Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=C)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.C[N+]1([O-])CC[O:26]CC1.S(=O)(O)[O-].[Na+]>C1COCC1.O.CC(O)(C)C.O=[Os](=O)(=O)=O>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]([CH2:17][CH:18]=[O:26])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1
Reactant: C=CCN(CC(C)(C)C)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)CN(CC=O)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 81.3 %

Procedure:
To a solution of 4-[(2,2-dimethylpropyl)(2-propen-1-yl)amino]-2-(trifluoromethyl)benzonitrile (1.46 g, 4.95 mmol) in THF/water (20:1, 45 mL) at rt was added a solution of OsO4 (1.02 g of a 2.5 wt % solution in t-BuOH, 0.10 mmol) in THF/water (20:1, 5 mL), followed by NMO (1.22 g, 10.4 mmol) in one portion. The resulting mixture was stirred 22 hours at rt, cooled to 0° C. and sodium bisulfite (0.300 g) was added in one portion. The mixture was stirred 1 h, filtered through a pad of Celite (EtOAc wash) and the filtrate/washings were partitioned between EtOAc/water (required addition of NaCl to separated layers). The aqueous layer was extracted with EtOAc (×1), combined organics were washed with brine and concentrated in vacuo. The residue was dissolved in acetone (50 mL), a solution of NalO4 (2.22 g; 10.4 mmol) in water (20 mL) was added, the mixture was stirred two hours at rt and partially concentrated in vacuo to an aqueous residue. The residue was partitioned between EtOAc/water and the aqueous layer was further extracted with EtOAc (×1). Combined organics were washed (water, brine), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording 1.20 g of the title compound as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.57 (d, J=8.8 Hz, 1H), 6.96 (d, J=2.5 Hz, 1H), 6.74 (dd, J=8.9, 2.7 Hz, 1H), 4.31 (s, 2H), 3.33 (s, 2H), 1.02 (s, 9H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@@H:15]1[C:19]([OH:21])=O)=[O:13].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][C:12]([CH:14]1[S:18][CH2:17][NH:16][C@@H:15]1[C:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:13]
Reactant: C1CCNC1
Reactant: O=C(CC1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)O
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: O=C(CC1CCc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCCC1
Yield: 52 %

Procedure:
Colorless crystals of 1-[3-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioprolyl]pyrrolidine were prepared in the same manner as in Example 1, except that 3-(1,2,3,4-tetrahydronaphthalen-2-ylacetyl)-L-thioproline and pyrrolidine were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 52%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)[O:6]CCO1.[Cl:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:17][C:18]1[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=1/[CH:26]=[CH:27]/[C:28]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:2](=[O:6])[CH3:1])[N:12]=1)=[O:29]
Reactant: CC1(CCCCn2ccc(N)n2)OCCO1
Reactant: O=C(O)/C=C/c1c(F)ccc(F)c1Cl
Product: CC(=O)CCCCn1ccc(NC(=O)/C=C/c2c(F)ccc(F)c2Cl)n1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-3-ylamine and (E)-3-(2-chloro-3,6-difluoro-phenyl)-acrylic acid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[CH:10]=[CH:11][CH:12]=1)=O.[NH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>C(O)C.CCOC(C)=O>[F:20][C:19]([F:21])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[CH:4]=[CH:3][N:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:25]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccc(-c2ccccc2C(F)(F)F)c1
Reactant: NNc1ccccn1
Solvent: CCOC(C)=O
Solvent: CCO
Product: FC(F)(F)c1ccccc1-c1cccc(-c2ccn(-c3ccccn3)n2)c1
Yield: 12.9 %

Procedure:
To a solution of the product from Step 1 (0.224 g, 0.7 mmol) in ethanol (3.5 mL) was added 2-hydrazinopyridine (0.076 g, 0.7 mmol) and the solution was refluxed for 16 hours. The reaction was cooled, diluted with EtOAc, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The organic phase was filtered, concentrated, and the crude product was purified by reverse phase HPLC (acetonitrile/water system) (gradient: 30% to 100% acetonitrile over 12 minutes) to give product A (0.033 g, 29% yield, retention time 5.28 minutes) and the regioisomeric product B (0.021 g, 18% yield, retention time 7.25 minutes).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Product: CS(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(Cl)c3)n2)c1

