Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:34]N1C(=O)CCC1=O>O1CCCC1>[Br:34][CH:17]1[CH2:18][CH2:19][N:15]([C:13]2[S:14][C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[O:9])=[C:11]([CH3:21])[N:12]=2)[C:16]1=[O:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(N2CCC(Br)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 50.8 %

Procedure:
To a solution of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide (0.35 g, 1.05 mmol) in anhydrous tetrahydrofuran (25 mL) at −78° C. was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.31 mL, 2.31 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 minutes, followed by the addition of N-bromosuccinimide (0.19 g, 1.05 mmol) dropwise. The reaction mixture was stirred at −78° C. for 10 min, quenched with aqueous saturated ammonium chloride solution (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic solutions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexanes (1/1) to afford the title compound as a white solid (0.22 g, 51%): 1H NMR (300 MHz, CDCl3) δ 7.34-7.24 (m, 2H), 7.07-6.97 (m, 2H), 5.98 (b s, 1H), 4.66-4.59 (m, 1H), 4.58 (d, J=5.8 Hz, 2H), 4.30-4.14 (m, 2H), 2.86-2.69 (m, 1H), 2.64 (s, 3H), 2.56-2.45 (m, 1H); MS (ES+) m/z 412 (M+1), 414 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1F.[NH2:13][C@H:14]([C:18]([O-:20])=[O:19])[CH:15]([CH3:17])[CH3:16].[K+].S1(CCCC1)(=O)=O.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[NH:13][CH:14]([CH:15]([CH3:17])[CH3:16])[C:18]([OH:20])=[O:19]
Reactant: CC(C)[C@H](N)C(=O)[O-]
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Temperature: 125 °C
Yield: 96 %

Procedure:
A mixture of 10 parts of 3-chloro-4-fluorobenzotrifluoride, 10 parts of potassium valinate and 50 parts of sulfolane was heated and maintained at about 125° C. for about 17 hours, with mixing. The mixture was then cooled to room temperature, diluted with water and acidified with hydrochloric acid to a pH of 1.0. The aqueous layer was extracted with diethyl ether. The ether layers were washed with water, then dried and concentrated by evaporation to yield 9.6 parts of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (96% purity); a yield of about 65% based on the 3-chloro-4-fluorobenzotrifluoride starting material.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[C:12]([C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2)([OH:14])=[O:13]>CO>[CH3:1][O:13][C:12]([C:15]12[CH2:24][CH:19]3[CH2:18][CH:17]([CH2:23][CH:21]([CH2:20]3)[CH2:22]1)[CH2:16]2)=[O:14]
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(=O)C12CC3CC(CC(C3)C1)C2

Procedure:
In the presence of an acid catalyst (p-toluenesulfonic acid), 1-carboxyadamantane obtained in Example 2 was allowed to react with an excess amount of methanol to give 1-methoxycarbonyladamantane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1)[CH3:2].[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>>[Br:16][CH2:15][C:11]1[C:7]2[C:8](=[O:10])[O:9][C:4]([O:3][CH2:1][CH3:2])=[N:5][C:6]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1nc2cccc(C)c2c(=O)o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCOc1nc2cccc(CBr)c2c(=O)o1

Procedure:
A solution of 2-ethoxy-5-methyl-4H-3,1-benzoxazin-4-one (330 mg), N-bromosuccinimide (340 mg) and AIBN (10 mg, 2,2'-azobis-iso-butyronitrile) was refluxed for 21/2 hours. The solution was evaporated to dryness. The residue was purified by column chromatography (silica gel) 10% ethyl acetate:petroleum ether 30-60). This afforded the title compound, 5-bromomethyl-2-ethoxy-4H-3,1-benzoxazin-4-one, m.p. 112°-114° C.; IR: 1760, 1630, 1590 cm-1.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O.[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-])=O)[C:24](F)=[CH:23][C:22]=1[F:31]>>[F:20][C:21]1[CH:26]=[C:25]2[C:24](=[CH:23][C:22]=1[F:31])[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH:13]1[C:17](=[O:19])[NH:27]2
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Product: O=C1Nc2cc(F)c(F)cc2N2CCNCC12
Yield: 16.7 %

