbenzoic acid (10 g, 46.4 mmol) in dry THF (360 mL) at −78° C. was added n-BuLi (1.6 M solution in hexane; 58.17 mL, 93.0 mmol) and DMF (8 mL). The reaction mixture was stirred at −78° C. for 1 h then was warmed to 25° C. and stirred for 1 h. The reaction mixture was quenched with 1 N HCl solution and extracted with EtOAc. The combined EtOAc extracts were washed with brine and dried over Na2SO4 and concentrated under reduced pressure. The residue was washed with n-hexane to afford the title compound as a solid (3.0 g, 40%): mp 196-198° C.; 1H NMR (400 MHz, DMSO-d6) δ 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H), 7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163.00 ([M−H]+).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([Br:20])=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C>C(O)=O>[CH:6]([OH:7])=[O:5].[Br:20][C:17]1[N:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][C:16]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(Br)c(OCc3cccc(Cl)c3)n2)CC1
Solvent: O=CO
Product: Clc1cccc(COc2nc(N3CCNCC3)cnc2Br)c1

Procedure:
A solution of 5′-bromo-6′-(3-chloro-benzyloxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3j (25 mg, 0.052 mmol) in formic acid (96%, 0.75 ml) was stirred at room temperature for 2 h, and concentrated in vacuo. The title compound 3-R was collected as a white solid (26 mg, >99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.[C:24]([O:28]C(=O)CC)(=[O:27])[CH2:25][CH3:26]>O>[C:24]([OH:28])(=[O:27])[CH2:25][CH3:26].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][OH:16])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1
Reactant: CCC(=O)OC(=O)CC
Agent: OCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: O
Product: CCC(=O)O

Procedure:
In a manner similar to Example 12, a mixture of 8-chloro-1-(hydroxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and propionic anhydride was heated on the water bath to give 8-chloro-1-(hydroxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine propionate (ester).
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][CH2:10][CH2:11][NH2:12].Cl[C:14]1[C:23]([C:24]([C:26](=[CH:32]N(C)C)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])=[CH:22][C:21]2[C:16](=[CH:17][C:18]([Cl:37])=[C:19]([F:36])[CH:20]=2)[N:15]=1>ClC(Cl)Cl>[Cl:37][C:18]1[C:19]([F:36])=[CH:20][C:21]2[C:16]([CH:17]=1)=[N:15][C:14]1[N:12]([CH2:11][CH2:10][F:9])[CH:32]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:24](=[O:25])[C:23]=1[CH:22]=2
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc2cc(F)c(Cl)cc2nc1Cl
Reactant: NCCF
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCF)c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 75 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
2.7 cm3 of triethylamine are added to a suspension of 1.9 g of 2-fluoroethylamine hydrochloride in 25 cm3 of trichloromethane. 3.5 g of ethyl 2-(2,7-dichloro-6-fluoroquinoline-3-carbonyl)-3-dimethylaminoacrylate are added to the solution obtained at about 20° C. After stirring at this temperature for 16 hours, the solution is concentrated to dryness under reduced pressure (20 kPa) at about 50° C. The residue is taken up in 20 cm3 of ethanol and 3 cm3 of triethylamine and heated at about 75° C., with stirring, for 2 hours. After cooling to about 20° C. the insoluble matter is drained and washed with twice 10 cm3 of ethanol and twice 10 cm3 of diisopropyl ether. 1.9 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 268° C., which is used for the subsequent step without further purification
Reaction SMILES: [Na].[CH3:2][Sn:3](Cl)([CH3:5])[CH3:4].Br[C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1>COCCOC.C(Cl)(Cl)Cl>[CH3:2][Sn:3]([CH3:5])([CH3:4])[C:8]1[C:17]([O:18][CH3:19])=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: COc1cc2ccccc2nc1Br
Reactant: C[Sn](C)(C)Cl
Agent: [Na]
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: COc1cc2ccccc2nc1[Sn](C)(C)C
Temperature: -10 °C
Reaction time: 4 h

Procedure:
