Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][Cl:5].[CH2:8](O)[CH2:9]CCO.N[C@H](C(O)=O)C(S)(C)C>CO>[Cl:5][CH2:4][CH:3]1[O:6][CH2:7][CH2:9][CH2:8][CH2:1][O:2]1
Reactant: COC(CCl)OC
Reactant: OCCCCO
Agent: CC(C)(S)[C@H](N)C(=O)O
Solvent: CO
Product: ClCC1OCCCCO1

Procedure:
500 gms of chloroacetaldehyde dimethyl acetal (Aldrich catalog no C1940-6), 360 gms of 1,4-butanediol (Aldrich catalog no. 88,480 7) and 10 gms of Dowex 50 resin (Aldrich catalog No. 21,749-2) were placed in a 1000 ml, 3-neck round bottom flask equipped with a thermometer, a mechanical stirrer, a 8 inch Pen State column, and a distillation head. The mixture was heated to 115° C. under nitrogen blanket and methanol was removed continuously and the amount collected was measured by weigh up. The reaction was monitored by analyzing samples taken from the distillate in a Gas Chromatograph with a dimethyl silicon column in the temperature range of 50° C. to 250° C. The reaction was stopped when the stoichiometric amount of methanol was collected. The crude reaction mixture was filtered to remove the ion exchange resin. The product 2-chloromethyl 1,3-dioxepane was isolated from the crude mixture by fractional distillation in an Oldershaw column under partial vacuum. The fraction boiling at 105° C. at 55 mm of Hg was collected. The structure was confirmed by elemental analysis and proton NMR. Elemental analysis: C-47.2 percent (48 percent calculated), H=7.58 percent (7.33 percent calculated), 0=22.64 percent (21.34 percent calculated), C1=22.57 percent (23.3 percent calculated). Proton NMR:1.71-1.34 ppm multiplet (--OCH2CH2CH2CH2O--), 3.46-3.48 ppm doublet (--CH2Cl), 3.66-2.96 ppm 2 sets of triplets (--OCH2 ; 2 sets, 4 protons), 4.83-4.87 ppm triplet (C1CH2CH(O)2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:26][CH2:25]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:19][CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[O:18])=[CH:15][C:14]=1[O:22][CH2:23][CH:24]1[CH2:25][CH2:26]1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(c1ccc(C(=O)O)cc1OCC1CC1)S(C)(=O)=O
Reactant: O=C(CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(c1ccc(C(=O)OCC(=O)OCc2ccccc2)cc1OCC1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)-benzoic acid (see for reference procedure Example 18, WO 2010/089107, which is incorporated herein by reference in its entirety) (2.5 g, 6.49 mmol), benzyl 2-hydroxyacetate (1.078 g, 6.49 mmol), EDC (3.73 g, 19.46 mmol) and DMAP (0.396 g, 3.24 mmol) were mixed in DCM (150 ml), and the resulting mixture was stirred at RT for 24 hours. Then the mixture was washed with HCl 1N and NaHCO3 sat. sol.; the organic layer was dried over Na2SO4, and the solvent was evaporated. The crude was sonicated in MeOH; 2-(benzyloxy)-2-oxoethyl 4-(N-(tert-butoxycarbonyl)methylsulfonamido)-3-(cyclopropylmethoxy)benzoate precipitated (2.6 g, 4.87 mmol, 75% yield, MS/ESI+ 556.0 [MNa]+), it was filtered and used as such in the following reaction without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[CH:9]=[C:10]([C:13](OCC)=[O:14])[NH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>C1COCC1>[N:1]1([CH2:6][CH2:7][C:8]2[CH:9]=[C:10]([CH2:13][OH:14])[NH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(CCN2CCCC2)c[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cc(CCN2CCCC2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product obtained in Step H (0.2 g) in THF (10 ml) at 0° C. there is added, in portions, lithium aluminium hydride. After stirring for 3 hours at ambient temperature, the reaction mixture is hydrolysed at 0° C. with aq. NaOH solution and water. After filtration, the filtrate is evaporated to dryness and the residue obtained is purified on silica gel (SiO2: gradient CH2Cl2/MeOH with the addition of 1.4N NH3 in the MeOH) to yield the title product, which is used directly in the next Step.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1.I[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[S:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[N:39][N:40]=3)[CH:34]=2)[N:29]([S:45]([C:48]2[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH:28]=1>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.CC(O)C.O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36]3[S:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[N:39][N:40]=3)[CH:34]=2)[N:29]([S:45]([C:48]2[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=2)(=[O:47])=[O:46])[CH:28]=1
