Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:13]3[C:12](=[O:14])[NH:11][CH2:10][CH2:9][C:8]=3[CH:7]=[CH:6][C:5]=2[N:15]=1.N([O-])=O.[Na+].[PH2](O)=O.[OH-].[K+]>P(O)(O)O.C(OCC)(=O)C.O>[S:3]1[C:4]2[C:13]3[C:12](=[O:14])[NH:11][CH2:10][CH2:9][C:8]=3[CH:7]=[CH:6][C:5]=2[N:15]=[CH:2]1
Reactant: Nc1nc2ccc3c(c2s1)C(=O)NCC3
Agent: O=N[O-]
Agent: O=[PH2]O
Agent: OP(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1NCCc2ccc3ncsc3c21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 10.6 %

Procedure:
2-Amino-7,8-dihydrothiazolo[4,5-h]isoquinolin-9(6H)-one (I-66b: 1.4 g, 0.006 mol) in orthophosphorous acid (30 mL) was heated at 40° C. when a clear solution was formed. This was followed by the addition of NaNO2 (2.64 g, 0.038 mol) and H2O (10 mL) at 0° C. The resulting reaction mass was stirred at 0° C. for 30 minutes and added hypo phosphorous acid (35 mL). The reaction mass was stirred at 0° C. for 2 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mass was diluted with ice-water, basified with KOH solution to pH 10 and extracted using ethyl acetate. The organic layer was concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (60% ethyl acetate in hexane) afforded 130 mg of the product (10% yield). LCMS: 99.03%, m/z=205.1 (M+1)
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:15]([CH2:18][OH:19])=[CH:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)(=O)C.C(O)C.[C].[Pd]>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[CH:14]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:15]([CH2:18][OH:19])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C1C(CO)=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1C(CO)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N12
Yield: 55.3 %

Procedure:
A suspension of 10% palladium carbon (16 g) in acetic acid (50 ml) was added to a solution of t-butyl 7-(2-phenylacetamido)-3-hydroxymethyl-2-cephem-4-carboxylate (9.0 g) in ethanol (300 ml.), and the mixture was subjected to catalytic reduction at 65° C. in the presence of hydrogen at 20 atm. for 9 hours. After removing the insoluble substance by filtration, the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate (150 ml.) and adjusted to pH 7.5 with aqueous solution of sodium bicarbonate. The organic layer was separated, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with petroleum ether and collected by filtration to give t-butyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (5.0 g.).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:12])[OH:11])=[O:5])[CH3:3].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[C:35](Cl)(=[O:53])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].O>C(Cl)Cl>[NH:1]([C:35]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:53])[C@H:2]([C:4]([NH:6][C@@H:7]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:8][CH2:9][C:10](=[O:11])[OH:12])=[O:5])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: C[C@H](N)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Yield: 93.7 %

Procedure:
L-Ala-D-Glu(OH)OBzl (1) (942 mg) was suspended in methylene chloride (40 ml), and bis(trimethylsilyl)acetamide (1.20 g) was added to the suspension under stirring. The resulting solution was treated with stearoyl chloride (900 mg) at ambient temperature and left for an hour. Evaporation of the solvent gave an oily residue which was treated with water to give white solides. The solides were collected by filtration, washed with water and dried over magnesium sulfate to give stearoyl-L-Ala-D-Glu(OH)OBzl (2) (1.60 g).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=[O:20].[Na+].[Na+].C(=O)(O)[O-].[Na+].OOS([O-])=O.[K+]>CCOC(C)=O.CCCCCC.O.C(#N)C>[CH:4]1[CH:5]=[CH:6][C:1]([C@@H:7]2[O:20][C@H:8]2[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:2][CH:3]=1
Reactant: C(=C/c1ccccc1)\c1ccccc1
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc([C@@H]2O[C@H]2c2ccccc2)cc1
Reaction time: 0.12 h
Yield: 99 %

