Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)=[O:3].[Cl:5][C:6]1[C:11]2[CH2:12][NH:13][CH2:14][CH2:15][S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1.Cl.C(N(CC)CC)C>ClCCl>[Cl:5][C:6]1[C:11]2[CH2:12][N:13]([S:2]([CH3:1])=[O:3])[CH2:14][CH2:15][S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)Cl
Reactant: Clc1cccc2c1CNCCS2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)N1CCSc2cccc(Cl)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphinyl chloride (0.98 g) in dichloromethane (10 ml) was added dropwise at room temperature to a stirred solution of 6-chloro-2,3,4,5-tetrahydro-1,4-benzothiazepine (1.99 g, prepared in a similar manner to its hydrochloride, Example 1 above) and triethylamine (1.01 g) in dichloromethane (50 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane/ethanol (98:2) as eluent gave 6-chloro-4-methylsulphinyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethylacetate/hexane. Yield 2.1 g (m.p. 82°-84° C.).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1(S(C=C)(=O)=O)C=CC=CC=1.[NH2:21][C@@H:22]([CH2:24][OH:25])[CH3:23].Cl[C:27]1[C:28]2[S:45][C:44](=[O:46])[N:43]([CH2:47][CH2:48][S:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:29]=2[N:30]=[C:31]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[F:42])[N:32]=1>C(#N)CCC.O>[F:42][C:36]1[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][S:33][C:31]1[N:32]=[C:27]([NH:21][C@H:22]([CH3:23])[CH2:24][OH:25])[C:28]2[S:45][C:44](=[O:46])[N:43]([CH2:47][CH2:48][S:49]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)(=[O:50])=[O:51])[C:29]=2[N:30]=1
Reactant: O=c1sc2c(Cl)nc(SCc3cccc(F)c3F)nc2n1CCS(=O)(=O)c1ccccc1
Reactant: C[C@@H](N)CO
Agent: C=CS(=O)(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Solvent: O
Product: C[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2c1sc(=O)n2CCS(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a stirred suspension of 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(31)-one (31.62 g), as prepared in Example 1 (c) above, in butyronitrile (150 ml) at room temperature was added diisopropylethylamine (16 ml, 1.0 eq), forming a solution. A butyronitrile line wash was applied (10 ml). Phenylvinylsulfone (20 g, 1.3 eq) was dissolved in butyronitrile (80 ml) in a separate flask and this solution was added to the vessel, followed by a line wash with butyronitrile (70 ml). The orange solution was heated to an internal temperature of 100° C. After 18 hours HPLC showed almost complete consumption of the starting material (3.36% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-2-(3H)-one remained)*. At this point further diisopropylethylamine (16 ml, 1.0 eq) was added to the mixture at 50° C., followed by a small line wash of butyronitrile (5 ml). D-alaninol (9.25 mLs, 1.3 eq) was added, followed by a line wash of butyronitrile (5 ml). After 6.5 hrs HPLC showed almost complete conversion of the reaction intermediate (2.52% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-a]pyrimidin-2-(3H)-one remained). The reaction was allowed to cool from 100 to 50° C. over 6.5 hrs and held at 50° C. under nitrogen for 64 hrs. In order to get a homogeneous sample the reaction was re-heated to 100° C. (1.19% 7-chloro-5-[[(2,3-difluorophenyl)methyl]thio]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one present by HPLC). The reaction was cooled from 100 to 50° C. over 1 hr and water (200 mLs) was added. A precipitate was observed. The mixture was cooled from 50° C. to 20° C. over 2 hrs. The precipitate was ‘aged’ at 20° C. for 1 hr and collected by filtration. The ‘cake’ was washed with 1:1 water/butyronitrile (70 ml) twice, then with butyronitrile (35 ml). The solid was then dried on the filter for 30 mins, collected and dried in a vacuum oven overnight at 50° C. A pale yellow solid 5-[[(2,3-difluorophenyl)methyl]thio]-7-[[(1R)-2-hydroxy-1-methylethyl]amino]-3-[2-(phenylsulfonyl)ethyl]thiazolo[4,5-d]pyrimidin-2-(3H)-one was obtained with 88% yield (44.33 g, HPLC area=98.75%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:7].C(O)C.[BH4-].[Na+]>O>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:6]([OH:7])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)CCCCCCC(=O)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCCC(O)c1ccco1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of 85g (0.337 mol) of ethyl 7-(2-furoyl)heptanoate (Example 3) in 500 ml of abs. ethanol is added 12.75g (0.337 mol) of sodium borohydride in small portions during 20 min. at 20°-35° C. The mixture is stirred at ambient temperature for 3.5 hr., poured into 2.5 l of water, and extracted with ether. The extract is washed with brine, dried over magnesium sulfate, and concentrated to give a pale yellow oil (85.8g).