Procedure:
Reaction of 3-((E)-3-dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) and (3-chloro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=427.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:7][CH2:6][N:5]([C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:4][CH2:3]1.[C:16]([C:18]1[N:19]=[C:20]([C:31](O)=[O:32])[N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=1)#[N:17].[K]>>[CH3:1][C:2]1([CH3:15])[CH2:3][CH2:4][N:5]([C:8]2[C:13]([NH:14][C:31]([C:20]3[N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:18]([C:16]#[N:17])[N:19]=3)=[O:32])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: CC1(C)CCN(c2ncccc2N)CC1
Agent: [K]
Product: CC1(C)CCN(c2ncccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
4,4-Dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-ylamine (as prepared in above step) was coupled with 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 11, step (d), as described in Example 32, step (c) to afford 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (4,4-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-yl)-amide which was subjected to SEM deprotection as described in Example 47, step (d) to afford the title compound. 1H-NMR (DMSO-d6; 400 MHz): δ 14.4 (s, 1H), 9.72 (s, 1H), 8.39 (m, 2H), 8.11 (dd, 1H, J=4.8, 1.7 Hz), 7.13 (dd, 1H, J=4.8, 1.7 Hz), 3.02 (m, 4H), 1.56 (m, 4H), 1.01 (s, 6H); Mass spectrum (ESI, m/z): Calcd. for C17H20N6O, 325.1 (M+H), found 325.2.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]>CO>[C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: CO
Product: O=C(O)[C@@H](O)c1ccccc1
Temperature: 35 °C
Reaction time: 24 h
Yield: 281.2 %

Procedure:
To a 100 mL flask equipped with a magnetic stirrer containing a solution of a 7:3 (enantiomer A: enantiomer B) mixture of the enantiomers (3.24 g, 11 mmol) in methanol (30 mL) at 35° C. was added (R)-(−)-mandelic acid (1.09 g, 7.2 mmol) dissolved in methanol (35 mL). The resulting mixture was stirred at an internal temperature of 35° C. for 24 h. The crystallized solid was filtered through a sintered glass funnel, washed with methanol at room temperature (3×16 mL) and dried under vacuum to afford 3.08 g (63%) of the title compound (enantiomer A and (R)-(−)-mandelic acid, HPLC 97% ee) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([NH:20][CH2:21][CH2:22][CH3:23])=[C:16]([CH2:18][CH3:19])[N:17]=2)[CH:12]=[CH:13][N:14]=1.[CH:24](=O)[CH2:25][CH3:26].S(=O)(=O)(O)O.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:11]([C:15]([N:20]([CH2:24][CH2:25][CH3:26])[CH2:21][CH2:22][CH3:23])=[C:16]([CH2:18][CH3:19])[N:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: CCCNc1c(CC)nc2c(-c3ccc(Cl)cc3Cl)nccn12
Reactant: CCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)c1c(CC)nc2c(-c3ccc(Cl)cc3Cl)nccn12
Reaction time: 3 h
Yield: 81.8 %