Procedure:
By the same procedure described for example 2 method 2B, from 1.5 g of racemic 4-carbobenzyloxypiperazine-2-carboxylic acid and 1,2,4-trifluoro-5-nitro-benzene, there was obtained 0.4 g (16.7%) of title compound as an orange-red residue.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH2:4][C:5]3[N:10]4[CH:11]=[CH:12][N:13]=[C:9]4[C:8](=[O:14])[NH:7][C:6]=3[C:15]=2[CH:16]=[CH:17][CH:18]=1.S(=O)(=O)(O)O.[N+:24]([O-])([O-:26])=[O:25].[K+]>>[N+:24]([C:18]1[CH:17]=[CH:16][C:15]2[C:6]3[NH:7][C:8](=[O:14])[C:9]4[N:10]([CH:11]=[CH:12][N:13]=4)[C:5]=3[CH2:4][C:3]=2[C:2]=1[Br:1])([O-:26])=[O:25]
Reactant: O=c1[nH]c2c(n3ccnc13)Cc1c(Br)cccc1-2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2c(n3ccnc13)Cc1c-2ccc([N+](=O)[O-])c1Br
Temperature: 20 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
1 g of 9-bromo-5H, 10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is added to 6 ml of concentrated sulphuric acid (20N) at a temperature close to 0° C. 0.3 g of potassium nitrate is then added in two portions to this solution while maintaining the temperature between 0° and 5° C. The reaction medium is stirred for 18 hours at 20° C., then poured into 50 ml of ice-cold water. The insoluble matter is filtered, washed with 50 ml of ethyl acetate and dried under reduced pressure (15 mmHg; 2 kPa) at 50° C. 0.77 g of 8-nitro-9-bromo-5H, 10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-4-one is thus obtained which melts above 260° C. (analysis: % calculated C: 44.98, H: 2.03, Br: 23.02, N: 16.14, % found C: 45.40, H: 2.20, Br: 21.30, N: 15.70).
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>CO.O>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: NC1CCCCNC1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (±)-α-amino-ε-caprolactam (256 mg, 2.0 mmol), 2,4,5-trichloropyrimidine (366 mg, 2.0 mmol, 1 equiv.) and NaHCO3 (168 mg, 2 mmol, 1 equiv.) in a mixture of MeOH (12 mL) and H2O (6 mL) was stirred at room temperature for 15 h. The resulting precipitate was collected by vacuum filtration and washed with small amounts of MeOH and water, providing the product 3-(2,5-dichloropyrimidin-4-ylamino)azepan-2-one; ESMS m/z 275.0 (M+H+).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[F:5][C:6]1[CH:7]=[C:8]([CH:14]=[C:15]([F:18])[C:16]=1[F:17])[CH:9]=[CH:10][N+:11]([O-:13])=[O:12].C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[C:8]([CH:9]2[CH:10]([N+:11]([O-:13])=[O:12])[CH2:4][CH:3]=[CH:2][CH2:1]2)[CH:14]=[C:15]([F:18])[C:16]=1[F:17]
Reactant: O=[N+]([O-])C=Cc1cc(F)c(F)c(F)c1
Reactant: C=CC=C
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])C1CC=CCC1c1cc(F)c(F)c(F)c1