Reaction SMILES: Cl[C:2]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5].[CH3:19][S:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:18][C:15]1[CH:16]=[N:17][C:2]([O:27][C:24]2[CH:25]=[CH:26][C:21]([S:20][CH3:19])=[CH:22][CH:23]=2)=[C:3]([CH:14]=1)[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][CH2:8]1)=[O:5]
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)c1cc(F)cnc1Cl
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1
Temperature: 55 °C
Reaction time: 18 h

Procedure:
2-Chloro-5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-nicotinamide (150 mg, 0.55 mmol), 4-methylsulfanyl-phenol (77 mg, 0.55 mmol) and caesium carbonate (358 mg, 1.10 mmol) were suspended in DMF (2 ml) and the reaction was heated to 55° C. and stirred at this temperature under nitrogen for 18 h. The reaction was quenched with sat. ammonium chloride solution (1.5 ml) and water (1.5 ml) and the organic phase was collected by passing the mixture through a chemelute cartridge, washing with ethyl acetate. The solvent was removed on a Genevac™ and the residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 changing to 96:4, by volume) to give 5-fluoro-N-(trans-4-hydroxy-cyclohexyl)-2-(4-methylsulfanyl-phenoxy)-nicotinamide (81 mg) as an off-white foam.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[CH3:5][C:4](=[O:6])[CH2:3][CH2:2][CH2:1][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:9]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CC(=O)CC(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCC(C)=O
Temperature: 90 °C
Yield: 95 %

Procedure:
To a 2 L two-necked round bottom flask equipped with water condenser, calcium chloride guard tube and mechanical stirrer, 70 g of 2,4-pentanedione, 650 g of 1-bromooctadecane, 8 g of 18-crown-6, anhydrous potassium carbonate 140 g and 600 ml of absolute ethanol were added with stirring. The mixture was refluxed at 90° C. with continuous stirring for 30 hrs; after refluxing at the said temperature, the mixture cooled to ambient temperature (25° C.), 600 ml of water was added to it and the 2-heneicosanone was extracted with dichloromethane from the mixture. On distillation of dichloromethane, 2-heneicosanone was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[C:10]([CH2:14][C:15]([NH2:17])=[O:16])[C:9]=2[CH:18]=1)[CH3:3].C[O:20][C:21](=O)[C:22]([C:24]1[C:32]2[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=O.CC([O-])(C)C.[K+]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:16])[NH:17][C:21](=[O:20])[C:22]=3[C:24]3[C:32]4[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[C:9]=2[CH:18]=1)[CH3:3]
Reactant: COC(=O)C(=O)c1c[nH]c2c(C)cccc12
Reactant: Cc1oc2ccc(CN(C)C)cc2c1CC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1oc2ccc(CN(C)C)cc2c1C1=C(c2c[nH]c3c(C)cccc23)C(=O)NC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a solution of 2-(5-dimethylaminomethyl-2-methyl-benzofuran-3-yl)-acetamide (111 mg, 0.406 mmol) and (7-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (132 mg, 0.608 mmol) in anhydrous THF (4.0 mL) is added dropwise a 1 M solution of t-BuOK in THF (2.0 mL) at 0° C. under an argon atmosphere. The resulting deep red reaction mixture is stirred for 1 h at 0° C., diluted with EtOAc, washed with a saturated aqueous NH4Cl solution and washed with brine. The combined aqueous phases are extracted with EtOAc and the combined organic phases are dried over Na2SO4, filtered and concentrated at reduced pressure to afford an orange solid. Purification by flash column chromatography (silica gel, EtOAc/acetic acid/water 7:1:1) affords the title compound as an orange solid (122 mg, 0.295 mmol, 73%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=11.88 (bs, 1H), 11.07 (bs, 1H), 7.91 (s, 1H), 7.38 (d, J=8.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 6.75 (d, J=6.8 Hz, 1H), 6.50 (t, J=7.5 Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 3.40-3.16 (m, 2H), 2.40 (s, 2H), 2.12 (s, 2H), 1.84 (s, 6H). MS (ES+): 414 (M(C26H23N3O3)+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:4][NH2:5].C(N(CC)CC)C.[Cl:36][CH2:37][CH2:38][CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[Cl:36][CH2:37][CH2:38][CH2:39][CH2:40][S:41]([NH:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:6][O:7][C:8](=[O:28])[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:43])=[O:42]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CN)OC
