Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[CH3:5][N:6]([C:16]1[C:17]([N+:34]([O-])=O)=[C:18]([CH2:26][C:27](=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=1)[CH2:7][CH2:8][O:9]C1CCCCO1.Cl.N>C1(C)C=CC=CC=1.[Fe].C(OCC)(=O)C.O1CCCC1>[CH3:5][N:6]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]2[C:17]=1[NH:34][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26]2)[CH2:7][CH2:8][OH:9]
Reactant: CCOC(=O)C(=O)Cc1c(C(F)(F)F)ccc(N(C)CCOC2CCCCO2)c1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(N(C)CCO)c2[nH]1
Temperature: 70 °C

Procedure:
A mixture of iron powder (2.42 g, 43.3 mmol) and acetic acid (40 ml) was stirred at 70° C. Then, a solution of ethyl [3-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl)oxyethyl]amino]-2-nitro-6-trifluoromethylphenyl]pyruvate (2.00 g, 4.33 mmol) in toluene (20 ml) was added dropwise to the aforesaid mixture, followed by stirring at 78-83° C. for 2 hours. The reaction mixture was cooled to 30° C., after which 2N hydrochloric acid (20 ml) and tetrahydrofuran (20 ml) were added and the resulting mixture was stirred at room temperature for 2.5 hours. Subsequently, the reaction mixture was poured into an aqueous ammonia solution and ethyl acetate (300 ml) was added and then stirred. After being separated, the aqueous layer was extracted with ethyl acetate (200 ml) and the combined organic layer was washed with a 5% aqueous sodium chloride solution and then a 5% aqueous sodium hydrogencarbonate solution. The washed organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to obtain ethyl 7-[N-methyl-N-(2-hydroxyethyl)amino]-4-trifluoromethyl-1H-indole-2-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccccc2F)nc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 94.4 %

Procedure:
A mixture of 6-Chloro-nicotinonitrile (7.26 g, 52.4 mmol) and 2-fluorophenyl boronic acid (11 g, 78.6 mmol) and Na2CO3 (11 g, 103 mmol) in toluene (200 mL) and water (10 mL) is degassed and filled with nitrogen for three times, then Pd(PPh3)4 (0.73 g) is added under nitrogen. The reaction mixture is heated at 90° C. After 12 hrs, the reaction mixture is cooled to room temperature, diluted with ethyl acetate, washed with water, dried, concentrated. Column chromatography on silica gel (Hexane/ethyl acetate as eluent) gave 9.8 g of 6-(2-Fluoro-phenyl)-nicotinonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH:34]2[CH2:39][CH2:38][S:37](=[O:40])[CH2:36][CH2:35]2)=[O:32])=[CH:5][CH:4]=1)#[N:2].C1(C)C=C(C)C=C(C)C=1S(O[NH2:53])(=O)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[N:12]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[C:11](=[O:30])[N:10]2[C:31]([NH:33][CH:34]2[CH2:39][CH2:38][S:37](=[NH:53])(=[O:40])[CH2:36][CH2:35]2)=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=O)CC2)cc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCS(=N)(=O)CC2)cc1
Temperature: 25 °C

Procedure:
4-(4-Cyanophenyl)-2,5-dioxo-N-(1-oxo-hexahydro-1λ4-thiopyran-4-yl)-1-(3-(trifluoromethyl)phenyl)-1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxamide (example 71, 67 mg, 0.12 mmol) is added to a solution of O-mesitylenesulfonylhydroxylamine (25 mg, 0.12 mmol) in dichloromethane (1.0 mL), and the mixture is stirred at room temperature over night. All volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 18 mg; ESI mass spectrum [M+H]+=586; Retention time HPLC: 0.92 min (Z018_S04).
Reaction SMILES: Cl[S:2]([C:5]1[C:9]2[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]=1)(=[O:4])=[O:3].[CH2:27]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])[CH3:28]>>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:10]2[C:9]3[C:5]([S:2]([NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[C:29]([CH2:27][CH3:28])[CH:30]=4)(=[O:4])=[O:3])=[CH:6][S:7][C:8]=3[CH:13]=[CH:12][N:11]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3scc(S(=O)(=O)Cl)c23)CC1
Product: CCc1cccc(NS(=O)(=O)c2csc3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c23)c1
Yield: 76.5 %