Procedure:
3.24 g (60 mmol) of butadiene were condensed at −78° C. into an autoclave under a nitrogen atmosphere. 2.03 g (10 mmol) of 3,4,5-trifluoro-β-nitrostyrene from example 2.2 dissolved in 6 ml of toluene and 30 mg of hydroquinone were added. A nitrogen atmosphere was applied (120 bar) and the suspension was heated for 12 h to 130° C. The reaction mixture was expanded and all volatiles were evaporated in vacuo. Column chromatography (SiO2, cyclohexane/ethylacetate 9:1) yielded 2.4 g (9.4 mmol, 94% of theory) of the title compound as yellowish crystals.
Reaction SMILES: C([N:3](CC)CC)C.[CH2:8]([O:15][CH2:16][C:17](Cl)=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][CH2:16][C:17]([NH2:3])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Starting with the 3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluoro-phenyl]-5-hydroxymethyl-oxazolidin-2-one which was formed as an intermediate in Example 3, the procedure of Example 1 was repeated to produce an azide compound in a yield of 90%. The azide compound (1.5 g) was reduced with triphenylphosphine/tetrahydrofuran/water by the same method as in Example 10 to provide a primary amine compound. The amine compound and triethylamine (1.2 ml) were added to dry dichloromethane (20 ml) and benzyloxyacetyl chloride (1.20 g) was subsequently added at 0° C. The reaction mixture was stirred overnight at room temperature and the resulting precipitate was filtered off. The filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography (methanol/dichloromethane=5/95) to afford a benzyloxyacetamide compound (2.7 g) in a yield of 100%. The benzyloxyacetamide compound (1.9 g) was dissolved in a mixed solvent consisting of methanol (30 ml) and dichloromethane (5 ml). To the solution, 10% palladium hydroxide/carbon (340 mg) was added and the mixture was stirred for 2 days under 3 atm hydrogen atmosphere. The palladium hydroxide was filtered off and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol/dichloromethane=7/93) to afford an α-hydroxyacetamide compound (780 mg) in a yield of 49%. To a tetrahydrofuran solution (10 ml) of the α-hydroxyacetamide compound (530 mg), p-toluenesulfonyl fluoride (450 mg) and tetrabutylammonium fluoride (1.0M tetrahydrofuran solution; 3.3 ml) were added and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane/acetone=2/3) to afford a monofluoroacetamide compound (562 mg) in a yield of 100%. To 10 ml of an acetone solution of the monofluoroacetamide compound, p-toluenesulfonic acid monohydrate (580 mg) and water (3 ml) were added and the mixture was heated under reflux for 2.5 h. The reaction mixture was cooled to room temperature, neutralized with solid sodium hydrogencarbonate, and concentrated under vacuum. Water was removed by azeotropy with toluene and the residue was purified by silica gel column chromatography (hexane/acetone=1/1) to afford the title compound (408 mg) in a yield of 81%.
Reaction SMILES: [Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][OH:5].FC(F)(F)S(O[Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])(=O)=O.CCN(C(C)C)C(C)C>ClCCl>[Br:1][C:2](=[CH2:6])[CH2:3][CH2:4][O:5][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: C=C(Br)CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(Br)CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 3-bromobut-3-en-1-ol (5.2 g, 34.4 mmol) in dichloromethane (69 mL) at rt was added tert-Butyldimethylsilyl trifluoromethanesulfonate (10 g. 37.9 mmol) and DIEA (7.22 mL, 41.3 mmol) and the mixture was stirred at rt for 30 min. The reaction mixture was partitioned between dichloromethane and water, and the crude product obtained from the dichloromethane layer was purified by chromatography eluting with 5-30% EtOAc/Hexanes to give the title compound as a colorless liquid (8.72 g, 95%). 1H NMR (400 MHz, CDCl3) δ 5.66 (1H, s), 5.48 (1H, s), 3.81 (2H, t, J=6.0 Hz), 2.64 (2H, t, J=6.0 Hz), 0.91 (9H, s), and 0.09 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:12]OC(OC)N(C)C.CO>CN(C)C=O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]2[NH:9][CH:12]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CN(C)C=O
Solvent: CO
Product: Brc1cnc2cc[nH]c2c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To a solution of 5-bromo-2-methyl-3-nitro-pyridine (1.58 g, 7.28 mmol) [prepared according to WO 2006/103449] in dimethylformamide (10 mL) was added dimethylformamide dimethyl acetal (1.65 mL, 12.37 mmol). The reaction mixture was stirred at 100° C. for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in glacial acetic acid (25 mL) and iron powder (3.25 g, 58.24 mmol) was added. The reaction mixture was stirred at 100° C. for 21 h, then it was cooled to room temperature. Methanol (25 mL) was added and the suspension was filtered and washed with Methanol. The filtrate was concentrated in vacuo. The residue was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, and adsorbed on silica gel. Purification on silica gel by flash chromatography using a gradient of 0-70% ethyl acetate/hexane provided 869 mg of the title compound as an ivory solid (60% yield): 1H NMR (DMSO-d6): δ 6.77 (s, 1H), 7.68 (s, 1H), 8.00 (s, 1H), 8.36 (s, 1H), 11.46 (broad s, 1H); MS (m/z) 197, 199 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=O)[CH2:8]1.Cl.[NH2:20][NH:21][C:22]([NH:24][OH:25])=[NH:23].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:18])=[CH:5][C:6]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=[N:20][NH:21][C:22](=[NH:23])[NH:24][OH:25])[CH2:8]1
Reactant: N=C(NN)NO
Reactant: Cc1n[nH]c2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)NO)CC(c1cc(Cl)sc1Cl)C2
Temperature: 90 °C
Reaction time: 4 h
Yield: 156.8 %