Procedure:
N-[8-(2,4-Dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N-propylamine (296 mg, 0.85 mmol) and propionaldehyde (0.19 mL, 2.6 mmol) were dissolved in tetrahydrofuran (1.1 mL), and 3M sulfuric acid (0.87 mL, 2.6 mmol) was added thereto. Sodium borohydride (70 mg) was added thereto under ice-cooling, and the mixture was stirred for 3 hours. Water was added to the reaction mixture, which was neutralized with a 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:2) to give N-[8-(2,4-dichlorophenyl)-2-ethylimidazo[1,2-a]pyrazin-3-yl]-N,N-dipropylamine (272 mg) as pale yellow crystals. The resulting free compound was converted into hydrochloride with hydrochloric acid-ether using the conventional method, to give the title compound (250 mg) as white crystals.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([O:13][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH:24]([OH:26])[CH3:25])=[CH:18][CH:17]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(O)c(Cl)c1=O
Reactant: CC(O)CCc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(O)CCc1ccc(COc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a solution of the product of Example 7A (505 mg, 2.447 mmol) in THF (19 mL) at 0° C. was added a 1M solution (in THF) of lithium aluminum hydride (12.2 mL, 12.237 mmol) dropwise. After completion of addition the ice bath was removed and the reaction was stirred at room temperature for 1 hour under nitrogen atmosphere. Then, in succession, was added water (183 μL), 15% NaOH solution (183 μL), and water (548 μL). The reaction stirred for an additional 15 minutes before it was filtered and washed with THF. The filtrate was then concentrated under reduced pressure to obtain 4-(4-hydroxymethyl-phenyl)butan-2-ol as a brown oil (314 mg, 71% yield). Then to a solution of 2-tert-butyl-4-chloro-5-hydroxy-2H-pyridazin-3-one (234 mg, 1.155 mmol) in THF (45 mL) was added 4-(4-hydroxymethylphenyl)butan-2-ol (312 mg, 1.732 mmol), triphenylphosphine (454 mg, 1.732 mmol), and then diisopropyl azodicarboxylate (DIAD, 335 μL, 1.732 mmol). The reaction was stirred at room temperature overnight under nitrogen atmosphere. Thin layer chromatography (100% ethyl acetate) indicated consumption of the pyridazinone starting material and the reaction was concentrated. The crude material was purified by flash column chromatography (4:1 hexane:ethyl acetate to 100% ethyl acetate) to obtain a clear oil (200 mg, 48% yield). 1H NMR (600 MHz, CDCl3): δ 7.73 (s, 1H), 7.32 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 5.30 (s, 1H), 5.27 (s, 2H), 3.83 (m, 1H), 2.80-2.76 (m, 1H), 2.71-2.66 (m, 1H), 1.63 (s, 9H), 1.23 (d, 3H, J=6.2); 13C (CDCl3 159.3, 153.9, 143.2, 132.5, 129.2, 127.6, 125.4, 150 MHz): δ HRMS calcd for 0118.5, 73.4, 67.6, 66.6, 40.9, 32.0, 28.1, 23.9.19H25ClN2O3: 365.162647, found 365.1624.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:35][CH3:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=O)[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:35]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[C:30]([CH3:31])=[C:29]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[NH:12][C:11]2=[O:17])[NH:28][C:27]=1[CH3:34])=[O:25])[CH3:36]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 59 %

Procedure:
To a solution of 4-(3-fluoro-phenyl)1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (69.0 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 5-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (70 mg, 59%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[C:7]2[N:8]([N:19]=[CH:20][N:21]=2)[C:9](N)=[N:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].N([O-])=O.[Na+].[ClH:26]>O>[Cl:26][C:9]1[N:8]2[N:19]=[CH:20][N:21]=[C:7]2[C:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1
Reactant: Cl
Reactant: CCOCCc1c(-c2ccccc2)nc(N)n2ncnc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Reaction time: 0.5 h