Reactant: O=S(=O)(Cl)CCCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCCl)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 1.2 g (3 mM) of 2-methoxy-3-octadecylcarbamoyloxypropylamine IVa1 in 24 ml of dichloromethane and 0.5 ml (3.6 mM) of triethylamine is added 0.75 g (3.93 mM) of 4-chlorobutanesulfonyl chloride with ice-cooling and the mixture is stirred at room temperature overnight. The product is isolated with dichloromethane extraction and dichloromethane layer is washed with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and evaporated. The residue is purified by the column chromatography on silica gel with a n-hexane-ethyl acetate (3:2) mixture as an eluent. The product is recrystallized from dichloromethane-n-hexane to give 1.28 g (2.305 mM) of 3-(4-chlorobutylsulfonylamino)-2-methoxy-1-octadecylcarbamoyloxypropane IIIa5 as colorless crystals in 77% yield.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[CH2:9]([C:17]1[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[S:20][CH:21]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:22]([C:19]1[S:20][CH:21]=[C:17]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:18]=1)(=[O:23])=[O:24]
Reactant: O=S(=O)(Cl)c1cc(CCc2ccccc2)cs1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2cc(CCc3ccccc3)cs2)c1Br
Yield: 22.6 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-4-(phenethyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 using 5-amino-4-bromo-3-methyl-isoxazole (132.75 mg, 0.75 mmole) and 4-(phenethyl)thiophene-2-sulfonyl chloride (Example 119D; 225.62 mg, 0.75 mmol). The product was purified by HPLC (5-95% acetonitrile with 0.1% TFA over 30 min.) to give N-(4-bromo-3-methyl-5-isoxazolyl)-4-(phenethyl)thiophene-2-sulfonamide as a brownish oil 72.3 mg, 32% yield.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([CH3:21])=[CH:4][N:3]=1.[CH3:22][N:23]1[CH:27]=[C:26]([NH2:28])[CH:25]=[N:24]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:21][C:5]1[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])=[N:7][C:2]([NH:28][C:26]2[CH:25]=[N:24][N:23]([CH3:22])[CH:27]=2)=[N:3][CH:4]=1
Reactant: Cn1cc(N)cn1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1C(C)C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(Nc2cnn(C)c2)nc1CCc1ccccc1C(C)C(N)=O
Yield: 59 %

Procedure:
A mixture of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)propanamide A49 (0.250 g, 0.823 mmol), 1-methyl-1H-pyrazol-4-amine (0.096 g, 0.99 mmol), and p-toluenesulfonic acid monohydrate (0.016 g, 0.082 mmol) in 1,4-dioxane (5 mL) was irradiated in the microwave at 120° C. for 3 hours. The volatiles were removed in vacuo and the residue was adsorbed onto silica and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 50-100% EtOAc in petroleum benzine 40-60° C., then 0-10% MeOH in EtOAc). The fractions containing suspected product were combined and the solvent removed in vacuo to give a green solid. The solid was adsorbed onto silica and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-10% MeOH in CHCl3) to give the title compound 51 as a white solid (0.178 g, 59%); 1H NMR (400 MHz, d6-DMSO) δ ppm 9.16 (s, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.46 (s, 1H), 7.41-7.35 (m, 1H), 7.24 (s, 1H), 7.20-7.10 (m, 3H), 6.87 (s, 1H), 3.86 (q, J=7.1, 7.0, 7.0 Hz, 1H), 3.78 (s, 3H), 3.23-3.11 (m, 1H), 3.08-2.97 (m, 1H), 2.96-2.78 (m, 2H), 2.05 (s, 3H), 1.33 (d, J=6.9 Hz, 3H). LCMS-D: rt 2.99 min; m/z 365 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:19])[C:6]2[C:11]([C:12](=[O:14])[CH:13]=1)=[CH:10][C:9]([CH2:15][CH3:16])=[C:8]([CH2:17][CH3:18])[CH:7]=2)=[N+]=[N-].S(=O)(=O)(O)O>>[C:4]([CH:13]=[C:12]1[C:11]2[C:6](=[CH:7][C:8]([CH2:17][CH3:18])=[C:9]([CH2:15][CH3:16])[CH:10]=2)[C:5](=[O:19])[O:14]1)#[N:1]