Procedure:
Prepared from tert-butyl 4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate (90.0 mg, 0.215 mmol) and 3-ethylaniline (33.9 mg, 0.28 mmol) to give the title compound as an off-white solid (82.7 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 1.03 (t, J=7.5 Hz, 3H), 1.48 (s, 9H), 2.47 (q, J=7.7 Hz, 2H), 3.00-3.53 (m, 6H), 4.02-4.44 (m, 2H), 6.66 (d, J=8.0 Hz, 1H), 6.75 (s, 1H), 6.66 (d, J=8.0 Hz, 1H), 7.02 (t, J=7.8 Hz, 1H), 7.67 (d, J=5.5 Hz, 1H), 8.24 (s, 1H), 8.39 (d, J=5.5 Hz, 1H), 9.80 (s, 1H). MS (ESI+) m/z 503.2 (M+H)+. HPLC 97%, RT: 3.93 min (5-99% MeCN over 3 min).
Reaction SMILES: Cl.Cl.[C:3]1([CH2:9][N:10]2[CH2:16][CH2:15][NH:14][NH:13][CH2:12][CH2:11]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C(N(CC)C(C)C)(C)C>CN(C)C=O>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:14]1[CH2:15][CH2:16][N:10]([CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:11][CH2:12][NH:13]1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: c1ccc(CN2CCNNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccccc1N1CCN(Cc2ccccc2)CCN1

Procedure:
A mixture of hexahydro-5-(phenylmethyl)-1H-1,2,5-triazepine dihydrochloride (35.0 g), 1-fluoro-2-nitrobenzene (21 ml), N,N-diisopropylethylamine (81 ml) in N,N-dimethylformamide (400 ml) was stirred and heated at 75°-80° (under reflux) under ntirogen for 5 hours. The solution was evaporated to a syrup under oil pump vacuum and the residue was mixed with chloroform and dilute sodium hydroxide. The aqueous phase was extracted several times with chloroform. The combined extracts were dried (MgSO4) and evaporated to a syrup wich was subjected to an oil pump vacuum. The syrup in toluene was applied to a column (94×8.7 cm) of dry column grade neutral alumina prepacked in toluene. Elution with toluene removed a faster moving yellow impurity. Fractions were monitored by t.l.c. on Alox-25 uv254 plates (Brinkmann) with chloroform as developer. As soon as the major component started to issue the eluting solvent was changed to toluene-chloroform (4:1), toluene-chloroform (1:1) and finally chloroform. Appropriate fractions were evaporated to a syrup which was crystallized from ether-heptane; wt. 35.7 g (86%), mp=90°-92°. Recrystallization from chloroform-ether-heptane gave pure titled product, mp=90°-92°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(N(CC)CC)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[O:1]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCc2c(O)cccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 4-hydroxy-1-indanone (25.0 g, 169 mmol) in DMF (500 ml) was triethylamine (22.2 g, 220 mmol) added, to the resulting solution was tert-butyldimethylchlorosilane (28.0 g, 186 mmol) added. The reaction mixture was stirred overnight at room temperature and treated with water (500 ml) and extracted with diethyl ether (500 ml). The organic phase was collected and dried over sodium sulfate. Evaporation gave a yellow oil which was distilled under reduced pressure to give the indanone (36.68 g, 140 mmol, 82.7%) as a colourless oil (120–121° C./0.1 mbar).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[NH:17][C:16]2=[O:25])[CH2:11][CH2:10]1)=[O:5].[C:31](OC(=O)C)(=[O:33])[CH3:32].[OH-].[NH4+]>O>[C:31]([NH:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=3[NH:17][C:16]2=[O:25])[CH2:11][CH2:10]1)=[O:5])(=[O:33])[CH3:32]
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 0.8 parts of 2-amino-N-{2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1yl)-1-piperidinyl]ethyl}-4-fluorobenzamide, 1 part of acetic acid anhydride and 10 parts of water is stirred for 30 minutes in a water-bath at 80°-90° C. The reaction mixture is cooled, alkalized with ammonium hydroxide and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated, yielding 0.5 parts of 2-(acetylamino)-N-{2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-4-fluorobenzamide; mp. 196.5° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.Cl[C:23]([O:25][CH3:26])=[O:24]>C(N(CC)CC)C>[CH3:26][O:25][C:23]([N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([O:7][CH2:6][C:5]3[CH:19]=[CH:20][CH:21]=[C:3]([F:2])[CH:4]=3)[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1)=[O:24]
Reactant: COC(=O)Cl
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 95 %