Procedure:
To an acetonitrile solution (1.5 mL) of trans-stilbene (18 mg. 0.1 mmol) and ketone 4 (29.6 mg, 0.1 mmol) at room temperature was added an aqueous Na2EDTA solution (1 mL, 4×10-4M). To this homogenous solution was added in portions a mixture of sodium bicarbonate (1.55 mmol) and Oxone® (1 mmol). The reaction was finished in 7 min as shown by TLC. The reaction mixture was poured into water (20 mL), extracted with CH2Cl2 (3×20 mL) and dried with Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by flash column chromatography; 20 g of silica gel (Merck, 230-400 mesh) in 100 mL of n-hexane with 2 mL of NEt3 was poured into a flash column of 20 mm diameter. The column was eluted with n-hexane (50 mL), followed by 5% EtOAc/n-hexane (150 mL) to give trans-stilbene epoxide (19.4 mg. 99% yield), and 40% EtOAc/n-hexane to give ketone 4 (27.6 mg. 93% yield of recovery).
Reaction SMILES: [CH2:1]([CH:4]([C:8]1[N:13]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]2[N:11]=[C:10]([CH3:18])[CH:9]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[I:19]N1C(=O)CCC1=O>C(#N)C.ClCCl>[CH2:1]([CH:4]([C:8]1[N:13]2[N:14]=[C:15]([CH3:17])[C:16]([I:19])=[C:12]2[N:11]=[C:10]([CH3:18])[CH:9]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCC(CCC)c1cc(C)nc2cc(C)nn12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClCCl
Product: CCCC(CCC)c1cc(C)nc2c(I)c(C)nn12
Temperature: 25 °C
Yield: 236.4 %

Procedure:
Dissolve 7-(1-propyl-butyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (3.08 g, 12.5 mmol) in anhydrous acetonitrile (25 mL) and add 6 portions (0.70 g each) of N-iodosuccinimide (4.2 g, 18.7 mmol) at 10 minute intervals. Stir over the weekend at room temperature. Strip off the acetonitrile and dilute the oil with dichloromethane (100 mL). Wash with saturated ammonium chloride solution (2×50 mL). Collect the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to yield a dark red oil. Purify the oil using flash chromatography, eluting with 100% hexane/0% (20% ethyl acetate/hexane) to 0% hexane/100% (20% ethyl acetate/hexane) in a step gradient of 50% increments to give an orange oil (10.97 g, 87%).
Reaction SMILES: [O:1]1[C@@:18]23[C@:19]4([CH3:28])[C:24](=[CH:25][CH2:26][C@@:2]12[C@H:3]1[C@:15]([CH3:29])([CH2:16][CH2:17]3)[C@@H:6]([C@H:7]([CH3:14])[CH2:8][CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:5][CH2:4]1)[CH2:23][C@@H:22]([OH:27])[CH2:21][CH2:20]4.[Li]>C(NCC)C>[CH3:13][CH:11]([CH2:10][CH2:9][CH2:8][C@H:7]([C@@H:6]1[C@:15]2([CH3:29])[C@H:3]([C@H:2]3[C@:18]([OH:1])([CH2:17][CH2:16]2)[C@:19]2([CH3:28])[C:24]([CH2:23][C@@H:22]([OH:27])[CH2:21][CH2:20]2)=[CH:25][CH2:26]3)[CH2:4][CH2:5]1)[CH3:14])[CH3:12]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@@H]2[C@]1(C)CC[C@@]13O[C@@]21CC=C1C[C@@H](O)CC[C@@]13C
Agent: [Li]
Solvent: CCNCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Reaction time: 3 h
Yield: 30.8 %

Procedure:
8α,9α-Epoxycholest-5-en-3β-ol(200 mg) is dissolved in 13 ml diethylamine at −20° C. Lithium (100 mg) is added in small portions. The reaction mixture is stirred for 3 hours. After aqueous work-up, a crude product (207 mg) is isolated. Crystallization from diisopropylether yields cholest-5-ene-3β,9α-diol (62 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3o2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cc4)ccc3O2)CC1
Temperature: 45 °C

