Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:57])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][C:30]3([CH2:45][C:46]([O:48]C(C)(C)C)=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[N:55][OH:56])=[O:7])(C)(C)C.Cl>O1CCOCC1>[C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:57])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][C:30]3([CH2:45][C:46]([OH:48])=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([OH:39])=[O:38])[C:31]3=[O:44])=[CH:53][CH:54]=1)([CH3:22])[CH2:14][C:13]2=[N:55][OH:56])([OH:7])=[O:5]
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=NO)CC(C)(COc1ccc(CC3(CC(=O)OC(C)(C)C)SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)O)C(=NO)CC(C)(COc1ccc(CC3(CC(=O)O)SC(=O)N(CC(=O)O)C3=O)cc1)O2

Procedure:
A mixture of 270 mg of di-t-butyl α,α'-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino -2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate (prepared as described in Example 56) and 3 ml of a 4N dioxane solution of hydrogen chloride was treated in the same manner described in Example 61, to give the title compound as a pale yellow powder, softening at 90°-100° C.
Reaction SMILES: [Cl:1][Si](C)(C)C.[CH3:6][C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11].CS(C)=O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C.O>[Cl:1][CH:9]([C:8](=[O:13])[C:7]([CH3:15])([CH3:14])[CH3:6])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)CC(=O)C(C)(C)C
Reactant: C[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CS(C)=O
Solvent: CC#N
Solvent: O
Product: CC(=O)C(Cl)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
Chlorotrimethylsilane (26.8 ml, 0.21 mol) was added dropwise to a stirred pale yellow solution of tetrabutylammonium bromide (1.139, 3.50 mmol) in dry acetonitrile (100 ml) at room temperature under nitrogen. The resulting solution was cooled in ice and 5,5-dimethylhexane-2,4-dione (10.0 g, 70.4 mmol) and then dry dimethylsulphoxide (14.7 ml, 0.21 mol) were added dropwise over 5 minutes producing a yellow solution which was allowed to warm slowly to room temperature with stirring over 3 hours. The mixture was diluted with water (1000 ml) and stirred for 10 min and then extracted with ether (1×500 ml, 2×250 ml). The combined ether layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a yellow oil. The crude product was purified by distillation under reduced pressure to provide the title compound (10.0 g) as a pale yellow oil, b.p. 220-225° C./60 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](Br)[CH:17]=[N:18][C:12]=2[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]([CH2:26][C:27]1[O:28][C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]=1[CH3:32])[C:22](=[O:25])[CH:23]=[CH2:24].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16](/[CH:24]=[CH:23]/[C:22](=[O:25])[N:21]([CH3:20])[CH2:26][C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]=3[CH3:32])[CH:17]=[N:18][C:12]=2[NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNc2ncc(Br)cc2C1
Reactant: C=CC(=O)N(C)Cc1oc2ccccc2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(C(=O)OC(C)(C)C)CCN3)oc2ccccc12
Reaction time: 0.08 h
Yield: 63 %

Procedure:
A solution of 7-bromo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepine-4-carboxylic acid tert-butyl ester (0.53 g, 1.6 mmol) and N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamide (0.41 g, 1.8 mmol) in propionitrile (8.0 mL) and DMF (2.0 mL) was de-oxygenated with Ar for 10 min. The mixture was treated with (i-Pr)2EtN (0.62 mL, 3.5 mmol) and was de-oxygenated with Ar for 5 min. Pd(OAc)2 (36 mg, 0.16 mmol) and P(o-tol)3 (100 mg, 0.33 mmol) were added simultaneously, and the mixture was de-oxygenated a third time for 10 min. The mixture was heated to reflux tor 6 h, then allowed to cool. The mixture was diluted with EtOAc (100 mL) and washed with H2O (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated to an orange oil. Purification by flash column chromatography (silica gel, CH2Cl2/MeOH, 98:2) gave the title compound (0.48 g, 62%) as a white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ8.15-8.10 (m, 1H), 7.87-7.74 (m, 1H), 7.57-7.42 (m, 3H), 7.32-0.77 (m, 4H), 4.97-4.78 (m, 2H), 4.51-4.42 (m, 2H), 3.59-3.57 (m, 2H), 3.43-3.41 (m, 2H), 3.1-2.92 (m, 3H), 2.26 (s, 3H), 1.38-1.24 (m, 9H); MS (ESI) m/e 477 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][OH:15].CN(C)C=O>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:13][CH2:14][OH:15])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: OCCBr
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(OCCO)cc1Cl
Temperature: 80 °C

