Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16].N1C=CC=CC=1>C(Cl)Cl>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]([NH:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[O:16])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 16 h
Yield: 121.4 %

Procedure:
tert-Butyl 3-(aminomethyl)azetidine-1-carboxylate (1.10 g, 5.91 mmol) was dissolved in methylene chloride (50 mL). Thereafter, 4-nitrophenyl chloroformate (1.19 g, 5.91 mmol) and pyridine (0.47 g, 5.91 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred for 16 hours. Thereafter, the reaction solution was concentrated in vacuo to obtain tert-butyl 3-((((4-nitrophenoxy)carbonyl)amino)methyl)azetidine-1-carboxylate (2.52 g, >100%) in the form of a white solid.
Reaction SMILES: CCCCCCCCCCCCCCCC([O:18][C@@H:19]1[CH2:24][C:23]([CH3:25])=[C:22](/[CH:26]=[CH:27]/[C:28](/[CH3:74])=[CH:29]/[CH:30]=[CH:31]/[C:32](/[CH3:73])=[CH:33]/[CH:34]=[CH:35]/[CH:36]=[C:37](\[CH3:72])/[CH:38]=[CH:39]/[CH:40]=[C:41](\[CH3:71])/[CH:42]=[CH:43]/[C:44]2[C:49]([CH3:51])([CH3:50])[CH2:48][C@H:47]([O:52]C(CCCCCCCCCCCCCCC)=O)[CH2:46][C:45]=2[CH3:70])[C:21]([CH3:76])([CH3:75])[CH2:20]1)=O>O>[CH3:70][C:45]1[CH2:46][C@@H:47]([OH:52])[CH2:48][C:49]([CH3:50])([CH3:51])[C:44]=1/[CH:43]=[CH:42]/[C:41](/[CH3:71])=[CH:40]/[CH:39]=[CH:38]/[C:37](/[CH3:72])=[CH:36]/[CH:35]=[CH:34]/[CH:33]=[C:32](\[CH3:73])/[CH:31]=[CH:30]/[CH:29]=[C:28](\[CH3:74])/[CH:27]=[CH:26]/[C:22]1[C:21]([CH3:76])([CH3:75])[CH2:20][C@H:19]([OH:18])[CH2:24][C:23]=1[CH3:25]
Reactant: CCCCCCCCCCCCCCCC(=O)O[C@@H]1CC(C)=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C[C@@H](OC(=O)CCCCCCCCCCCCCCC)CC2(C)C)C(C)(C)C1
Solvent: O
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1
Reaction time: 0.05 h

Procedure:
100 g of berries were hydrated and milled with 1000 g hot water (80-100° C.). Paste was centrifuged 3 min at 3000 Rpm. Settling with 5-71 Bx and moisture less that 82% was extracted 3 times with 400 g ethyl acetate at a temperature of 60° C. The extracts were combined, filtered and evaporated under reduced pressure to apparent dryness to form an organic solvent-free homogenous oleoresin containing zeaxanthin dipalmitate for saponification. Zeaxanthin dipalmitate concentration in oleoresin 13-15%.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[N:8]([N:12]=[C:13]([NH2:15])[N:14]=3)[CH:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.Cl[C:17]1[CH:25]=[C:24]2[C:20]([C:21]([CH3:28])([CH3:27])[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>>[CH3:27][C:21]1([CH3:28])[C:20]2[C:24](=[CH:25][C:17]([NH:15][C:13]3[N:14]=[C:7]4[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)=[N:11][CH:10]=[CH:9][N:8]4[N:12]=3)=[CH:18][CH:19]=2)[NH:23][C:22]1=[O:26]
Reactant: Nc1nc2c(-c3cn[nH]c3)nccn2n1
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Product: CC1(C)C(=O)Nc2cc(Nc3nc4c(-c5cn[nH]c5)nccn4n3)ccc21

