Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:5]1[O:7][C@@H:6]1[C:8]([OH:10])=O)[CH2:2][CH2:3][CH3:4].CCCCC(F)(F)C(O)CC[C@@H]1[C@@H](CCCCCC[C:31]([OH:33])=[O:32])C(=O)C[C@H]1O.[CH2:38]1[CH2:43][CH2:42][CH:41]([NH:44]C2CCCCC2)[CH2:40][CH2:39]1.C(Cl)(=O)C(C)(C)C>O1CCCC1>[CH2:31]1[O:33][C:38]2[CH:43]=[CH:42][C:41]([NH:44][C:8]([C@@H:6]3[C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[O:7]3)=[O:10])=[CH:40][C:39]=2[O:32]1
Reactant: CCCC[C@H]1O[C@@H]1C(=O)O
Reactant: CCCCC(F)(F)C(O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(=O)O
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CCCC[C@H]1O[C@@H]1C(=O)Nc1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Under ice-cooling, to 10 ml of an anhydrous tetrahydrofuran solution containing 299 mg (1.84 mmol) of (2S-trans)-3-butyl-oxiranecarboxylic acid.dicyclohexylammonium salt was added 2 ml of an anhydroustetrahydrofuran solution containing 222 mg (1.84 mmol) of pivaloyl chloride, and the resulting mixture was stirred at the same temperature for 15 minutes. Moreover, the temperature of the reaction mixture was returned to room temperature, and the mixture was stirred for 2 hours. After insoluble material in the reaction mixture was filtered off, the filtrate was added to 10 ml of an anhydrous tetrahydrofuran solution containing 252 mg (1.84 mmol) of 3,4-methylene-dioxyaniline under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. Under reduced pressure, the reaction mixture was concentrated, ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 484 mg (Yield: 100%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([NH:7][C:8](=[N:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])SC)=[O:6])[CH3:3].[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.CCN(CC)CC.CS>CN(C=O)C.CCOC(C)=O.[Hg]Cl>[C:2]([O:4][C:5](=[O:6])[NH:7][C:8](=[N:11][C:12]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:18])[N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1)([CH3:1])([CH3:3])[CH3:19]
Reactant: C1CSCCN1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: CS
Agent: Cl[Hg]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCSCC1
Reaction time: 18 h

Procedure:
A solution of [[[(1,1-dimethylethoxy)carbonyl]amino]-(methylthio)methylene]-carbamic acid, 1,1-dimethylethyl ester [CAS 107819-90-9] (21 g, 0.0723 mol) in DMF (450 mL) was treated sequentially with thiomorpholine (7 mL, 0.0723 mol), mercury chloride (19.6 g, 0.0723 mol), and Et3N (30 mL, 0.22 mol) and the reaction mixture was stirred for 18 h. The mixture was diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was concentrated, diluted with water and EtOAc and filtered again through a pad of diatomaceous earth. The filtrate aqueous layer was separated and extracted with EtOAc (2×). The combined organic layers were washed with water, then satd. aq. NaCl, dried, and concentrated. The solid was triturated with 20% Et2O/40-60° C. petrol. The solid was filtered off and was washed with 20% Et2O/40-60° C. petrol followed by 40-60° C. petrol. The solid was dried under vacuum to give 21.2 g (85%) as a white solid. Note: The reaction was performed with a trap for gaseous loss of methanethiol.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:28]=1)[C:24]1[CH:23]=[C:22]([OH:25])[CH:21]=[C:20]([F:26])[C:19]=1[O:18][C:17]1[C:12]2=[CH:13][C:14](Br)=[CH:15][CH:16]=1.[F:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1.CN(C=O)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[O:9][CH2:10][C@@:11]2([N:28]=1)[C:24]1[CH:23]=[C:22]([OH:25])[CH:21]=[C:20]([F:26])[C:19]=1[O:18][C:17]1[C:12]2=[CH:13][C:14]([C:35]2[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=2)=[CH:15][CH:16]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Temperature: 85 °C

Procedure:
A RBF was charged with sodium carbonate (2 M, 2 mL), tetrakis(triphenylphosphine)palladium (0.237 g, 0.205 mmol), (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (0.75 g, 2.054 mmol), and 2-fluoro-3-pyridineboronic acid (0.579 g, 4.11 mmol) and DMF (5 ml). The solution was heated at 85° C. overnight. The solution was diluted with water (25 ml) and filtered. The solids were triturated with methanol and dried under vacuum to afford (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a tan solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([C:19]([CH:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH2:22]1)=[O:20])[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]1)=[O:4].O[Li].O>C1COCC1.CO.O>[CH3:27][CH:24]1[CH2:25][CH2:26][CH:21]([C:19]([N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13]2)[C:9]2[CH:8]=[C:7]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[S:6][C:5]=2[C:3]([OH:4])=[O:2])=[O:20])[CH2:22][CH2:23]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(CC1CCCN(C)C1)C(=O)C1CCC(C)CC1
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1CCC(C(=O)N(CC2CCCN(C)C2)c2cc(-c3ccccc3)sc2C(=O)O)CC1
Temperature: 55 °C
Yield: 118.9 %