3.00 g (130 mmol) of sodium are introduced in a sealed Schlenck-type apparatus under argon inert gas into 3 ml of absolute DME. The sodium is cut into very small pieces and, before being added to the reaction solution, is washed with absolute DME to remove any adhering paraffin. After the sodium has been suspended in DME, the reaction solution remains clear, and only a slight evolution of gas can be observed. The reaction mixture is cooled to -10° C. using an ice/common salt mixture and 1.16 g (5.84 mmol) of trimethyltin chloride are then added in solid form. After the addition, the reaction solution still remains clear. After a reaction time of 1 h, the reaction solution has a milky cloudy color. After a reaction time of 3 hours, the reaction solution becomes milky, gray and cloudy. Shortly afterwards, the reaction solution turns deep green. The solution is stirred for a total of 4 hours. The last hour of the reaction is carried out without ice cooling. In order to remove excess sodium, the reaction solution is filtered under argon inert gas through a D-2 Schlenck-type frit. 0.70 g (2.92 mmol) of 2-bromo-3-methoxyquinoline dissolved in 3 ml of absolute DME is added dropwise to the filtered cloudy and green reaction solution. Upon dropwise addition of the educt, the reaction solution spontaneously turns blood red. During the addition of the educt, the reaction solution is cooled with ice. After a short time, the reaction solution has a dark brown color, which, after a reaction time of 1.5 hours, clears to light brown. After a reaction time of 4 hours with ice cooling, the reaction mixture is filtered through a D-4 frit to remove the solids formed. This gives a light yellow reaction solution. A gray solid remains in the frit. The solvent is washed with more [lacuna], the runoff being dark brown. After evaporation of the solvent, a dark brown oil is obtained. A thin-layer chromatogram obtained in chloroform shows that the desired product is obtained. Slight traces of the hydrolysis product 3-methoxyquinoline can be detected by 1H-NMR spectroscopy.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].CC1C=CC(S(O[CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])(=O)=O)=CC=1.O>O1CCCC1>[C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH3:53])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 80.2 %

Procedure:
To a stirred solution of the product of step (b) (25 g) in tetrahydrofuran (500 mL) at −20° C. was added a solution of potassium tert-butoxide in tetrahydrofuran (1.61M, 50 mL) over 1 hour, maintaining the temperature at about −20° C. The reaction mixture was stirred for a further 15 minutes then a solution of the product of step (a) (29.7 g) in tetrahydrofuran (100 mL) was added over 90 minutes, maintaining the temperature at about −20° C. After stirring at −20° C. for a further 3 hours, the mixture was allowed to warm to 20° C. and stirred for 16 hours. Water (125 mL) was then added and the resultant mixture was concentrated in vacuo to 140 mL. Sodium chloride (12.5 g) was added to the stirred concentrate, which was then washed with diisopropyl ether (4×125 mL). The aqueous phase was diluted with water (50 mL) and extracted with dichloromethane (3×125 mL). The combined dichloromethane extracts were concentrated in vacuo to give the title compound as an orange-brown oil (27.93 g). GC retention time 21.8 mins
Reaction SMILES: [CH:1]([N:4]([CH:12]([CH3:14])[CH3:13])[P:5](Cl)[O:6][CH2:7][CH2:8][C:9]#[N:10])([CH3:3])[CH3:2].[C:15]([O:18][CH:19]([O:58][C:59](=[O:61])[CH3:60])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([OH:57])[CH2:32][O:33][C:34]([C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:22][CH:21]=1)(=[O:17])[CH3:16].CO.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C.CCCCCC>[C:15]([O:18][CH:19]([O:58][C:59](=[O:61])[CH3:60])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([O:57][P:5]([N:4]([CH:12]([CH3:14])[CH3:13])[CH:1]([CH3:3])[CH3:2])[O:6][CH2:7][CH2:8][C:9]#[N:10])[CH2:32][O:33][C:34]([C:41]2[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)([C:49]2[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:22][CH:21]=1)(=[O:17])[CH3:16]
Reactant: CC(C)N(C(C)C)P(Cl)OCCC#N