Procedure:
The title compound was prepared in analogy to Example 1d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and methyl chloroformate with triethylamine as the base. Yield: 95% of theory as a colourless oil; MS: m/e=330 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O-:16])=[O:15])[C@H:11]([CH2:17][C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC(O[CH2:28][CH:29]=[CH2:30])=O.[OH-].[Na+].C(OCC)(=O)C>O1CCCC1.O>[CH2:30]([O:15][C:14]([N:12]1[CH2:13][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:10][C@H:11]1[CH2:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1)=[O:16])[CH:29]=[CH2:28]
Reactant: Cn1ccnc1C[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)[O-]
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1nccn1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2R,4R)-4-(t-butyldimethylsilyloxy)-2-{(1-methylimidazol-2-yl)methyl}pyrrolidineformate (20.0 g) in tetrahydrofuran (300 ml) and water (200 ml) was added dropwise a solution of allyl chloroformate (7.45 ml) in THF (20 ml), adjusting pH to 9.0~9.5 with 5N-aqueous sodium hydroxide solution, at -3°~1° C. over 10 minutes. The mixture was stirred at the same temperature for 50 minutes. To the reaction mixture was added ethyl acetate (600 ml) and ice water (400 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-{(1-methylimidazol-2-yl) methyl}pyrrolidine (20.5 g) as an oil.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].CN1C(=O)N(C)CCC1.[F:16][C:17]1([K])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]1[F:23].O>C1COCC1>[CH2:1]([C:19]1[C:18]([F:23])=[C:17]([F:16])[CH:22]=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: FC1C=CC=CC1(F)[K]
Reactant: CCCCCBr
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: CCCCCc1cccc(F)c1F
Reaction time: 1 h

Procedure:
0.1 mol of pentyl bromide and subsequently 13 ml of DMPU are added dropwise to the solution of 1,2-difluorophenyl potassium in THF prepared according to 1c). After stirring below -85° C. for 60 minutes, the mixture is warmed in the course of 30 minutes to -40° C. and water is added at this temperature. The mixture is subsequently worked up as customary. b.p.30: 112 ° C. The following are prepared analogously:
Reaction SMILES: [C:1]([CH:3]([C:13]1[N:14]([CH2:27][CH3:28])[C:15](=[O:26])[N:16](COC)[C:17](=[O:22])[C:18]=1[CH:19]([CH3:21])[CH3:20])[C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8])#[N:2].CSSC>ClCCl>[C:1]([CH:3]([C:13]1[N:14]([CH2:27][CH3:28])[C:15](=[O:26])[NH:16][C:17](=[O:22])[C:18]=1[CH:19]([CH3:21])[CH3:20])[C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH3:12])[CH:11]=1)[C:7]#[N:8])#[N:2]
Reactant: CCn1c(C(C#N)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)n(COC)c1=O
Solvent: CSSC
Solvent: ClCCl
Product: CCn1c(C(C#N)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 72 h
Yield: 89.2 %