Procedure:
3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (162 mg, 0.27 mmol) was dissolved in a mixture of THF:MeOH:H2O (3:2:1, 2.8 mL) and treated with LiOH.H2O (35 mg, 0.81 mmol). The solution was heated at 55° C. for 3 h. The solvents were removed and the residue was acidified using HCl to pH 4. The product was extracted with EtOAc and the organic layers were washed with brine, dried and evaporated to provide 3-[(4-Methyl-cyclohexanecarbonyl)-(1-methyl-piperidin-3-ylmethyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (146 mg, 92% yield). 1H NMR (CDCl3, 400 MHz): 9.98 (br s, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.48-7.24 (m, 9H), 5.20-5.05 (m, 2H), 4.35-3.95 (m, 3H), 3.00 (m, 1H), 2.85-2.52 (m, 2H), 2.15 (m, 1H), 1.82-1.18 (m, 12H), 0.78 (d, 3H), 0.68 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH3:2].[CH3:26][C:27]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[C:28]=1[C:29](Cl)=[O:30].[Al+3].[Cl-].[Cl-].[Cl-].[C:42](Cl)(=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][C:47](Cl)=[O:48]>C(Cl)Cl>[CH2:1]([CH:3]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:4][N:5]1[C:17]2[C:12](=[CH:13][C:14]([C:29](=[O:30])[C:28]3[C:27]([CH3:26])=[CH:35][C:34]([CH3:36])=[CH:33][C:32]=3[CH3:37])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=2)[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][C:47]([C:9]1[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=1)[N:5]([CH2:4][CH:3]([CH2:1][CH3:2])[CH2:22][CH2:23][CH2:24][CH3:25])[C:17]1[C:12]3=[CH:13][C:14]([C:29](=[O:30])[C:28]3[C:32]([CH3:37])=[CH:33][C:34]([CH3:36])=[CH:35][C:27]=3[CH3:26])=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=1)=[O:48])[CH:10]=2)[CH3:2]
Reactant: CCCCC(CC)Cn1c2ccccc2c2ccc3ccccc3c21
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: O=C(Cl)CCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccc(C(=O)CCCCC(=O)c3ccc4c(c3)c3cc(C(=O)c5c(C)cc(C)cc5C)c5ccccc5c3n4CC(CC)CCCC)cc2c2cc(C(=O)c3c(C)cc(C)cc3C)c3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 11-(2-ethylhexyl)-11H-benzo[a]carbazole (1.65 g; 5.00 mmol) in CH2Cl2 (15 mL) are added 2,4,6-trimethylbenzoyl chloride (0.92 g; 5.11 mmol) and AlCl3 (0.70 g; 5.25 mmol) at 0° C. After stirring at room temperature for 1 hour, AlCl3 (0.70 g; 5.30 mmol) is added at 0° C. and adipoyl chloride (0.43 g; 2.33 mmol) is added dropwise, and then the mixture is stirred at room temperature overnight. The reaction mixture is poured into ice-water, and the crude product is extracted twice with CH2Cl2. The combined organic layer is washed with water and brine, dried over MgSO4, and concentrated to give a green solid. The crude product is purified by column chromatography on silica gel eluting with a mixed solvent of CH2Cl2 and n-hexane (1:1) to give a beige solid (0.85 g; 34.4%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.82 (t, 6H), 0.89 (t, 6H), 1.17-1.42 (m, 16H), 1.93 (br, 4H), 2.21 (s, 12H), 2.26 (m, 2H), 2.40 (s, 6H), 3.18 (br, 4H), 4.69 (m, 4H), 6.97 (s, 4H), 7.54 (d, 2H), 7.69-7.78 (m, 4H), 8.08 (s, 2H), 8.39 (s, 2H), 8.61 (br, 4H), 9.53 (d, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](=[O:21])/[CH:18]=[CH:19]/[CH3:20].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH:19]([CH3:20])[C:18]([CH:17]=[O:21])=[CH:13][C:12]=2[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Reactant: C/C=C/C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1Oc2ccc(Oc3ccccc3)cc2C=C1C=O