Procedure:
A mixture of 4-[5-(4-methanesulfonyl-phenyl)-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.70 g), 10% palladium on carbon (200 mg), ethanol (100 mL), and ethyl acetate (50 mL) is shaken under hydrogen atmosphere (5 bar) at 45° C. until the starting material is completely consumed. The catalyst is filtered off, the filtrate is concentrated in vacuo, and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate/methanol 70:30:0→50:40:10) to give the title compound. LC (method 1): tR=1.75 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:18].[Cl-].[NH4+].[OH-].[NH4+].C[N:24]([CH:26]=[O:27])C>O.[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:18][C:3]1[C:2]([C:26]([NH2:24])=[O:27])=[N:7][CH:6]=[C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:4]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: NC(=O)c1ncc(-c2ncccc2C(F)(F)F)cc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
Heat a solution of 6′-chloro-3-trifluoromethyl-[2,3′]bipyridinyl-5′-ylamine (25 g, 0.091 mol), zinc cyanide (6.75 g, 0.058 mol), tris[dibenzylidineacetone]di-palladium (also referred to as “pd2(dba)3”; 2.63 g, 2.86 mmol), 1,1′-bis(diphenylphosphino)ferrocene (also referred to as “DPPF”; 3.16 g, 5.72 mmol) in DMF (250 mL) and water (2.5 mL), under a nitrogen atmosphere, at 120° C. for 1 hour. Add water (30 mL) and heat the solution at 120° C. for a further 4 hours to complete the hydrolysis. Cool the reaction to 0° C. and add a solution of saturated ammonium chloride (200 ml), water (200 mL) and concentrated ammonium hydroxide (50 mL). After stirring at 0° C. for 1 hour, filter the yellow precipitate, and wash with water (200 mL) and a 1:1 mixture of ether-hexane (200 mL). Dry the solid in air and then in a vacuum oven to give (23 g, 90%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][NH2:38]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([C:17]2[NH:18][C:19]([CH3:24])=[C:20]([Cl:23])[C:21]=2[Cl:22])=[O:16])[C@H:10]([CH2:25][NH:38][CH3:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2NC(=O)c2[nH]c(C)c(Cl)c2Cl)cc1
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 100 °C

Procedure:
Cis(±)tert-butyl-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-piperidine-1-carboxylate (Intermediate 72; 500 mg, 0.89 mmol) was dissolved in 5 ml of a 2.0 M THF solution containing MeNH2. The reaction vessel was sealed and heated to 100° C. for 2 h. The mixture was cooled to room temperature and diluted with EtOAc, then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated to a crude solid foam which was used without further purification. MS (ES)MH+: 419 for C18H28Cl2N4O3.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:18](=NO)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2].FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:24]>CC#N.O>[C:1]([C:3]1[N:4]=[C:5]2[C:18](=[O:24])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]2=[N:7][C:8]=1[C:9]([NH2:11])=[O:10])#[N:2]
Reactant: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=NO
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: N#Cc1nc2c(nc1C(N)=O)-c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A suspension of 33 (522 mg, 1.97 mmol) and [bis(trifluoroacetoxy)iodo]benzene (1.69 g, 3.9 mmol) in CH3CN/H2O (9:1, 20 ml) was stirred 24 h at room temperature. The solid was collected by filtration and washed with CH3CN. The residue was dissolved in DMSO (2 ml) and precipitated by addition of H2O. The obtained solid was filtered and dried under vacuum, affording 36 (286 mg, 58%) as light brown solid. 1H NMR (300 MHz, DMSO d6): δ 8.65 (bs, 1H), 8.31 (bs, 1H), 8.09 (dd, 1H), 7.93 (m, 2H), 7.77 (ddd, 1H). ESI+MS: calcd for C13H6N4O2: 250.22; found: 251.1 (MH+).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:32])[CH:11]([CH2:17][C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[O:25][C:20]=3[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl.C(=O)([O-])O.[Na+]>C(OCC)C.[Cl-].[Zn+2].[Cl-].O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:32])[CH:11]([CH2:17][C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([F:28])([F:29])[C:24]([F:27])([F:26])[O:25][C:20]=3[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(=O)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc2c(c1)OC(F)(F)C(F)(F)O2)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of zinc chloride (2.79 g, 20.5 mmol) in diethyl ether (100 ml) was added sodium borohydride (1.55 g, 40.9 mmol), and the mixture was stirred at room temperature for 30 min. Insoluble material was filtered off, and to the filtrate was added a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-[(2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)methyl]propanoate (4.4 g, 10.2 mmol) in diethyl ether (50 ml) at 0° C. The mixture was stirred for 30 min. and 1N hydrochloric acid was added to stop the reaction. After neutralization with saturated aqueous sodium hydrogen carbonate solution, water (200 ml) was further added and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure to give the objective substance (4.40 g, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].ClC1C=CC=CC=1.Br.O>C(O)(=O)C.BrBr>[C:6]1(=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[C:1](=[O:3])[CH2:2][O:7]1
Reactant: CC(=O)c1ccccc1C(=O)O
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Solvent: O
Product: O=C1COC(=O)c2ccccc21
Temperature: 30 °C
Yield: 74.5 %