Reactant: CCc1cc2c(cc1CC)C(=O)C(N=[N+]=[N-])=CC2=O
Agent: O=S(=O)(O)O
Product: CCc1cc2c(cc1CC)C(=CC#N)OC2=O
Temperature: 0 °C
Yield: 91.7 %

Procedure:
2-Azido-6,7-diethyl-1,4-naphthoquinone (6.0 g; 0.024 mole) was added portionwise to cold (0°-5° C), stirred concentrated sulphuric acid (100 ml) over 2 hours and the red solution stirred at this temperature till no further nitrogen evolution was noticed (ca. 15 mins.). The products from two such reactions carried out simultaneously were poured into 1200 ml of ice-water and the lilac solid filtered off and washed well with water. Recrystallisation from ethanol in the presence of charcoal give the title compound 5.00 g (47%) as an off-white solid of m.p. 147°-158° C. Further recrystallisation gave a white sample of m.p. 159°-168° C. shown by nmr to be a mixture of E and Z isomers. (Found; C, 73.70; H, 5.95; N, 5.94; C14H13NO2 requires; C, 73.99; H, 5.77; N, 6.16%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]([CH2:13][OH:14])[CH2:11][CH2:10][CH:9]1[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:26]I.O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]([CH2:13][O:14][CH3:26])[CH2:11][CH2:10][CH:9]1[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCC1CCC(CO)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCC1CCC(CO[Si](C)(C)C(C)(C)C)N1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzyl-2-t-butyldimethylsilyloxymethyl-5-hydroxymethylpyrrolidine (10 g) in tetrahydrofuran (100 ml) was added portionwise sodium hydride (2.3 g) at 0° C. The mixture was stirred at the same temperature for 30 minutes. And then methyl iodide was added to the mixture. After stirring for an hour at room temperature, water and ethyl acetate was added thereto. The aqueous layer was separated and washed twice with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate, water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure to give 1-benzyl-2-t-butyldimethylsilyloxymethyl-5-methoxymethylpyrrolidine (9.99 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:21])[CH:8]=2)[O:3]1.[CH:23](O)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH:11]([OH:12])[CH:10]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([OH:20])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:21][CH:23]=[O:24])[CH:8]=2)[O:3]1
Reactant: O=CO
Reactant: CC1(C)Oc2ccc(N)cc2C(Oc2ccnc(O)c2)C1O
Solvent: c1ccncc1
Product: CC1(C)Oc2ccc(NC=O)cc2C(Oc2ccnc(O)c2)C1O

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-amino-3-chromanol in 15 ml of HCOOH and 1 ml of pyridine is boiled for 19 hours and evaporated. After customary working up, 2,2-dimethyl-4-(2-hydroxy-4-pyridyloxy)-6-formamido-3-chromanol is obtained.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].CC(C)([O-])C.[Na+].Cl[C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].Cl.C>C(OCC)(=O)C.O.CN(C=O)C>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccccc1Cl
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccccc1OCC(F)(F)F
Temperature: 120 °C
Reaction time: 5 h
Yield: 87.9 %

Procedure:
To a solution of 2,2,2-trifluoroethanol (40.0 g) and DMF (100 ml) was added sodium tert-butoxide (23.0 g) at 0° C. The solution was stirred at 20 to 25° C. for 1 hour at which point 2-chlorobenzoic acid (25.0 g) was added followed by cupric bromide (2.0 g). The mixture was stirred at 120° C. for 5 hours, cooled to 10° C., and water (30 ml) was added followed by 20% HCl solution (90 ml). The solution was extracted with dichloromethane (3×50 ml). The combined organic layers were washed with water (3×50 ml) and the volume was concentrated to 90 ml. Hexane (150 ml) was added to the residues, and the mixture was concentrated to volume of 120 ml and a further portion of hexane (30 ml) was added. The mixture was heated at 50° C. for 30 minutes and then stirred at room temperature for 1 hour. The solids were filtered to yield the crude product. This material was dissolved in ethyl acetate (50 ml), charcoal (1.7 g) was added and the mixture was stirred at room temperature a further 2 hours. The solution was filtered through Celite™ and crystallized from ethyl acetate/hexane to yield the pure product (30.9 g, yield 88.0%) as a white solid, m.p. 85–86° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:11](#N)[CH2:12]CCCC#N.[CH2:19](O)[CH3:20].C(C(CCC)C(OCC)=O)#N>>[C:1]([O:10][CH2:19][CH3:20])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:11][CH3:12])=[O:7]