Procedure:
8-(1H-Pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine synthesized as descried earlier, is reacted with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one under Buchwald Hartwig conditions using general procedure 2.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16].Cl[C:20]([S:22]Cl)=[O:21]>>[OH:1][C:2]1[C:10]([C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:9][C:5]([C:6]2[O:7][C:20](=[O:21])[S:22][N:8]=2)=[CH:4][C:3]=1[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(Cl)SCl
Reactant: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(-c2nsc(=O)o2)cc(C(C)(C)C)c1O

Procedure:
The procedure of Example 1 is repeated using 3.03 grams of 4-hydroxy-3,5-di-tert-butylbenzamide and 3.18 grams of chlorocarbonylsulfenyl choride. Recrystallization from toluene:heptane (1:1) affords the title compound as a white crystalline solid: mp 155°-157° C. (dec.).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[C:5]1(=[O:12])[O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>O>[OH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([NH:3][CH2:2][CH2:1][NH:4][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:12])=[O:11])=[O:12]
Reactant: NCCN
Reactant: O=C1CCCCCO1
Solvent: O
Product: O=C(CCCCCO)NCCNC(=O)CCCCCO
Temperature: 20 °C
Reaction time: 15 h

Procedure:
C2C monomer is prepared by reacting 1.2 kg ethylene diamine (EDA) with 4.56 kg of ε-caprolactone under a nitrogen blanket in a stainless steel reactor equipped with an agitator and a cooling water jacket. An exothermic condensation reaction between the ε-caprolactone and the EDA occurs which causes the temperature to rise gradually to 80 degrees Celsius (° C.). A white deposit forms and the reactor contents solidify, at which point the stirring is stopped. The reactor contents are then cooled to 20° C. and are then allowed to rest for 15 hours. The reactor contents are then heated to 140° C. at which temperature the solidified reactor contents melt. The liquid product is then discharged from the reactor into a collecting tray. A nuclear magnetic resonance study of the resulting product shows that the molar concentration of C2C in the product exceeds 80 percent. The melting point of the C2C product is determined to be 140° C.
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[CH2:13]([O:15][CH:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH:35][CH3:36])[CH:29]=2)=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])[CH3:14].C(N(CC)CC)C>ClCCl>[C:8]([O:7][C:1]([CH2:36][NH:35][CH2:34][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][CH:16]([O:15][CH2:13][CH3:14])[C:17]([O:19][CH3:20])=[O:18])=[CH:23][CH:24]=2)[CH:33]=[CH:32][CH:31]=1)=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CCOC(Cc1ccc(-c2cccc(CNC)c2)cc1)C(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(Cc1ccc(-c2cccc(CNCC(=O)OC(C)(C)C)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
A solution of 0.4 g (1.9 mmol) of di-tert-butyl carbonate in 5 ml of dichloromethane is added dropwise to a solution of 0.6 g (1.9 mmol) of methyl 2-ethoxy-3-(3′-methylaminomethylbiphenyl-4-yl)propionate and 0.25 ml (1.9 mmol) of triethylamine in 10 ml of dichloromethane. After stirring at room temperature for 48 hours, the medium is washed with water, extracted with dichloromethane, dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained is purified by chromatography on a column of silica eluted with a 9/1 heptane/ethyl acetate mixture. 0.78 g of methyl 3-{3′-[(tert-butoxycarbonylmethylamino)methyl]biphenyl-4-yl}-2-ethoxypropionate is obtained in a yield of 85%.
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[C:30]([CH2:31][NH:32]C(OC(C)(C)C)=O)=[N:29][N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:32][CH2:31][C:30]1[N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:27]=[N:28][N:29]=1
Reactant: CC(C)(C)OC(=O)NCc1nnnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)N1S(=O)(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nnnc1CN)c1csc(N)n1)C(=O)O
Yield: 27.9 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(((tert-butoxycarbonyl)amino)methyl)-1H-tetrazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (100 mg, 0.126 mmol), DCM (1.26 mL) and TFA (584 μL, 7.58 mmol) for 1.5 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (18.7 mg, 28%) as a white powder. LCMS: Rt=0.31 min, m/z=533.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=8.8 Hz, 1H), 7.28 (s, 2H), 6.79 (s, 1H), 5.35 (dd, J=8.8, 5.8 Hz, 1H), 4.79-4.61 (m, 2H), 4.59-4.53 (m, 1H), 4.47-4.35 (m, 2H), 1.36 (br s, 6H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:28][CH3:29])[C:11]2[C:6](=[CH:7][C:8]([N+:23]([O-])=O)=[C:9]([NH:12][C:13](=O)[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:10]=2)[N:5]([CH3:26])[C:4]1=[O:27])[CH3:2]>[Ni]>[CH2:1]([C:3]1([CH2:28][CH3:29])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[N:23][C:8]3=[CH:7][C:6]=2[N:5]([CH3:26])[C:4]1=[O:27])[CH3:2]
Reactant: CCC1(CC)C(=O)N(C)c2cc([N+](=O)[O-])c(NC(=O)c3ccc(OC)cc3)cc21
Agent: [Ni]
Product: CCC1(CC)C(=O)N(C)c2cc3nc(-c4ccc(OC)cc4)[nH]c3cc21