Procedure:
A stirred mixture of 2-acetylbenzoic acid (compound of formula (XI)) (1.00 Kg, 6.09 mol) and chlorobenzene (10.0 L) was treated with 5.5 molar hydrobromic acid in acetic acid (55 mL) and bromine (310 mL) then warmed to approximately 30° C. After 3 hours water (10.0 L) was added and the reaction heated to reflux. After 3 hours the reaction was cooled to 60° C. and the organic layer removed. The aqueous layer was extracted with chlorobenzene (2.0 L) and the combined organic layers concentrated under reduced pressure to approximately 3.0 L. Propan-2-ol (5.0 L) was charged and the slurry cooled to 0° C. before being filtered and washed with propan-2-ol (2.0 L). The resulting solid was dried in vacuo at 50° C. to give the title compound (736 g, 75%); 1H NMR (400 MHz, CDCl3): δ 5.14 (2H, s, H-9), 7.82-7.91 (2H, m, H-2 and 3), 8.08-8.10 (1H, m, H-1), 8.28-8.30 (1H, m, H-4); 13C NMR (100 MHz, CDCl3) δ 73.4, 125.6, 128.0, 130.9, 131.8, 134.7, 135.9, 161.4 and 189.5.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[CH3:17][O:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1[CH:24]=O>N1CCCCC1.CC(O)C>[CH3:17][O:18][C:19]1[CH:23]=[CH:22][NH:21][C:20]=1/[CH:24]=[C:3]1/[C:4]2[CH:9]=[C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[S:7][C:5]=2[NH:6][C:2]/1=[O:1]
Reactant: CC(C)(C)OC(=O)c1cc2c(s1)NC(=O)C2
Reactant: COc1cc[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2sc(C(=O)OC(C)(C)C)cc21
Temperature: 75 °C
Yield: 40.3 %

Procedure:
tert-Butyl 5,6-dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxylate (915 mg, 3.8 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (10 ml). 3-Methoxypyrrole-2-carboxaldehyde (3.8 mmol, 480 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (15 ml) and the precipitated solid was collected by filtration and washed with water to give 530 mg of tert-butyl (Z)-5,6-dihydro-4-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-oxo-4H-thieno [2,3-b]pyrrole-2-carboxylate as a red solid. MS(ES): m/e 347 [M+H].
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[C:28]([F:36])=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>CCCCCCC.CCOC(C)=O>[Cl:26][C:27]1[C:28]([F:36])=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: OB(O)c1cccc(Cl)c1F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccc(Cl)c1F