Procedure:
The starting material is prepared as follows: A mixture of 5-phenoxysalicylaldehyde (6.52 g, 30.4 mmol), crotonaldehyde (3.2 g, 45.7 mmol) and potassium carbonate (8.41 g, 60.9 mmol) in 100 ml of 1,4-dioxane is heated at reflux for 2 hours. The mixture is cooled, diluted with water, and extracted three times with dichloromethane. The combined organic layers are dried (MgSO4) and evaporated. Purification by flash chromatography (silica gel, 7% ethyl acetate/hexane) yields 6-phenoxy-2-methyl-2H-1-benzopyran-3-carboxaldehyde which is converted to 6-phenoxy-2-methyl-3-(N-hydroxyaminomethyl)-2H-1-benzopyran as described above.
Reaction SMILES: ClC1C=CC(OC)=C(C=1)CC1CNC(=O)CN(S(C2C=CC(Cl)=CC=2)(=O)=O)C1=O.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:42])[O:39][CH2:40][CH3:41])=[C:33](/[CH:43]=[C:44]2\[CH2:45][NH:46][C:47](=[O:62])[CH2:48][N:49]([S:52]([C:55]3[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=3)(=[O:54])=[O:53])[C:50]\2=[O:51])[CH:32]=1>>[CH2:40]([O:39][C:38](=[O:42])[NH:37][C:34]1[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][C:33]=1[CH2:43][CH:44]1[C:50](=[O:51])[N:49]([S:52]([C:55]2[CH:56]=[CH:57][C:58]([Cl:61])=[CH:59][CH:60]=2)(=[O:53])=[O:54])[CH2:48][C:47](=[O:62])[NH:46][CH2:45]1)[CH3:41]
Reactant: CCOC(=O)Nc1ccc(Cl)cc1/C=C1\CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O
Agent: COc1ccc(Cl)cc1CC1CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O
Product: CCOC(=O)Nc1ccc(Cl)cc1CC1CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O

Procedure:
Instead of the starting material of Example 29, that is, the compound I, the compound of Example 278 was used for the similar procedure as in Example 29 to obtain the title compound.
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[F:6][C:7]([F:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]([F:10])[F:9].[OH-].[Na+:20]>>[F:6][C:7]([F:18])([O:11][C:12]1[CH:13]=[CH:14][C:15]([S:1]([O-:3])(=[O:5])=[O:2])=[CH:16][CH:17]=1)[CH:8]([F:9])[F:10].[Na+:20]
Reactant: O=S(=O)(O)O
Reactant: FC(F)C(F)(F)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=S(=O)([O-])c1ccc(OC(F)(F)C(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 58.9 %

Procedure:
A 50 mL flask equipped with a stir-bar and a nitrogen bubbler was charged with concentrated sulfuric acid (14.55 g) and 4-(1,1,2,2-tetrafluoroethoxy)benzene (4.9 g) at room temperature. The reaction mixture was stirred at room temperature for 17 h. A sodium hydroxide solution (12.25 g, in 40.02 g water) was slowly added to the reaction mixture while the reaction mixture was cooled with an ice-water bath. The resulting solid was filtered off. The filtrate was neutralized with concentrated hydrochloric acid (˜3 mL) and used to wash the solid. This wash solution was neutralized with sodium bicarbonate to pH˜7, and used to wash the solid again. The solid was extracted with refluxing ethanol. The ethanol solution was dried to give sodium 4-(1,1,2,2-tetrafluoroethoxy)benzenesulfonate (4FEBSNa) 4.4 g (yield 59%): 1H NMR (D2O) 6.34 (tt, 52, 3 Hz, 1H), 7.45 (d, J=9 Hz, 2H), 7.88 (m, 2H) ppm; 19F NMR (D2O) −88.7 (m, 2F), −138.0 (dt, J=52, 5 Hz, 2F) ppm.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:10]=1[Cl:11])=[O:5])C.O1CCCC1.CO.[H-].[OH-].[Li+]>O>[Cl:11][C:10]1[O:9][C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc(-c2ccccc2)oc1Cl
Agent: [H-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1nc(-c2ccccc2)oc1Cl
Yield: 88.2 %