Procedure:
A solution containing 100.8 g of 8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine (0.36 moles) dissolved in 600 ml of concentrated hydrochloric acid and 420 ml. of water is cooled to 3° C. with constant stirring. To the cooled solution is added (below the surface of the solution) a mixture containing 54 g. of sodium nitrite (0.72 moles) in 75 ml of water over a period of fifteen minutes. The reaction mixture is stopped and stirred in an ice-bath for 0.5 hour and then stirred at room temperature for one hour. To the reaction mixture is added 150 ml of water and the resulting mixture is allowed to remain overnight at room temperature. A precipitate formed and the mixture is filtered and the precipitate is washed with water and dried yielding a crude product. The crude product is recrystallized from diethylether yielding 5-chloro-8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine represented by the structural formula ##STR18## as a white solid having a melting point of 134°-135° C. and the following elemental analysis:
Reaction SMILES: [O:1]([C@@H:9]([C@H:11]1[C@@H:14]([S:15]([CH3:18])(=[O:17])=[O:16])[NH:13][C:12]1=[O:19])[CH3:10])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[SnH4].[Si](Cl)(C(C)(C)C)(C)C.N12CCCC1=NCCC2.CI.CC(C)([O-])C.[K+]>C(Cl)Cl>[O:1]([C@@H:9]([CH:11]1[CH:14]([S:15]([CH3:18])(=[O:17])=[O:16])[NH:13][C:12]1=[O:19])[CH3:10])[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:4])[CH3:3]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@@H]1S(C)(=O)=O
Agent: C1CN=C2CCCN2C1
Agent: CC(C)(C)[O-]
Agent: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CI
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)C1C(=O)NC1S(C)(=O)=O

Procedure:
A multistep synthesis of (3R,4R)-3-[1(R)-(t-butyldimethylsiloxy)ethyl]-4-methylsulfonylazetidin-2-one (formula III, X=SO2CH3) from methyl (3S,5R,6S)-6-bromo-6[1(R)-hydroxyethyl]penicillanate is reported by Hirai et al., Tetrahedron Lett. 23, 4021 (1982). The synthesis involves tin hydride debromination of the starting material followed by protection of the hydroxy group of the 6-substituent by silylation with t-butyldimethylsilyl chloride and oxidation of the resulting product to the cis sulfone derivative. The crucial step of the synthesis, reported to be isomerization of the cis sulfone to the trans sulfone, was "satisfactorily" achieved by means of a catalytic amount of 1,5-diazabicyclo [4.3.0]non-5-ene (DBN) in methylene chloride at room temperature. Ring opening of the trans sulfone by treatment with excess methyl iodide and potassium t-butoxide afforded 3-[1(R)-(t-butyldimethylsiloxy)-ethyl]-4-methylsulfonylazetidin-2-one.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:15](O)[CH3:16]>>[F:1][C:2]([F:9])([F:8])[CH:3]([OH:7])[C:4]([O:6][CH2:15][CH3:16])=[O:5]
Reactant: CCO
Reactant: O=C(O)C(O)C(F)(F)F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(O)C(F)(F)F
Reaction time: 43 h
Yield: 68 %

Procedure:
The step (b) of the present invention was conducted as follows. At first, 2.84 g of the crude product obtained by Example 1 (containing 16.07 mmol (1.00 eq.) of 3,3,3-trifluoro-2-hydroxypropionic acid) and 19.6 mg (0.20 mmol, 0.01 eq.) of 98% sulfuric acid were added to 20 ml of ethanol, followed by stirring for 43 hr with heating under reflux. The resulting reaction liquid itself was subjected to a vacuum distillation (52° C./3,500 Pa), thereby obtaining 1.87 g of white, needle-like crystals of ethyl 3,3,3-trifluoro-2-hydroxypropionate of the following formula 8. The yield was 68%. The obtained crude product (the white, needle-like crystals) was used in the following step (c) of Example 3 without conducting a further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1>C(O)C.O=[Mn]=O>[OH:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH:2]=[O:1])=[CH:8][CH:7]=1
Reactant: OCCCc1ccc(CO)cc1
Agent: O=[Mn]=O
Solvent: CCO
Product: O=Cc1ccc(CCCO)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
A solution of 3-(4-hydroxymethyl-phenyl)-propan-1-ol (500 mg, 3 mmol) in ethanol (40 mL) is treated with MnO2. The suspension is stirred at 80° C. for 5 h before it is filtered and evaporated to give 4-(3-hydroxy-propyl)-benzaldehyde (470 mg) as a brownish oil; LC-MS: tR=0.71 min; 1H NMR (CDCl3): δ 9.97 (s, 1H), 7.81 (d, J=7.6 Hz, 2H), 7.36 (d, J=7.6 Hz, 2H), 3.69 (t, J=6.1 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 1.97-1.85 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Na].[CH2:8](Br)[CH2:9][CH3:10]>C(O)C>[CH2:8]([S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1)[CH2:9][CH3:10]
Reactant: Sc1nc[nH]n1
Reactant: CCCBr
Agent: [Na]
Solvent: CCO
Product: CCCSc1nc[nH]n1
Temperature: 25 °C