Procedure:
To a solution of 3.00 g (15.7 mmol) A1 and 1.4 ml (19.7 mmol) 2-bromoethanol in 50 ml dry dimethyl formamide 3.06 g (22.1 mmol) potassium carbonate were added the mixture was heated to 80° C. for 2 hours. Every 30 minutes, 0.2 ml 2-bromoethanol were added until no A1 was longer observed by TLC (hexanes/ethyl acetate 1:1). The solvent was removed in vacuo and the residue was partitionated between ethyl acetate and water. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was treated with ether and filtered off to yield 3.03 g (82%) A12, m.p. 83-85° C.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([N:9]([C@H:15]3[CH:20]4[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]4)[CH2:16]3)C[C@H:11]3[CH2:12][CH2:13][CH2:14][C:3](=[C:4]23)[CH:2]=1)=[O:8].C1(C(O)=O)C2CCCCC=2C=CC=1.N[C@H]1C2CCN(CC2)C1>>[N:17]12[CH2:18][CH2:19][CH:20]([CH2:21][CH2:22]1)[C@H:15]([NH:9][C:7]([C:5]1[C:4]3[CH2:11][CH2:12][CH2:13][CH2:14][C:3]=3[CH:2]=[CH:1][CH:6]=1)=[O:8])[CH2:16]2
Reactant: O=C1c2cccc3c2[C@H](CCC3)CN1[C@@H]1CN2CCC1CC2
Agent: N[C@@H]1CN2CCC1CC2
Agent: O=C(O)c1cccc2c1CCCC2
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2c1CCCC2

Procedure:
The synthetic route for preparing palonosetron is described in U.S. Pat. No. 5,202,333, wherein 5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (Compound II) is reacted with (S)-3-amino-1-azabicyclo[2.2.2]octane (Compound III) to obtain (S)—N-(1-azabicyclo-[2.2.2]oct-3-yl)-5,6,7,8-tetrahydro-1-naphthalenecarboxamide (Compound IV), which is recrystallized from a mixture of ethyl acetate and hexane. Reaction of Compound IV with n-butyl lithium in hexane in presence of dimethylformamide (DMF) affords (S)-2-(1-azabicyclo-[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one (Compound V), and treatment of Compound V using palladium hydroxide on carbon with hydrogen affords a diastereomeric mixture containing 98.9% of Compound A. This process is depicted in Scheme 1 below.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5]1.[Cl:17][C:18]1[CH:19]=[C:20](F)[CH:21]=[CH:22][CH:23]=1.[Na+].[Cl-].CN1CCC=C(C2C=CC=CC=2)C1.Cl>CN(C=O)C.CCOCC>[ClH:17].[Cl:17][C:18]1[CH:23]=[C:22]([CH:21]=[CH:20][CH:19]=1)[O:10][C@H:7]1[CH2:8][CH2:9][N:4]([CH3:3])[CH2:5][C@H:6]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1cccc(Cl)c1
Reactant: CN1CCC(O)C(c2ccccc2)C1
Agent: CN1CCC=C(c2ccccc2)C1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CC[C@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 1.9 g of sodium hydride, 12.07 g of 1-methyl-3-phenyl-4-piperidinol (mixture of isomers) of Example 1 and 70 ml of dry DMF is heated at approximately 100° C. for 1 hour under nitrogen, then cooled to room temperature. A solution of 16.45 g of 3-chlorofluorobenzene in 40 ml of DMF is added all at once, and the mixture is stirred for 18 hours at room temperature, then heated slowly so that after 4 hours the pot temperature is 68° C. After stirring for about 64 hours at room temperature, another 0.76 g of sodium hydride is added and the mixture is again heated slowly to approximately 70° C. After 2 hours the mixture is cooled and treated with 50 ml of saturated aqueous NaCl solution, then poured into a mixture of saturated aqueous NaCl solution and ether. The phases are separated and the aqueous phase is extracted with ether. The combined ether extracts was washed with water, saturated NaCl solution, and then concentrated in vacuo. The residue is partitioned between dichloromethane and water. The phases are separated and the aqueous phase is extracted with more dichloromethane. The combined dichloromethane phases are extracted with 2 N HCl solution, then washed successively with 10% aqueous NaOH solution, water, saturated aqueous NaCl solution, and dried over anhydrous Na2SO4. Concentration in vacuo affords an oil, which TLC shows to be a mixture of product isomers. This material is chromatographed on silica gel, using acetone as the initial solvent. The trans product is eluted with 25% methanol/acetone as solvent. The cis product is eluted with 25% and then 50% methanol/acetone, giving a crude free base which NMR shows to be an 8:3 mixture of cis product to 1-methyl-3-phenyl-1,2,5,6-tetrahydropyridine. The hydrochloride salt is prepared by dissolving the free base in ether and treating with HCl-saturated ether solution until the mixture is acidic to pH paper. The crude salt is filtered and washed with ether to afford a solid, m.p. s 180°, 207°-220° C. Recrystallization from acetone affords a solid of cis-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine hydrochloride, mp s 230°, 231°-232.5° C.
Reaction SMILES: CN(C)[CH2:3][CH2:4][NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=2[N:10]=1.C(N)C[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[N+:15]([C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][CH2:4][CH2:3][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[S:7][C:8]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: NCCc1ccccc1
Reactant: CN(C)CCNc1nc2ccc([N+](=O)[O-])cc2s1
Product: O=[N+]([O-])c1ccc2nc(NCCc3ccccc3)sc2c1