Reactant: CCO
Reactant: N#CCCCCC#N
Reactant: O=C(O)CCCCC(=O)O
Agent: CCCC(C#N)C(=O)OCC
Product: CCOC(=O)CCCCC(=O)OCC
Temperature: 240 °C
Reaction time: 3 h
Yield: 3.1 %

Procedure:
Then, 29.1 g (0.199 mole) of adipic acid and 21.0 g (0.194 mole) of adiponitrile were added to the liquid distillation residue, and the resulting mixture was introduced into a 1-liter, stainless autoclave. after purging with nitrogen, the content was stirred at 240° C. for 3 hours. After cooling the reaction mixture, 138.0 g (3.000 moles) of ethanol was added and the resulting mixture was stirred at 190° C. for 3 hours. As a result of analysis, it was confirmed that 60.3 g (0.389 mole) of ethyl cyanovalerate and 1.2 g (0.006 mole) of diethyl adipate were formed.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])(CC)C.Br[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH:13]1[CH2:35][C:36]1[CH:45]=[CH:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Reactant: BrCc1ccc2ccccc2c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1Cc1ccc2ccccc2c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of 4-benzyl-piperazine-1-carboxylic acid tert-butyl ester (2 g) in diethylether (35 mL) was added tetramethylethylenediamine (1.4 mL). The resulting mixture was cooled to −70° C. and sec-butyllithium (7 mL of a 1.3 M solution) was added dropwise, after complete addition the solution was slowly warmed to −10° C., at which temperature the mixture was stirred for one hour. Subsequently, the mixture was recooled to −70° C.; then a solution of 2-(bromomethyl)naphthalene (2 g) in diethylether was added dropwise and stirring continued at −70° C. was continued for one hour. The resulting mixture was stirred and allowed to come to room temperature overnight, then partitioned between saturated ammonium chloride (aq) and ethyl acetate. The organic layer was dried over magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 99/1) to afford 4-benzyl-2-(naphthalen-2-ylmethyl)piperazine-1-carboxylic acid tert-butyl ester as an oil. 0.8 g (27 %) Rf 0.47 (CH2Cl2/MeOH 99/1), MH+ 417.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([S:17](Cl)(=[O:19])=[O:18])=[CH:10][CH:9]=1.Cl.[NH2:22][C@H:23]([C@H:26]1[O:30][C:29](=[O:31])[C@H:28]([CH2:32][CH2:33][CH3:34])[CH2:27]1)[CH2:24][OH:25].O1CCCC1>O>[OH:25][CH2:24][C@H:23]([NH:22][S:17]([C:11]1[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=1[N+:14]([O-:16])=[O:15])(=[O:19])=[O:18])[C@@H:26]1[CH2:27][C@@H:28]([CH2:32][CH2:33][CH3:34])[C:29](=[O:31])[O:30]1
Reactant: CCC[C@@H]1C[C@@H]([C@@H](N)CO)OC1=O
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCC[C@@H]1C[C@@H]([C@H](CO)NS(=O)(=O)c2ccccc2[N+](=O)[O-])OC1=O
Reaction time: 2 h
Yield: 52 %

Procedure:
23.9 g of triethylamine (237 mmol) and 26.7 g of O-nitrobenzenesulfonyl chloride (120 mmol) were added to a solution of (3R,5S)-5-[(S)-1-amino-2-hydroxyethyl]-3-propyldihydrofuran-2-one hydrochloride obtained in the above reaction in a mixed solvent of tetrahydrofuran (350 ml) and water (35.0 ml) at 0° C. The mixture was stirred at the same temperature for two hours and further stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure and 500 ml of water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with water, a saturated sodium bicarbonate aqueous solution and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:ethyl acetate). Further, 30 ml of diisopropyl ether and 30 ml of ethyl acetate were added, and the precipitated solid was collected by filtration to obtain 14.6 g of the title compound (total yield over two steps: 52%).