Reactant: COc1ccc(C(OCC(O)CCCCOc2ccc(C(OC(C)=O)OC(C)=O)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(C(OCC(CCCCOc2ccc(C(OC(C)=O)OC(C)=O)cc2)OP(OCCC#N)N(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Cyanoethyl diisopropylchlorophosphoramidite (0.49 ml, 2.19 mmol) was added to a solution of 9 (0.83 g, 1.29 mmol) dissolved in 32 ml of anhydrous methylene chloride containing 0.67 ml of N,N-diisopropylethylamine. The reaction solution was stirred for 1.0 h at 25 ° C. under argon and then treated with 1.0 ml of methanol and poured into 300 ml of 5% sodium bicarbonate solution. The mixture was extracted with ethyl acetate (300 ml) and the extract was dried over sodium sulfate and evaporated. The crude product was purified by silica gel chromatography eluting with a gradient of 25-50% ethyl acetate in hexane (2% triethylamine). The pure phosphoramidite fractions were evaporated affording a homogenous oil: 0.61g (56%) yield; TLC (1:1, ethyl acetate/hexane), Rf=0.62; 31P NMR (DMSO-d6) 147.82 (singlet). Anal. Calcd for C47H59N2O10P .0.2 H2O: C, 66.68; H, 7.07; N, 3.31. Found: C, 66.46; H, 7.27; N, 2.94
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.CCN(CC)CC.[C:15]([O:19][C:20](=O)[O:21]C(C)(C)C)([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([OH:1])[CH2:3]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: OC1CCCNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A solution of 10.0 g (72.67 mmol) 3-hydroxypiperidine in 100 mL dry THF at 0° C. was added 10.1 mL (72.67 mmol) NEt3 and 15.86 g (72.67 mmol) di-t-butylcarbonate in 100 mL THF and the reaction allowed to warm to rt and stirred overnight. The solvent was removed under reduced pressure, the resulting residue dissolved in 300 mL CH2Cl2 and the solution extracted with H2O (2×200 mL), dried over MgSO4, filtered and rotary evaporated to yield 12.66 g (87%) of N-(t-butoxycarbonyl)-3-piperidinol as an oil which slowly solidified to a white solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:9]=[C:8]([Cl:10])[S:7][C:6]=1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4].B(Cl)([C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1)[C@@H]1[C@@H](C)C2C(C)(C)C(C2)C1.[OH-].[Na+]>COC(C)(C)C>[Cl:10][C:8]1[S:7][C:6]2[S:11](=[O:13])(=[O:12])[NH:14][CH2:2][C@@H:3]([OH:4])[C:5]=2[CH:9]=1
Reactant: NS(=O)(=O)c1sc(Cl)cc1C(=O)CBr
Agent: C[C@H]1C2CC(C[C@@H]1B(Cl)[C@H]1CC3CC([C@@H]1C)C3(C)C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Product: O=S1(=O)NC[C@@H](O)c2cc(Cl)sc21
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A 50-L, 5-necked flask equipped with a mechanical stirrer and a thermometer was flushed with nitrogen overnight. Working under nitrogen, the flask was charged with 3-bromoacetyl-5-chloro-2-thiophenesulfonamide (4, 855 g, 2.68 mol) and t-butyl methyl ether (12.5 L). The stirred suspension was cooled to -40° C. using a dry-ice/2-propanol bath and (+)-β-chlorodiisopinocampheylborane (4.5 L of a 1.2M solution in t-butyl methyl ether, 5.4 mol, 2 eq) was added via a cannula over 30 minutes, causing the temperature to rise to -32° C. The reaction mixture was maintained between -25° to -20° C. for 3.5 hours, after which TLC analysis indicated complete reduction. The mixture was warmed to 0° C. and 1M aqueous sodium hydroxide (11 L) was added from an addition funnel over 10 minutes, causing the temperature to rise to 22° C. The biphasic mixture was stirred vigorously at ambient temperature for 2 hours, after which TLC analysis indicated complete cyclization. The phases were split and the dark aqueous layer was extracted with t-butyl methyl ether (3 L), acidified to pH 1 using concentrated hydrochloric acid, and extracted with ethyl acetate (2×4 L). The combined ethyl acetate extracts were washed with saturated aqueous sodium chloride (3 L), dried over sodium sulfate (1 kg), filtered, and concentrated to a volume of about 1 liter by rotary evaporation, at which point toluene (2 L) was added. As the remainder of the ethyl acetate was stripped, the product crystallized from toluene. It was collected by filtration, washed with toluene (2 L) and methylene chloride (2 L), and dried in air at ambient temperature to a constant weight of 498 grams (77%) of 5: mp 126°-127° C.; IR (KBr) 3550, 3230, 1430, 1410, 1320, 1170, 860, 720, 550, 470 cm-1 ; 1H NMR (DMSO-d6) δ8.18-8.11 (m, 1H), 7.19 (s, 1H), 5.8 (br, 1H), 4.60-4.54 (m, 1H), 3.68-3.55 (m, 1H), 3.50-3.35 (m, 1H); [α]25D -5.9° (c=1, CH3OH); Analysis for C6H6ClNO3S2 : Calcd: C, 30.06; H, 2.52; N, 5.84. Found: C, 30.14; H, 2.56; N, 5.80.