Procedure:
To a mixture of 6-(2,5-dichlorothiophen-3-yl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (0.211 g) and 1-amino-3-hydroxyguanidine hydrochloride (102 mg) were added ethanol (4 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 90° C. for 4 hours. Under reduced pressure, the solvent was evaporated, and to the residue was ethanol (2 ml). Precipitated crystals were filtered, washed with ethanol and dried to give 6-(2,5-dichlorothiophen-3-yl)-4-(1-hydroxyguanidin-3-yl)imino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 128) (0.225 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:14](N)=[O:15]>>[CH:14]([NH:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:15]
Reactant: NC=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: O=CN[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
Under a nitrogen atmosphere, a slurry of 1.81 gm (10 mmol) tyrosine in 4.0 ml (100 mmol) formamide was heated at 90° C. for 19 hours and 10 minutes. Examination of the resulting homogeneous solution by proton NMR showed an 84% conversion of the tyrosine to its N-formyl derivative.
Reaction SMILES: [CH2:1]([CH:4]1[C@:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])([CH3:10])[N:8]=[C:7]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]([CH3:37])([CH3:36])[S:5]1(=[O:39])=[O:38])[CH:2]=C.C(=O)(O)[O-:41].[Na+].C(Cl)Cl.[BH4-].[Na+]>CO>[C:24]([O:23][C:22]([N:21]([C:7]1[C:6]([CH3:37])([CH3:36])[S:5](=[O:38])(=[O:39])[CH:4]([CH2:1][CH2:2][OH:41])[C@:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])([CH3:10])[N:8]=1)[C:29](=[O:30])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: O=C([O-])O
Reactant: C=CCC1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@](C)(c2cc([N+](=O)[O-])ccc2F)C(CCO)S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
A 3-necked round bottom flask equipped with a mechanical stirrer, Claisen adapter with thermocouple and a nitrogen inlet was charged with tert-butyl N-[(3R)-2-allyl-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (4.00 g, 7.02 mmol, 2.85:1 ratio of diastereomers), sodium bicarbonate (1.180 g, 14.04 mmol), DCM (30 mL) and MeOH (10.00 mL), and the resulting solution was cooled to Tinternal<−65+/−1° C. Ozone was bubbled through the reaction mixture until starting material was consumed according to LCMS (˜1.5 h). The solution was purged with oxygen and then nitrogen, and sodium borohydride (0.531 g, 14.04 mmol) added in one portion. The cooling bath was removed, and the reaction mixture was allowed to warm to RT overnight. 2 mL acetone was added, followed by 10 mL sat. aq.NH4Cl. After stirring for 10 min, 5 mL water was added and the layers were separated. The organic portion was dried over magnesium sulfate, filtered and concentrated in vacuo to provide tert-butyl N-tert-butoxycarbonyl-N-[(3R)-3-(2-fluoro-5-nitro-phenyl)-2-(2-hydroxyethyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]carbamate (4.04 g, 2.85:1 ratio of diastereomers) as a white solid that was used without further purification. LC/MS (ESI+) m/z=596.2 (M+Na).
Reaction SMILES: [CH2:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=N)[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C[O:20]CCO>Cl.O>[CH2:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][CH:10]2[S:14][C:13](=[O:20])[NH:12][C:11]2=[O:16])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: COCCO
Reactant: CC(=O)Cc1ccc(CC2SC(=N)NC2=O)cc1
Agent: Cl
Solvent: O
Product: CC(=O)Cc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
5-(4-Acetonylbenzyl)-2-iminothiazolidine-4-one (1g) was heated under reflux in a mixture of 2-methoxyethanol 20 ml and 2N HCl (5 ml) for 8 h. The cooled mixture was diluted with water and the resulting precipitate filtered and dried under vacuum to give 5-(4-acetonylbenzyl)thiazolidine-2,4-dione as a white solid, mp 133°-135° C.
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:9]=[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[CH:12][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([C:10]2[CH:11]=[CH:12][C:13]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([F:7])[CH:9]=2)=[CH:22][CH:21]=1)[CH3:24]
Reactant: CCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Reactant: Brc1ccc[se]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(-c3ccc[se]3)c(F)c2)cc1