Procedure:
3-Mercapto-1,2,4-triazole (20.2 g.) was added to a solution of 4.8 g. sodium in 150 ml. absolute ethanol. When dissolution was complete 24.6 g. propyl bromide was added. The stirred mixture was gradually heated to boiling under reflux, refluxed for 1 hour, cooled to room temperature and filtered. The filtrate was distilled to dryness under reduced pressure and the residue was dissolved in ether. The resulting solution was filtered, dried over anhydrous sodium sulphate and distilled under reduced pressure to give 3-propylthio-1,2,4-triazole, b.p. 143° - 144°C./1 mm. This product solidified, m.p. 53° - 56°C.
Reaction SMILES: [CH:1]([NH2:3])=[S:2].Br[CH:5]([CH3:23])[C:6]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=1)=O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:19]([C:10]1[CH:9]=[C:8]([C:6]2[N:3]=[CH:1][S:2][C:5]=2[CH3:23])[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(Br)C(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: NC=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1scnc1-c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 39.7 %

Procedure:
A mixture of 0.7 g of thioformamide, 3.4 g of 4-(2-bromopropionyl)-2,6-di-tert-butylphenol, and 15 ml of absolute ethanol was heated to 50°-60° C. for 2-3 hours. After cooling, the reaction mixture poured into a diluted aqueous solution of potassium carbonate. The precipitates thus formed were recovered by filtration and recrystallized from a mixture of cyclohexane and hexane to provide 1.2 g of 4-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-methylthiazole.
Reaction SMILES: OO.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[C:12](=[O:24])[C@@H:11]([CH2:25][C:26]#[N:27])[O:10][C@H:9]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[C:8]=2[CH:38]=1.C(=O)([O-])[O-:40].[K+].[K+]>C(O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[CH3:23])[C:12](=[O:24])[C@@H:11]([CH2:25][C:26]([NH2:27])=[O:40])[O:10][C@H:9]([C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=[CH:30][CH:29]=3)[C:8]=2[CH:38]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nccn1CCCCN1C(=O)[C@@H](CC#N)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Agent: OO
Agent: [K+]
Solvent: CCO
Product: Cc1nccn1CCCCN1C(=O)[C@@H](CC(N)=O)O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc21
Temperature: 60 °C
Yield: 37.9 %

Procedure:
Hydrogen peroxide solution (30% w /v in H2O, 4 ml) was added to a suspension of trans-7-chloro-5-(1-naphthyl)-1-(4-(2-methylimidazol-1-yl)butyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetonitrile (250 mg, 0.5 mmol) and potassium carbonate (69 mg, 0.5 mmol) in ethanol (10 ml). The mixture was heated at 60° C. for 18 hours. The solvent was removed under reduced pressure, the resulting residue dissolved in dichloromethane and washed with brine. The organic layer was dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane/methanol/ammonia solution 97:3:1) to give a colorless oil. The oil was triturated with hot ethyl acetate/diethyl ether/hexane to give the title compound (98 mg, 38%)as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](N)[CH:4]=1.[CH3:10][N:11]1[C:15](=[O:16])[CH:14]=[CH:13][C:12]1=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[C:12]([N:11]([CH3:10])[C:15](=[O:16])[CH:14]=2)=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: COc1cccc(N)c1
Product: COc1cccc(C2=CC(=O)N(C)C2=O)c1

Procedure:
A 61.13 g portion of m-anisidine and 55.1 g of N-methylmaleimide were reacted as described in Example 6, giving 33.07 g of 2-(m-methoxyphenyl)-N-methylmaleimide.