Procedure:
To a stirred solution of 3-[cyano-(3-ethyl-5-isopropyl-1-methoxymethyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-methyl]-5-methyl-benzonitrile (190 mg, 0.5 mmol) in dichloromethane (5 mL) at room temperature, were added dimethyl disulfide (804 μL, 10 mmol) and boron trifluoride-diethyl etherate (300 μL, 2.37 mmol). After stirring for 3 days, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:1)) to give 150 mg (89%) of 3-[cyano-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yl)-methyl]-5-methyl-benzonitrile as a white solid. The product was recrystallized from chloroform-methanol-ether. m.p. 260-261° C.; 1H-NMR (200 MHz, DMSO-d6) δ 0.77 (3H, d, J=6.6 Hz), 1.07 (3H, t, J=7.0 Hz), 1.19 (3H, d, J=6.6 Hz), 2.41 (3H, s), 2.49 (1H, m), 3.68 (1H, m), 4.00 (1H, m), 6.22 (1H, s), 7.59 (1H, s), 7.71 (1H, s), 7.73 (1H, s), 11.45 (1H, s); m/z (EI) 336 (M+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1.[SH:19][CH2:20][C:21]([CH2:25][SH:26])([CH2:23][SH:24])[CH3:22].[H-].[Na+].O>CN(C)C=O>[SH:19][CH2:20][C:21]([CH2:25][SH:26])([CH3:22])[CH2:23][S:24][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[C:9]([CH3:17])([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(CS)(CS)CS
Reactant: CC(C)(C(=O)c1ccc(F)cc1)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(CS)(CS)CSc1ccc(C(=O)C(C)(C)N2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.6 g (14.3 mmol) of 1-(4-fluorophenyl)-2-methyl-2-morpholin-4-yl-propan-1-one and 12 g (71.3 mmol) of 1,1,1-trismercaptomethylethane are dissolved in 70 ml of dry dimethylformamide, and 28.6 mmol of sodium hydride are added. The solution is stirred at room temperature for 2 h. Then the solution is poured into water. The crude product is extracted with methylene chloride, washed with water, dried over MgSO4, and concentrated. The residue is purified by column chromatography on silica gel with methylene chloride as an eluent. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm] 1.12 (s, 3H), 1.30 (t, 2H), 1.31 (s, 6H), 2.57 (t, 4H), 2.62-2.72 (m, 4H), 3.14 (s, 2H), 3.69 (t, 4H), 7.33 (d, 2H), 8.49 (d, 2H).
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@:8]2([O:10][CH2:9]2)[C@H:7](/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:6][CH2:5][C@@H:4]1[CH3:20].[CH:21]1[N-:25][CH:24]=[N:23][CH:22]=1.[Na+]>CN(C)C=O.O>[N:23]1([CH2:9][C@:8]2([OH:10])[C@@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[CH2:5][O:6][C@H:7]2/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:22]=[CH:21][N:25]=[CH:24]1
Reactant: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@@]12CO2
Reactant: c1c[n-]cn1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCC/C=C/[C@@H]1OC[C@H](C)[C@H](OC)[C@@]1(O)Cn1ccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.7 %

Procedure:
A mixture of (3S,4S,7S,8S)-8-methoxy-7-methyl-4-[(E)-1-nonenyl]-1,5-dioxaspiro[2,5]octane (4.2 mg) and imidazole sodium derivative (14.0 mg) in dry N,N-dimethylformamide(0.5 ml) was stirred for 15 hours at room temperature. The reaction mixture was diluted with water. The mixture was extracted with dietyl ether, the combined ethereal extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by preparative thin layer chromatography (ethyl acetate as an eluent) gave (2S,3S,4S,5S)-3-(1H-imidazol-1-ylmethyl)-4-methoxy-5-methyl-2-[(E)-1-nonenyl]tetrahydro-2H-pyran-3-ol (4.1 mg, y. 79%) as colorless oil; EI-MS: m/z 351 (M+); 1H-NMR (CDCl3)d: 0.88 (3H,t,J=8 Hz), 1.10 (3H,d,J=7 Hz), 1.2-1.5 (10H,m), 2.1 (3H,m), 2.39 (1H,br.s, --OH), 2.93 (1H,d,J=5 Hz), 3.39 (3H,s), 3.40 (1H, dd, J=3 & 12 Hz), 3.61 (1H,d,J=8 Hz), 3.76 (1H,dd,J=4 & 12 Hz), 3.96 (1H,d,J=14 Hz), 4.13 (1H,d,J=14 Hz), 5.87 (2H,m), 6.91 (1H, s), 7.14 (1H,s), 7.46 (1H,s).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([CH3:27])=[CH:6][CH:7]=[CH:8][C:9]([CH3:26])=[CH:10][CH:11]=[CH:12][CH:13]=[C:14]([CH3:25])[CH:15]=[CH:16][CH:17]=[C:18]([CH3:24])[C:19](OCC)=[O:20])C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[OH-].[Na+]>C(Cl)Cl.O>[CH3:24][C:18](=[CH:17][CH:16]=[CH:15][C:14]([CH3:25])=[CH:13][CH:12]=[CH:11][CH:10]=[C:9]([CH3:26])[CH:8]=[CH:7][CH:6]=[C:5]([CH3:27])[CH2:4][OH:3])[CH2:19][OH:20]
Reactant: CCOC(=O)C(C)=CC=CC(C)=CC=CC=C(C)C=CC=C(C)C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C=CC=C(C)CO)=CC=CC=C(C)C=CC=C(C)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of 2,6,11,15-tetramethyl-hexadeca-2,4,6,8,10,12,14-heptaenedioic acid diethyl ester (200 g, 0.52 mol) in 3000 mL of DCM was added dropwise a solution of diisobutylaluminum hydride in toluene (1.5 M, 1533 mL, 2.30 mol) at −78° C. The mixture was stirring at 0° C. for 2 h. 100 mL of water was added the 200 ml of 2N NaOH was added to quench the reaction. The suspension was filtered off and solid was washed by a large amount of THF. The combined organic layer were dried over Na2SO4 and evaporated to give 133.16 g (85%) brown solid. 1H NMR (300 Hz, CDCl3) δ 6.41 (m, 10H, CH), 4.16 (s, 4H, CH2), 1.95 (m, 12H, CH3)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21](Br)=[N:20][C:19]([Br:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:11][C:12]1[C:21]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:20][C:19]([Br:23])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1cc(Br)nc(Br)c1N
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)nc(-c2ccc(Cl)cc2)c1N
Temperature: 93 °C
Yield: 300 %