Procedure:
A mixture of 34.2 g (0.16 mol) of 2-bromoselenophene, 40.0 g (0.16 mol) of 3-fluoro-4′-ethylbiphenyl-4-ylboronic acid, 10.0 g (8.65 mmol) of tetrakis-(triphenylphosphine)palladium(0) and 200 ml of 2 N sodium carbonate soln. in 500 ml of toluene/ethanol (2:3) is heated at 90° C. for 2 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with water, and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=9:1). 2-(4′-Ethyl-3-fluorobiphenyl-4-yl)-selenophene is obtained as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][NH:14][C:15](=[O:17])[CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>C(Cl)Cl>[C:15]([NH:14][CH2:13][C:7]1([C:1]2[CH:6]=[CH:5][C:4]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)(=[O:17])[CH3:16]
Reactant: CC(=O)NCC1(c2ccccc2)CCCCC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(=O)NCC1(c2ccc(S(=O)(=O)Cl)cc2)CCCCC1
Temperature: 50 °C
Reaction time: 10 h

Procedure:
4.5 g of N-(1-Phenyl-cyclohexylmethyl)-acetamide were dissolved in 80 ml of methylenechloride and 3.8 ml of chlorosulfonic acid were added. The reaction mixture was stirred at 50° C. for 10 hours and was poured on ice water. The organic layer was separated, washed twice with 50 ml brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 1.5 g of a light yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH:18]C=O)[S:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2].Cl.C(O)C>O1CCCC1>[CH2:1]([O:3][C:4]([CH2:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1)[C:10]([OH:12])=[O:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)CON=C(C(=O)O)c1csc(NC=O)n1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
A mixture of 2-ethoxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (7.2 g.), conc. hydrochloric acid (10 ml.), ethanol (70 ml.) and tetrahydrofuran (20 ml.) was stirred for 2 hours at ambient temperature. After removing the solvent from the reaction mixture in vacuo, water was added thereto and the mixture was adjusted to pH 3.3 with an aqueous solution of sodium bicarbonate under ice-cooling. Precipitates were collected by filtration and dried to give 2-ethoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (4.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:12]([CH2:13][OH:14])=[CH:11][N:10]([CH3:15])[N:9]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:24][C:25]=1[CH3:26])[CH2:6][O:7][C:8]1[C:12]([CH:13]=[O:14])=[CH:11][N:10]([CH3:15])[N:9]=1
Reactant: COc1cc(COc2nn(C)cc2CO)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(C)cc2C=O)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
A mixture of (3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazol-4-yl)methanol (3.40 g), activated manganese dioxide (10.03 g) and tetrahydrofuran (50 mL) was stirred overnight at room temperature. Manganese dioxide was removed by filtration, and the filtrate was concentrated to give 3-{[3-methoxy-4-(5-methyl-2-phenyl-1,3-oxazol-4-ylmethoxy)benzyl]oxy}-1-methyl-1H-pyrazole-4-carbaldehyde (3.25 g, yield 96%) as colorless crystals. The crystals were recrystallized from acetone-hexane. melting point: 123-124° C.