Procedure:
The title compound was prepared following the procedure for N,N-dimethyl-N′-(6-nitrobenzothiazol-2-yl)-ethane-1,2-diamine, using 4 eq of phenethylamine. Modified workup: Solid that had precipitated during course of reaction (amine salt) was filtered; no aqueous workup was conducted. 1H NMR (400 MHz, CDCl3): δ=3.03 (t, J=6.4 Hz, 3H), 3.77 (q, J=6.4 Hz, 2H), 7.23-7.30 (m, 3H), 7.33-7.38 (m, 2H), 7.52 (d, J=8.8 Hz, 1H), 8.21 (dd, J=8.8, 2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H). MS (ES+): m/z 300.10 [MH+]. HPLC: tR=3.57 min (ZQ2000, polar—5 min).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH:12]([C:19]([O:21][CH3:22])=[O:20])[C:13](=O)[CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl-].[NH4+].C(=O)([O-])O.[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(N(CC)CC)C.CN(C1C=CN=CC=1)C.CO>[CH2:3]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C1C(=O)CC2CCC1N2Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)C1=CCC2CCC1N2Cc1ccccc1
Reaction time: 14.5 h
Yield: 42.1 %

Procedure:
In an ice bath, NaBH4 (412 mg, 10.6 mmol) was added to a methanol (55 ml) solution of the methyl 8-benzyl-3-oxo-8-azabicyclo[3.2.1]octane-2-carboxylate (1.45 g, 5.32 mmol) obtained in Example 17, and the mixture was stirred for 14.5 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture and the excess solvent was evapolated under reduced pressure. The residue was adjusted to pH 8.0-8.5 with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over Na2SO4, filtered and then concentrated in vacuo, and the resulting residue was dissolved in chloroform (30 ml) under a nitrogen atmosphere. To the resulting solution were added triethylamine (1.48 ml, 10.6 mmol) and DMAP as a catalyst, and trifluoroacetic anhydride (1.13 ml, 7.98 mmol) was added thereto in an ice bath, and then the resulting mixture was stirred at room temperature for 21 hours. After completion of the reaction, the reaction mixture was adjusted to pH 9.0 with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The extract was dried over Na2SO4, filtered and then concentrated in vacuo, and the thus obtained crude product was purified by a silica gel column chromatography (AcOEt:hexane=1:8) to obtain 577 mg of the title compound methyl 8-benzyl-8-azabicyclo[3.2.1]octan-2-ene-2-carboxylate. The yield from the above two steps was 42 mol %. The compound obtained in the present example was a d1-form and was used as a reference standard compound for optical purity measurement.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[NH4+]>O1CCCC1.[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C>[Cl:11][CH2:12][CH2:13][C:14]([C:2]1[O:1][CH:5]=[CH:4][N:3]=1)=[O:15]
Reactant: c1cocn1
Reactant: O=C(Cl)CCCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(CCCl)c1ncco1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 228.6 %