Procedure:
7,7-Diethyl-2-(4-methoxy-phenyl)-5-methyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one is prepared from N-(3,3-diethyl-1-methyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methoxy-benzamide (250 mg) by hydrogenation at 70° C. as described in Example 1b using Raney nickel (70 mg) as catalyst. The crude material is purified by flash chromatography on silica gel eluted with light petroleum/EtOAc (1:2) to give the compound (95 mg).
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCCCCCC.[Li]CCCC.CCCCCC.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C1COCC1>[C:30]([C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: Cc1cccc(C(=O)O)c1Br
Reactant: CC(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)O)c1C(=O)C(C)C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
The solution of 2-bromo-3-methyl-benzoic acid (1.5 g, 6.98 mmol) in 10 mL THF is treated with 1M Bu2Mg/heptane at −15° C. under argon. After stirring for 30 min, 1.6M n-BuLi/hexane is added dropwise at −15° C. and the mixture is left for 1 hr. Then isobutyryl chloride (2.95 ml, 27.9 mmol) is added dropwise. After another 30 min stirring, the reaction is quenched with 2N HCl aqueous solution (2 ml). After concentration, the residue is purified by HPLC to give a pure product (227) as white solid (840 mg, 58%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18].Cl>C(=S)=S>[C:17]([C:4]1[CH:5]=[CH:6][C:1]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:2][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCOC(=O)Cc1ccc(C(C)=O)cc1
Yield: 21.9 %

Procedure:
To a solution of ethyl 2-phenylacetate (A-1) (50.9 g, 305 mmol) in CS2 (220 mL) was added AlCl3 (93.6 g, 702 mmol) at 0˜10° C. over 10 min. After addition, acetyl chloride (30.5 mL, 427 mmol) was added at 0˜10° C. over 10 min. After addition, the reaction mixture was slowly heated to reflux overnight, then poured into ice-cooled 5N HCl solution (600 mL), extracted with EA (200 mL×3). The combined organic phase was washed with water (200 mL), sat. NaHCO3 (200 mL) and brine (200 mL), dried over Na2SO4, concentrated to afford a brown oil. Recrystallized with PE/acetone (150 mL/20 mL) in refrigerator to afford A-2 as a yellow crystal solid (13.8 g, 19%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]#[N:12])=[CH:9][N:8]=[C:7](SC)[N:6]=1)[CH2:2][CH3:3].C1C=C(Cl)C=C(C(OO)=O)C=1.ClCCl.C(=O)([O-])O.[Na+].[N:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.C(Cl)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.ClCCl>[C:11]([C:10]1[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7]([NH:42][CH2:41][CH2:40][C:37]2[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=2)=[N:8][CH:9]=1)#[N:12]
Reactant: CCCNc1nc(SC)ncc1C#N
Reactant: NCCc1ccncc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O=C(Cl)c1ccccc1
Product: CCCNc1nc(NCCc2ccncc2)ncc1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 40 mL of dichloromethane, 4-n-propylamino-5-cyano-2-methylthiopyrimidine obtained in Step 1 was dissolved, then mCPBA-dichloromethane solution (0.50 mol/L, 25 mL, 12.5 mmol) was added thereto over 5 minutes, followed by stirring at room temperature for 2 hours. The reaction mixture was added with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then the solvent evaporated under reduced pressure. The residue was dissolved in THF (40 mL), then 2-(4-pyridyl)ethylamine (1.47 g, 12.0 mmol) was added thereto, followed by stirring at room temperature for 12 hours. After completion of the reaction was confirmed by thin-layer chromatography, chloroform (80 mL), benzoylchloride polymer bound [about 2.5 mmol/g, 4.6 g, Canadian Journal of Chemistry, Vol. 55, p. 3351 (1977)] and poly(4-vinylpyridine) (4.6 g) were added thereto, followed by further stirring at room temperature for 12 hours. After resins in the reaction mixture were filtered out, the filtrate was concentrated to give 5-cyano-4-n-propylamino-2-[2-(4-pyridyl)ethylamino]pyrimidine [Compound (Y) in which R1 is n-propylamino and R1 is 2-(4-pyridyl)ethylamino].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[ClH:21].O1CCOCC1>>[ClH:21].[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Brc1cnc(N2CCNCC2)nc1
Yield: 94 %