Reactant: CC1(C)OB(c2ccc(F)cc2F)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3F)c3cc(-c4nnc(S(C)(=O)=O)s4)ccc32)cc1
Temperature: 80 °C
Yield: 37.5 %

Procedure:
A mixture of potassium phosphate tribasic (1.309 g, 6.17 mmol, Aldrich), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.044 g, 0.062 mmol, Aldrich), 2,4-difluorophenylboronic acid pinacol ester (0.740 g, 3.08 mmol, Aldrich), 2-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (1.15 g, 2.056 mmol), and IPA/H2O (70%, 10 mL) was heated at 80° C. for 2 h. The mixture was partially concentrated to remove most IPA, and the aq. layer was extracted with DCM. The aq. layer was acidified with 2M HCl and extracted again with DCM. The combined DCM fractions were evaporated and purified by prep HPLC (50-95% AcCN/H2O/0.1% TFA) to give 2-(3-(2,4-difluorophenyl)-1-tosyl-1H-indol-5-yl)-5-(methylsulfonyl)-1,3,4-thiadiazole (0.42 g, 0.770 mmol, 37.4%) as a light yellow solid. MS (ESI, pos. ion) m/z 546 (M+1).
Reaction SMILES: [O:1](C)[S:2]([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].CC1CN2CCN1CC2.C(O)C.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[O-]S(C(F)(F)F)(=O)=O.[CH3:38][N+:39]12[CH2:46][CH2:45][N+:42]([CH3:47])([CH2:43][CH2:44]1)[CH2:41][CH:40]2C>C(#N)C>[O-:4][S:2]([C:5]([F:8])([F:7])[F:6])(=[O:3])=[O:1].[CH3:38][N+:39]12[CH2:46][CH2:45][N+:42]([CH3:47])([CH2:43][CH2:44]1)[CH2:41][CH2:40]2.[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22]
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: CC1C[N+]2(C)CC[N+]1(C)CC2
Agent: CC1CN2CCN1CC2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCO
Product: C[N+]12CC[N+](C)(CC1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl triflate (3.2 g, 19.5 mmol) was added dropwise to a cold (0 ° C) stirred solution of 2-methyl-1,4-diazabicyclo [2,2,2]octane (2.5 g, 20.0 mmol) in dry acetonitrile under an atmosphere of dry nitrogen. The mixture was stirred at 0° C. for 1 hour and then at 20° C. overnight. The orange solution obtained was treated dropwise with ethanol until precipitation of a white solid ceased; this solid was recovered by filtration, washed with ethanol, dried in vacuo at room temperature and shown by n.m.r. spectroscopy (1H and 19F) to be 1,2,4-trimethyl-1,4-diazoniabicyclo[2,2,2]octane ditriflate (0.45 g, 0.99 mmol, 5%). Removal of acetonitrile from the filtrate in vacuo left an orange oil (3.6 g, 12.4 mmol, 64%), shown by n.m.r. spectroscopy (1H and 19F) to be methyl-N-methyl-1,4-diazabicyclo [2,2,2]octane triflate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].C1COCC1.Br[CH2:20][C:21]([CH3:23])=[CH2:22]>CCOC(C)=O.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:22][C:21]([CH3:23])=[CH2:20]
Reactant: O=C(CCCl)c1ccccc1
Reactant: C=C(C)CBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)CC(O)(CCCl)c1ccccc1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
To a well stirred mixture of 3-chloropropiophenone (10.0 g, 59.3 mmol), zinc powder (4.0 g, 1.03 equiv), satd aq NH4Cl solution (150 mL), THF (70 mL), a solution of the 3-bromo-2-methylprop-1-ene (16 g, 2 equiv) was added slowly. The reaction was exothermic mildly. After the addition, the mixture was heated to reflux for 1.5 h. After being cooled to rt, the mixture was diluted with EtOAc (200 mL), separated, washed with brine (35 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120 g silica gel column, eluted with a 0-10% methanol in CH2Cl2 gradient, to afford 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (8.67 g product, 65% yield).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.Br.[NH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20])=[O:15].C(N(CC)CC)C.Cl>CN(C)C=O.O>[C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:9])[NH:12][CH2:13][C:14]([NH:16][C:17]2[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=2[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:20])=[O:15])[CH:2]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1ccccc1