Procedure:
To a solution of oxazole (2.93 g, 42.5 mmol) in tetrahydrofuran (150 ml) at −70° C. under a nitrogen atmosphere was added n-butyllithium (2.5 M solution in hexanes, 17 ml) dropwise and the solution stirred for 20 minutes. Zinc chloride (1 M solution in diethyl ether, 84.9 ml) was added and the solution warmed to 0° C. over 45 minutes. Solid cuprous iodide (8.09 g, 42.5 mmol) was added and after 10 minutes, 3-chloropropionyl chloride (8.38 ml, 87.8 mmol) was added. After 1 h, ethyl acetate and aqueous ammonium chloride solution were added. The organic layer was separated and washed sequentially with aqueous ammonium chloride solution, water and brine. The solution was dried (sodium sulphate) and evaporated to yield the crude product as a red oil (15.5 g). This material was used without further purification.
Reaction SMILES: [N:1]1([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(CC)C.Br[C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([S:29]([O:32][C:33]1[C:38]([F:39])=[C:37]([F:40])[C:36]([F:41])=[C:35]([F:42])[C:34]=1[F:43])(=[O:31])=[O:30])=[CH:24]2.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[OH-].[NH4+]>[Cl-].[Zn+2].[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1COCC1>[F:43][C:34]1[C:35]([F:42])=[C:36]([F:41])[C:37]([F:40])=[C:38]([F:39])[C:33]=1[O:32][S:29]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[C:19]([CH:2]1[CH2:3][CH2:4][CH2:5][N:1]1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:28][CH:27]=[CH:26]2)(=[O:31])=[O:30]
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Br)cccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1cccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
A 100-mL round-bottom flask was charged with tert-butyl 1-pyrrolidinecarboxylate (Sigma-Aldrich, St. Louis, Mo., 0.774 ml, 4.41 mmol) and THF (22.07 ml) to give a clear solution. The flask was flushed with Ar (g), then cooled in a −30° C. dry ice-acetone bath for 10 min. sec-butyllithium (1.4 M in cyclohexane) (3.15 ml, 4.41 mmol) was added dropwise over 2 min. The resulting mixture was stirred for 15 min, during which time the bath had warmed to −25° C., then zinc chloride (1M in diethyl ether) (3.31 ml, 3.31 mmol) was added dropwise. The cooling bath was removed. After 25 min, a solid mixture of perfluorophenyl 5-bromonaphthalene-2-sulfonate (Intermediate M, 1.00 g, 2.207 mmol), palladium(ii) acetate (0.050 g, 0.221 mmol), and tri-tert-butylphosphonium tetrafluoroborate (0.064 g, 0.221 mmol) was added in one portion. The resulting mixture was stirred further for 2 h. A 30% aq ammonium hydroxide solution (1 mL) was added, and the mixture was stirred vigorously for 10 min. The mixture was then filtered through diatomaceous earth with the aid of ethyl acetate. The filtrate was washed with 0.5N aq. HCl, and the aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g, 0 to 30% EtOAc/Heptane) to give tert-butyl 2-(6-((perfluorophenoxy)sulfonyl)naphthalen-1-yl)pyrrolidine-1-carboxylate (709.11 mg, 1.305 mmol, 59.1% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=8.85-8.73 (m, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H), 7.99 (d, J=8.3 Hz, 1H), 7.80-7.68 (m, 1H), 7.62-7.42 (m, 1H), 5.81-5.50 (m, 1H), 3.77-3.65 (m, 1H), 3.62-3.49 (m, 1H), 1.98-1.60 (m, 3H), 1.42 (br. s., 4H), 1.29-1.19 (m, 1H), 0.92 (s, 5H); m/z (ESI) 488.2 (M+H-t-Bu)+.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.[Cl-].[K+:16]>C(OC(=O)C)(=O)C>[K+:16].[S:6]1[CH:7]=[C:8]([S:1]([O-:3])(=[O:5])=[O:2])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: O=S(=O)(O)O
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=S(=O)([O-])c1csc2ccccc12