Procedure:
A solution of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (5 g, 14.6 mmol) in 4 M HCl-dioxane (50 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 5-bromo-2-(piperazin-1-yl)pyrimidine HCl salt (crude, 3.3 g, 94%) as a white solid. MS (ES+) C8H11BrN4 requires: 242, 244, found: 243, 245 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([S:11][CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18]O>C(O)(C(F)(F)F)C(F)(F)F.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([S:11]([CH3:12])=[O:18])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OO
Reactant: COc1c(SC)cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.5 g of 5-tert-butyl-2-methoxy-1-methylsulphanyl-3-nitro-benzene are dissolved in 15 ml of 1,1,1,3,3,3-hexafluoroisopropanol, combined with 1.1 ml of a 9 M solution of hydrogen peroxide in water and stirred for 5 hours at ambient temperature. Then the mixture is cooled to 0° C. and diluted with 10% aqueous sodium thiosulphate solution. The mixture is extracted 3 times with ethyl acetate and the combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying with sodium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (petroleum ether/ethyl acetate 95:5).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[OH:12]O.[OH-].[Na+]>CO.O>[C:9]([C@@H:5]1[CH2:6][C@@H:7]2[C@@:2]([CH3:1])([O:8]2)[C:3](=[O:12])[CH2:4]1)([CH3:11])=[CH2:10]
Reactant: OO
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(C)[C@H]1CC(=O)[C@]2(C)O[C@@H]2C1
Reaction time: 5 h