Procedure:
A mixture of 4-chlorophenylboronic acid (3.03 g, 19.4 mmol), methyl 3-amino-2,6-dibromoisonicotinate (5.0 g, 16 1 mmol), tetrakistriphenylphosphine palladium (0) (1.12 g, 0.968 mmol), sodium carbonate (4.10 g, 38 7 mmol) was flushed with nitrogen, toluene (40 mL), and MeOH (13 mL) were added and the reaction was heated in a 93° C. for 30 hr. This was partitioned between EtOAc and water and the organic phase was washed with brine, dried with sodium sulfate, and the solvent removed. Silica gel chromatography (step gradient elution with DCM containing 75 to 0% hexane) afforded methyl 3-amino-6-bromo-2-(4-chlorophenyl)isonicotinate (3.86 g, 11 3 mmol, 70% yield) as a yellow fluffy solid. MS (ESI) m/z 343.02 (M+H). 1 H NMR (500 MHz, chloroform-d) δ ppm 7.81 (1H, s), 7.54-7.60 (2H, m), 7.43-7.49 (2H, m), 5.91 (2H, br.s.), 3.93 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([O:21][CH2:22][O:23][CH3:24])=[CH:9][CH:8]=[CH:7]1.C(N(CC)CC)C.[Cr](Cl)([O-])(=O)=[O:33].[NH+]1C=CC=CC=1>CS(C)=O.ClCCl.F[B-](F)(F)F.[Ag+]>[CH:2]([C:3]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([O:21][CH2:22][O:23][CH3:24])=[CH:9][CH:8]=[CH:7]1)=[O:33]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: COCOc1cc(CBr)c2nc3cccc(OCOC)c3nc2c1
Agent: [Ag+]
Agent: F[B-](F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: COCOc1cc(C=O)c2nc3cccc(OCOC)c3nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 205 %

Procedure:
To a solution of silver fluoroborate (359 mg, 1.86 mM) in anhydrous dimethylsulfoxide (15 ml) was added 6-bromomethyl-1,8-di(methoxymethoxy)phenazine (600 mg, 1.53 mM) and the resulting suspension was stirred overnight at room temperature under an argon atmosphere. It was then treated with triethylamine (0.5 ml) and the stirring continued for 30 more minutes. The reaction was diluted with dichloromethane and filtered through Celite. The filtrate was thoroughly washed with water, brine and dried over anhydrous magnesium sulfate. Evaporation under reduced pressure provided yellow solid which was taken up in dry dichloromethane (5 ml) and added to a solution of pyridinium chlorochromate (130 mg, 0.6 mM) in the same solvent (2 ml). After stirring for 3 hours, the reaction was worked up in a standard fashion (ether quench) to give orange solid. Purification by flash chromatography on silica gel (Whatman LPS-1) using chloroform as eluent gave the title compound (406 mg) as yellow needles, melting point 148°-150° C. from chloroform-ether.