Procedure:
Concentrated sulphuric acid (0.43 ml) was added to a cooled, stirred mixture of benzothiophene (1 g) in acetic anhydride (0.93 ml), giving a brown viscous oil, which was left to stir for 50 mins under nitrogen. The mixture was then diluted with ice to give 20 ml, extracted with ether (2×10 ml) and the aqueous phase concentrated in vacuo to give 5 ml. This was then treated with a hot saturated solution of potassium chloride (2 g), cooled and filtered to give the title compound as a pale brown solid (3.935 g).
Reaction SMILES: [CH3:1][S:2][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])=[N:9][CH:10]=1)[CH3:4].[N:18]#[C:19][NH2:20].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1>[F:16][C:11]([F:17])([C:8]1[N:9]=[CH:10][C:5]([CH:3]([S:2]([CH3:1])=[N:20][C:19]#[N:18])[CH3:4])=[CH:6][CH:7]=1)[C:12]([F:13])([F:14])[F:15]
Reactant: N#CN
Reactant: CSC(C)c1ccc(C(F)(F)C(F)(F)F)nc1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: C1CCOC1
Product: CC(c1ccc(C(F)(F)C(F)(F)F)nc1)S(C)=NC#N
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To a stiffed solution of the 5-(1-methylthioethyl)-2-pentafluoro-ethylpyridine (A) (0.16 g, 0.6 mmol) and cyanamide (0.025 g, 0.6 mmol) in THF (3 mL) cooled to 0° C. was added iodobenzene diacetate (0.19 g, 0.6 mmol) in one portion and the resulting mixture was stiffed at 0° C. for 2 h and then at room temperature overnight. The solvent was removed in vacuo and the resulting mixture was suspended in brine-saturated NaHCO3 (9:1), which was then extracted with CH2Cl2-EtOAc (1:1, v/v) two times. The combined organic layer was dried over Na2SO4, filtered, concentrated, and dried to give 0.16 g of (1-{6-[pentafluoroethyl]pyridin-3-yl}ethyl)(methyl)-λ4-sulfanylidenecyanamide (B) as a brownish oil in 85% yield. LC-MS: mass calcd for C11H10F5N3S [M]+ 311.28. Found [M-1]+309.84
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH:21]([NH2:24])([CH3:23])[CH3:22]>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17][NH:24][CH:21]([CH3:23])[CH3:22])([O:15][NH:24][CH:21]([CH3:23])[CH3:22])=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CC(C)N
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Solvent: CCOCC
Product: CCOC(=O)CN(CP(=O)(ONC(C)C)ONC(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (6.6 g, 0.02 mole) in 200 ml. of ether was added dropwise with good stirring isopropylamine (4.9 g, 0.08 mole) in 70 ml. of ether. The reaction temperature was controlled by cold water bath. The reaction was stirred at room temperature overnight, then was filtered and the filtrate concentrated in vacuo. The residue was taken up in ether, washed with water, dried, concentrated in vacuo, extracted into hot petroleum ether and concentrated to give ethyl N-trifluoroacetyl-N-(bis(isopropylamino)phosphonomethyl)glycinate as a light yellow oil-gum, ND =1.4495.
Reaction SMILES: [OH-:1].[Na+].[CH:3](=[C:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]>>[OH:1][CH:3]([CH:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[O:13])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC=C1CCCC1=O
Reactant: [OH-]
Agent: [Na+]
Product: CCCCC(O)C1CCCC1=O
Reaction time: 2 h
Yield: 2571.4 %

Procedure:
Additional 15.8 g (0.19 mol) 48% NaOH was added thereto, and the mixture was stirred at the same temperature for 2 hours. After the reaction was finished, the mixture was neutralized and analyzed in the same manner as in Example 1. The result indicated that the reaction mixture contained 521 g (3.06 mol) 2-(1-hydroxy-n-pentyl)cyclopentanone (yield 83.8%) and 18.2 g (0.119 mol) 2-pentylidene cyclopentanone.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][P:6]([O-:10])[O:7][CH2:8][CH3:9])[CH3:4].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17]Cl>CCCCC>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][P:6]([O:7][CH2:8][CH3:9])([O:5][CH2:3][CH3:4])=[O:10]
Reactant: ClCOCCCCBr
Reactant: CCOP([O-])OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Product: CCOP(=O)(COCCCCBr)OCC
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a slurry of 6.26 g (149 mmol) of 57% NaH and 300 mL of n-pentane at 0° C. was added 17.14 g (124 mmol) of diethylphosphite and the mixture was stirred for 1 hour at 0°. The mixture was then cooled to -70° and 25 g (124 mmol) of 1-bromo-4-(chloromethoxy)butane was added and the reaction mixture warmed to 0° and stirred for 1 hour. The mixture was then filtered and evaporated. The residue was purified by SiO2 chromatography to give 26 g (70%) of 1-bromo-4-(diethylphosphonomethoxy)butane as a colorless oil.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16]([CH3:26])=[CH:17][C:18](=[O:25])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.[Br:28][CH2:29][CH2:30]Br>C(O)C>[CH3:3][O:4][C:5](=[O:27])[CH:6]([NH:15][C:16]([CH3:26])=[CH:17][C:18](=[O:25])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:30][CH2:29][Br:28])=[CH:10][CH:9]=1
Reactant: COC(=O)C(Cc1ccc(O)cc1)NC(C)=CC(=O)c1cccnc1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)NC(C)=CC(=O)c1cccnc1
Yield: 15.2 %

Procedure:
To a solution of potassium hydroxide (0.17 g, 2.95 mmol) in ethanol (20 ml) is added 2-[1-methyl-3-oxo-3-(3-pyridyl)-propenylamino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (1.00 g, 2.95 mmol) and 1,2-dibromoethane (5.54 g, 29.50 mmol). Then the mixture is heated to reflux for 8 hours. After cooled, the reaction mixture is filtered to remove the solid formed, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give the title compound (0.20 g, 15%).