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 3-chloro-2-fluorophenylboronic acid (CAS RN 352535-82-1) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (64%). MS (ESI): m/z=477.061 [M+H]+.
Reaction SMILES: [OH-].[Na+].[O:3]=[CH:4][C@@H:5]([C@H:7]([C@@H]([C@@H](CO)O)O)O)[OH:6].[Na+].[Cl-].C([C:22]1([O:31][C@H:30]([CH2:32][OH:33])[C@@H:28]([OH:29])[C@H:26]([OH:27])[C@H:24]1[NH2:25])[OH:23])(=O)C(C)O>O>[C:4]([NH:25][C@@H:24]1[C@@H:26]([OH:27])[C@H:28]([OH:29])[C@@H:30]([CH2:32][OH:33])[O:31][CH:22]1[OH:23])(=[O:3])[CH:5]([CH3:7])[OH:6]
Reactant: CC(O)C(=O)C1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1N
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
30 g of liquid product as described in example 2 was dissolved in 120 g of water. The pH of the solution was adjusted to 6 with 50% NaOH solution. Finally 60 g of maltodextrin (with a dextrose equivalent of 10) and 30 g of NaCl were dissolved in the solution. The viscous liquid obtained was then spray-dried to get a powder flavour ingredient containing N lactoyl glucosamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][OH:11].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C(Cl)Cl>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][O:11][S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCc1ccccc1O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 79.2 g of the diol from Example 2 in 400 ml of methylene chloride is added 100 ml of tiethylamine, followed by 91 g of tosyl chloride in 200 ml methylene chloride. The reaction mixture is stirred at room temperature overnight. The salts are then filtered off and the mixture washed with water, brine and water. The organic layer is dried (MgSO4), filtered and concentrated to obtain 3-(o-hydroxyphenyl)-1-tosyloxypropane as a light brown oil which is used directly in the next step.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].FS(O)(=O)=O.[CH3:18]O>O>[CH3:18][O:1][C@H:2]1[O:10][CH:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CO
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)F
Solvent: O
Product: CO[C@H]1OC(CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an autoclave of 300 cc volume, 50 g of anhydrous crystalline glucose, 5 g of perfluorosulfonic acid resin ("NAFION" powder 511) and 133 g of methyl alcohol were charged. The reaction was effected at 120° C.±1° C. for 30 minutes while stirring at 600 r.p.m. The gauge pressure was 6.0 Kg/cm2. After cooling to room temperature, NAFION was separated by filtration whereby a colorless, transparent methanolic solution was obtained. By adding water and evaporating methanol at 40° C. under reduced pressure, an aqueous methyl glucoside solution was obtained. The aqueous solution was essentially colorless and transparent and 53.6 g of solid matters were contained therein. By liquid chromatography and enzymatic method, the composition of the solid matters was found to be the following:
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([C:31]([O:33]CC)=[O:32])([CH:11]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[O:14][CH2:13][CH2:12]1)[C:6]([O:8]CC)=[O:7])C.[OH-].[Na+]>CO>[C:31]([C:5]([CH:11]1[C:20]2[C:15](=[CH:16][C:17]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)(=[O:23])=[O:22])=[CH:18][CH:19]=2)[O:14][CH2:13][CH2:12]1)([C:4]([OH:36])=[O:3])[C:6]([OH:8])=[O:7])([OH:33])=[O:32]
Reactant: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(C(=O)O)(C(=O)O)C1CCOc2cc(S(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 65 °C

Procedure:
To a solution of 2-Ethoxycarbonyl-2-[7-(3-fluoro-benzenesulfonyl)-chroman-4-yl]-malonicacid diethyl ester (5.0 g, 9.6 mmol) in MeOH (50 ml) was added NaOH (25 ml, 3N in H2O). The milky mixture was heated at 65° C. overnight. The solvent was evaporated to give crude 2-Carboxy-2-[7-(3-fluoro-benzenesulfonyl)-chroman-4-yl]-malonic acid as a solid.