Reactant: Cc1cccc(N=C=O)c1
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)NCC(=O)Nc2ccccc2C(=O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of m-tolylisocyanate (0.846 g, 6.35 mmol) in dimethylformamide (3 ml) is added to a solution of the salt 3a prepared in Preparation 3 (1.937 g, 5.78 mmol) in dimethylformamide (8 ml). Triethylamine (32 ml) is added at 0° C. The mixture is stirred at 0° C. for 30 minutes and then at room temperature overnight. Water and then 10% hydrochloric acid are added. The mixture is extracted with ethyl acetate. The extract is washed with water and dried (sodium sulfate), and then the solvent is distilled off under reduced pressure. The residue is recrystallized from acetonitrile to obtain the objective compound 4a (1.39 g; yield 62%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13](=[O:18])[C@@H:14]([CH3:17])[CH2:15]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(OCC)(=O)C>[CH3:11][O:12][C:13](=[O:18])[C@@H:14]([CH3:17])[CH2:15][O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: COC(=O)[C@@H](C)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)COc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (1.0 g, 7.3 mmol), (S)-3-hydroxy-2-methyl-propionic acid methyl ester (0.8 mL, 7.3 mmol) and triphenylphosphine (2.3 g, 8.8 mmol) at room temperature, diethyl azodicarboxylate (1.4 mL, 8.8 mmol) was added dropwise. The mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed successively with dilute aqueous sodium hydroxide, dilute aqueous hydrochloric acid, brine, and dried (MgSO4). Solvents were stripped in vacuo. The resulting oil was washed with diethyl ether and the precipitate was filtered off. The mother liquor was adsorbed onto silica gel and the product purified by flash column chromatography (40% ethyl acetate/hexane), affording 0.14 g of a yellow oil (8% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[S:12][C:13]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[O:9])=[CH:4][N:3]=1.[OH2:29]>N1CCOCC1>[C:21]([C:13]1[S:12][C:11]([NH:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:3]3[CH2:4][CH2:5][O:29][CH2:7][CH2:2]3)=[N:3][CH:4]=2)=[O:9])=[N:15][C:14]=1[C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1)c1ccc(Cl)nc1
Solvent: C1COCCN1
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)c2ccccc2)s1)c1ccc(N2CCOCC2)nc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Compound 147 (100 mg, 0.244 mmol) was dissolved in morpholine (1 mL), followed by stirring at 80° C. for 1 hour. Water was added to the reaction system, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 148 (81.0 mg, 72%).
Reaction SMILES: OC1C(C(CC)(C)C)=CC(C(CC)(C)C)=CC=1N=NC1C=CC=CC=1[N+]([O-])=O.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:37])=[CH:32][C:31]=1[N:44]=[N:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[N+:52]([O-])=O.[OH-].[Na+].[N+](C1C=CC=CC=1N=NC1C=CC=CC=1)([O-])=O>>[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:38])[CH3:37])=[CH:32][C:31]=1[N:44]1[N:52]=[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]2=[N:45]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: O=[N+]([O-])c1ccccc1N=Nc1ccccc1
Agent: [Na+]
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 62.6 %

Procedure:
When in Example 1, the 2'-hydroxy-3',5'-di-tert-amyl-2-nitroazobenzene was replaced by an equivalent amount of 2'-hydroxy-5'-tert-octyl-2-nitroazobenzene and the moles of sodium hydroxide per mole of o-nitroazobenzene intermediate was increased from 0.42/1 to 1.2/1, the product 2-(2-hydroxy-5-tert-octylphenyl)-2H-benzotriazole was obtained in an isolated yield of 62.6% of theory with a melting point of 104°-107° C. The mother liquor contained a compound believed to be an isomer of the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCOC(COCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reaction time: 4 h

Procedure:
To a stirring solution of (+/−)-N-(t-butoxycarbonyl)-2-(phenylmethoxymethyl)-morpholine (595 mg, 1.94 mmol) and 20% palladium on carbon (120 mg, Aldrich) in MeOH (20 mL) was added 50 psi of hydrogen. The reaction was stirred for 4 h. The reaction was filtered and the filtrate was conc. in vacuo to a colorless oil. The oil can be used without further purification. MS (CI) 218 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[S:10]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11]1.BrC1C=C(F)C(F)=CC=1O.S1C=CC=C1B(O)O>>[S:10]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[OH:9])=[CH:11]1
Reactant: OB(O)c1ccsc1
Reactant: Oc1cc(F)ccc1Br
Agent: OB(O)c1cccs1
Agent: Oc1cc(F)c(F)cc1Br
Product: Oc1cc(F)ccc1-c1ccsc1

Procedure:
2-Bromo-5-fluorophenol is coupled with thiophene-3-boronic acid; 2-bromo-4,5-difluorophenol is coupled with thiophene-2-boronic acid; and 2-bromo-4,5-difluorophenol is coupled with thiophene-3-boronic acid in Suzuki reactions substantially as described for Epoxide 48, to yield 2-(thien-3-yl)-5-fluorophenol; 2-(thien-2-yl)-4,5-difluorophenol; and 2-(thien-3-yl)-4,5-difluorophenol, respectively. These phenolic products are reacted with (2S)-glycidyl 3-nitrobenzenesulfonate substantially as described for Epoxide 1 to yield the title epoxides.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:15][O:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C=O)ccc([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 2-hydroxy-3-methoxy-4-nitro-benzaldehyde (10.4 g, 52.8 mmol, prepared as described in: J. Heterocyclic Chem., 1996, 33, 1171-78) in DMF (100 ml) was added potassium carbonate (11.04 g, 80 mmol), followed by methyl iodide (4 mL, 64 mmol) and the mixture stirred at 90° C. for 1 hour. The mixture was partitioned between ethyl acetate and water, separated, the organic phase was washed with brine, dried (Na2SO4), filtered, and the solvents were removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, 20% ethyl acetate in cyclohexane) to give the title compound as a yellow oil (8.2 g, 74%). LCMS (Method B): RT=3.76 min, [M+H]+=212.
Reaction SMILES: [CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:8][C@H:9]2[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@H:12]([OH:17])[O:11][C@@H:10]2[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]>C([O-])(=O)C>[CH2:1]([OH:23])[C@H:2]1[O:7][C@H:6]([O:23][CH2:1][C@H:2]2[O:7][C@H:6]([O:8][C@@H:9]([C@H:14]([OH:15])[C@@H:13]([OH:16])[CH:12]=[O:17])[C@H:10]([OH:11])[CH2:18][OH:19])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]2[OH:22])[C@H:5]([OH:20])[C@@H:4]([OH:21])[C@@H:3]1[OH:22]
Reactant: OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O
Agent: CC(=O)[O-]
Product: O=C[C@H](O)[C@@H](O)[C@H](O[C@H]1O[C@H](CO[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@H](O)[C@H]1O)[C@H](O)CO
Reaction time: 0.5 h

Procedure:
Glucoamylase equivalent to 1 to 5 DU is taken in a test tube and diluted to 0.25 ml with (0.02M) acetate buffer, final pH 4.8. Then 0.25 ml of 0.02M acetate buffer containing acarbose is added to give a final concentration of 50 μg acarbose/DU of glucoamylase and the mixture is incubated at 37° C. for 30 minutes. After the specified time, 0.5 ml maltose (20% concentration) in 0.02M acetate buffer, pH 4.8 is added and the mixture incubated for another 60 minutes at 37° C. Enzymatic reaction is terminated by heating the mixture in a boiling water bath for 15 minutes. A blank reaction mixture, serving to correct for any trisacharride contaminant in the substrate, is prepared similarly except that maltose is added after thermal inactivation of the TG. Transglucosidase activity is then measured by determining, using liquid chromatography, the amount of panose formed. A standard curve, made using pure panose is prepared to calibrate the instrument. For glucoamylose samples containing low amounts of TG, a more prolonged incubation period, i.e. 15 to 20 hours, if necessary. The conditions for liquid chromatography were as follows:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:11][C:10]([S:12]([N:15]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24]OC4CCCCO4)=[O:23])=[CH:16]3)(=[O:14])=[O:13])=[CH:9][CH:8]=2)[CH:4]=[N:3]1.C[OH:33]>>[OH:33]/[C:21](=[CH:20]/[C:17]1[CH:18]=[CH:19][N:15]([S:12]([C:10]2[S:11][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][CH:9]=2)(=[O:14])=[O:13])[CH:16]=1)/[C:22]([NH2:24])=[O:23]