Procedure:
(R)-Carvone was epoxidized according to a modification of the method of E. Klein and G. Ohloff (Tetrahedron, 1963, 11, 1091-1099). Thus H2O2 (31%, 95 mL, 836 mmol, 1.3 equivalents) was added to a solution of (L)-carvone (100 mL, 640 mmol) in 650 mL of methanol at <5° C. After cooling to <0° C., 6N NaOH (10.5 mL, 63 mmol, 0.1 equivalents) was added. The reaction temperature was maintained at <5° C. After 5 hours, the reaction was diluted with 650 mL water, then quenched with 0.5 N KH2PO4 (250 mL) and 325 mL of 1 molal Na2SO3, keeping the temperature at <25° C. The reaction was extracted with 2×750 mL tert-butyl methyl ether. The combined tert-butyl methyl ether extracts were washed with 500 mL each of 20% aqueous NaCl then 10% then 25% to provide a clear organic layer which was dried over MgSO4, then filtered and concentrated, then chased with 100 mL of methanol. The resulting solution assayed (GC) at 101.3 g (96%) of the titled compound, which contained 5% of the minor isomer. 1H NMR (400 MHz, CDCl3) δ ppm 1.40 (s, 3 H) 1.70 (s, 3 H) 1.89 (ddd, J=14.75, 11.11, 1.17 Hz, 1 H) 2.02 (dd, J=17.56, 11.66 Hz, 1 H) 2.31 -2.41 (m, 1 H) 2.58 (ddd, J=17.56, 4.67, 1.37 Hz, 1 H) 2.65-2.76 (m, 1 H) 3.44 (dd, J=3.09, 1.03 Hz, 1 H) 4.70 (d, J=0.69 Hz, 1 H) 4.75-4.80 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54](I)=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:58]([OH:62])(=[O:61])[CH:59]=[CH2:60].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54](/[CH:60]=[CH:59]/[C:58]([OH:62])=[O:61])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)O
Reactant: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(I)cc3)c12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(/C=C/C(=O)O)cc3)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-methyl-1H-indole (1.18 g) in N,N-dimethylformamide (10 mL) was added 55% sodium hydride (87 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-iodobenzyl bromide (0.62 g) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-3/1) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-iodo-benzyl)-7-methyl-1H-indole (1.48 g). A mixture of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-iodobenzyl)-7-methyl-1H-indole (1.06 g), acrylic acid (0.18 g), palladium(II) acetate (14 mg), tris(2-methylphenyl)phosphine (37 mg), triethylamine (2 mL) and acetonitrile (2 mL) was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was diluted with diethyl ether, and the mixture was stirred at room temperature for 10 minutes. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/3) to give the title compound (0.85 g).
Reaction SMILES: [CH3:1][Mg]Cl.[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7][CH2:6]1>O1CCCC1>[OH:4][C:5]1([CH3:1])[CH2:6][CH2:7][CH:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1(O)CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 5.3 %

Procedure:
A solution of methyl magnesium chloride (3M in tetrahydrofuran, 57 ml, 171 mmol) was added to a solution of tert-butyl 4-oxocyclohexylcarbamate (12 g, 56 mmol) (WO9613262) in tetrahydrofuran (240 ml) at −78° C. The mixture was allowed to warm to ambient temperature and was stirred for 18 h. The mixture was quenched by the addition of saturated ammonium chloride solution (100 ml) and the volatile solvents were removed under reduced pressure. The residue was taken up in water (200 ml) and dichloromethane (400 ml) and solid citric acid was added until the layers separated. The organic phase was washed with saturated sodium bicarbonate solution, water, brine, dried over MgSO4, and the solvent removed under reduced pressure to give a gum which was purified by flash column chromatography using ethyl acetate:cyclohexane (20:80 to 80:20) as eluant to give the less polar diastereoisomer of tert-butyl 4-hydroxy-4-methylcyclohexylcarbamate (680 mg) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:13]=[C:14]=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[NH:26][C:27](=[O:48])[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([C@@H:35]2[CH2:40][CH2:39][NH:38][C@@H:37]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:36]2)[CH2:31][CH2:30]1>C(Cl)Cl>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:38]2[CH2:39][CH2:40][C@@H:35]([N:32]3[CH2:33][CH2:34][N:29]([CH2:28][C:27]([NH:26][C:20]4[C:21]([CH3:25])=[CH:22][CH:23]=[CH:24][C:19]=4[CH3:18])=[O:48])[CH2:30][CH2:31]3)[CH2:36][C@@H:37]2[CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN[C@@H](Cc3ccccc3)C2)CC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: Cc1cccc(C)c1NC(=O)CN1CCN([C@@H]2CCN(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](Cc3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
3,5-di(trifluoromethyl)-1-isocyanatobenzene (0.0025 mol) in DCM (10 ml) was added to a mixture of (±)-trans-N-(2,6-dimethylphenyl)-4-[2-(phenylmethyl)-4-piperidinyl]-1-piperazineacetamide (0.0025 mol) in DCM (15 ml). The mixture was stirred at RT overnight. The precipitate was filtered off and dried, yielding 0.66 g (40%) of (±)-trans-4-[1-[[[3,5-bis(trifluoromethyl)phenyl]amino]carbonyl]-2-(phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1-piperazineacetamide (compound 143).