Reactant: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)s2)cn1
Reactant: CO
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C(/O)C(N)=O)c3)s2)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.099 g (E)-3-{1-[5-(1-methyl-1H-pyrazol-4-yl)-thiophene-2-sulfonyl]-1H-pyrrol-3-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide with 3.0 ml methanol and 6.0 ml 1M aqueous HCL is stirred at ambient temperature for 24 h. The suspension is filtered and washed with water and ethyl acetate. The title compound is dried in vacuo. By this method 0.037 g light pink solid are obtained. Melting point: 163-166° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=1.C[Si](C)(C)N[Si](C)(C)C.[Li]>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:14]([C:13]2[CH:18]=[CH:19][C:10]([CH3:9])=[CH:11][CH:12]=2)=[O:15])[CH:3]=1
Reactant: COC(=O)c1ccc(C)cc1
Reactant: Cc1cc(Br)ccn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
Under a stream of nitrogen, 1 g (5.81 mmol) of 4-bromo-2-methylpyridine and 1.75 g (11.60 mmol) of methyl 4-methylbenzoate are placed in a round-bottomed flask and dissolved in 30 mL of anhydrous tetrahydrofuran. The solution is cooled to 5° C. and 14 mL (14 mmol) of a lithium hexamethyldisilazane solution (1M in tetrahydrofuran) are added dropwise. After addition, the mixture is stirred at room temperature for 2 hours 30 minutes and then cooled to 5° C., followed by gradual addition of 20 mL of water. The medium is then diluted with 200 mL of ethyl acetate and 200 mL of water. The organic phase is separated out, dried over sodium sulfate and filtered. 5 g of silica are then added to the filtrate, which is then concentrated under reduced pressure. The powder obtained is used as a solid deposit for a chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (95/5) to give 1.03 g (61%) of compound in the form of a yellow powder.
Reaction SMILES: C1(N(C[CH2:22][C:23]2[CH:28]=CC=CC=2)C(=O)NC2SC(SCC(O)=O)=CN=2)CCCCC1.C(=O)CC(C)C.C1([C@H]2CC[C@H](NCOC)CC2)CC1.[CH3:48][O:49][CH2:50][CH:51]1[CH2:56][CH2:55][CH:54]([N:57]([CH2:71][CH2:72][CH:73]([CH3:75])[CH3:74])[C:58](=[O:70])[NH:59][C:60]2[S:61][C:62]([S:65][CH2:66][C:67]([OH:69])=[O:68])=[CH:63][N:64]=2)[CH2:53][CH2:52]1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:28]1([CH2:48][O:49][CH2:50][C@H:51]2[CH2:56][CH2:55][C@H:54]([N:57]([CH2:71][CH2:72][CH:73]([CH3:75])[CH3:74])[C:58](=[O:70])[NH:59][C:60]3[S:61][C:62]([S:65][CH2:66][C:67]([OH:69])=[O:68])=[CH:63][N:64]=3)[CH2:53][CH2:52]2)[CH2:23][CH2:22]1
Reactant: COCC1CCC(N(CCC(C)C)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Agent: CC(C)CC=O
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: COCN[C@H]1CC[C@H](C2CC2)CC1
Product: CC(C)CCN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](COCC2CC2)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using isovaleraldehyde, trans-4-cyclopropyl-methoxymethyl-cyclohexylamine (prepared in accordance with the general method given for the preparation of {2-[3-(4-methoxymethyl-cyclohexyl)-3-(3-methyl-butyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid) and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:24])[CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[OH-].[Li+]>COCCOC.O>[C:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:10][C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[C:3]([OH:25])=[O:2])=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: O=C(O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
N-(3,3-diphenylpropionyl)-L-proline methylester (2.10 g, 6.23 mmol) was dissolved in DME (50 ml) and H2O (50 ml). Lithium hydroxide monohydrate (1.57 g, 37.39 mmol) was added and the mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated to remove DME and the remaining aqueous layer was acidified with 1N HCl to pH 3. The acidic layer was washed with EtOAc (3×75 ml). Organic washes were combined, dried with Na2SO4, filtered and concentrated to give 1.92 g (94%) of N-(3,3-diphenylpropionyl)-L-proline.