Procedure:
Solution of 5-chloro-2-phenyl-oxazole-4-carboxylic acid ethyl ester (92 mg, 0.37 mmol) in a mixture solution of tetrahydrofuran, methanol and water (3:1:1, 5 mL) was treated with lithium hydroxide monohydride (44 mg, 1.1 mmol) at room temperature for two hours. After the reaction was complete, solvent was evaporated. To the residue, water was added, and pH value of the aqueous layer was adjusted to ˜1-2 by addition of dilute hydrochloride acid (1N). The white precipitation was collected by centrifugation to give 5-chloro-2-phenyl-oxazole-4-carboxylic acid (73 mg, 88%). LCMS calcd for C10H6ClNO3 (m/e) 223, obsd 224 (M+H).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6]O[CH2:4][CH2:3]1.Cl[C:9]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10].Cl.[CH3:17][O:18][C:19](=[O:32])[CH:20]([NH2:31])[C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=[O:22]>O1CCCC1>[CH2:12]([O:11][C:9]([N:2]1[CH2:3][CH2:4][CH:20]([C:19](=[O:18])[NH:31][CH:20]([C:19]([O:18][CH3:17])=[O:32])[C:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[F:30])=[O:22])[CH2:6][CH2:7]1)=[O:10])[C:13]1[CH:15]=[CH:24][CH:23]=[CH:21][CH:14]=1
Reactant: COC(=O)C(N)C(=O)c1ccc(F)cc1F
Reactant: CN1CCOCC1
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)C1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(F)cc1F
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a three neck 1 liter round bottom flash fitted with mechanical stirrer, nitrogen inlet and dropping funnel are added n-carbobenzyloxy-isonipecotic acid (22.64 g, 86.2 mmol). 550 mL of dry tetrahydrofuran, and N-methyl morpholine, (19 mL, 712.4 mmol). The mixture is cooled to negative 20° C. and then isobutyl chloroformate (11.2 mls, 86.2 mmol in 90 mL of dry tetrahydrofuran) is added dropwise while maintaining the internal temperature at negative 20° C. After 1 hour at negative 20° C., the 2-Amino-3-(2,4-difluoro-phenyl)-3-oxo-propionic acid methyl ester, hydrochloride (22.89 g, 86.2 mmol) is added, followed by N-methyl morpholine, 9.5 mL. The reaction is allowed to come to room temperature is stirred for an additional 16 hours. The reaction is concentrated to a thick slurry and then extracted with dichloromethane, 350 mL, and water, 300 mL. The organic layer is washed with additional water. The aqueous layers are combined and washed with dichloromethane. The organic layers are combined and washed with brine and then dried with magnesium sulfate, filtered, and concentrated to give an oil. The oil is purified by preparative high performance liquid chromatography to give upon concentration of the desired fractions to yield the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1.O.[NH2:12][NH2:13].O.[ClH:15]>C(O)C.C(OCC)C>[ClH:15].[NH:12]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([CH3:10])[CH:3]=1)[NH2:13]
Reactant: Cc1cc(F)ccc1C#N
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(NN)ccc1C#N
Temperature: 80 °C
Yield: 37 %

Procedure:
In a dried reaction flask, 4-fluoro-2-methylbenzonitrile (4.055 g, 30.0 mmol) and hydrazine hydrate (85%) (3.54 mL, 60.0 mmol) were dissolved in ethanol (15.9 mL). In the protection from light and under the nitrogen atmosphere, the solution was heated under reflux at 80° C. for 48 hr. Water was added to the reaction solution. The mixture was filtered. The filtered cake was rinsed with water to produce a pale yellow solid, which was suspended in ethyl ether. A hydrogen chloride gas was passed into the suspension under an ice-salt bath. The suspension was filtered. The filtered cake was rinsed with ethyl ether to produce an off-white solid (2.04 g) in 37.0% yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12](=O)[C:13]([OH:19])([CH3:18])[C:14]([F:17])([F:16])[F:15])(O)=[O:2].S(Cl)(Cl)=O.OC(C(F)(F)F)(C)C(O)=O.IC1C=C(C(O)=O)C([NH2:45])=CC=1.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[F:15][C:14]([F:17])([F:16])[C:13]([C:12]1[NH:45][C:1](=[O:2])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([I:10])[CH:9]=2)[N:11]=1)([OH:19])[CH3:18]
Reactant: CC(O)(C(=O)Nc1ccc(I)cc1C(=O)O)C(F)(F)F
Reactant: Nc1ccc(I)cc1C(=O)O
Agent: CC(O)(C(=O)O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(O)(c1nc2ccc(I)cc2c(=O)[nH]1)C(F)(F)F
Temperature: -15 °C
Reaction time: 1 h

Procedure:
N-(2-Carboxy-4-iodophenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide.Thionyl chloride (5 g) was slowly added to a stirred solution of 2-hydroxy-2-trifluoromethyl propionic acid (6.64 g) in dimethylacetamide (100 mL) cooled to and maintained at -15° C. After 1 hour, 5-iodoanthranilic acid (10 g) was added in one portion and the temperature was allowed to slowly rise to ambient temperature. After stirring overnight, the reaction mixture was poured into water (1500 mL). The aqueous mixture was treated with solid sodium bicarbonate to pH 4, filtered, washed (water), and dried to give the amide (13.1 g) as a tan solid; mp 240°-243° C. Leaching with cold methylene chloride raises the mp to 247°-250° C.; NMR: 1.58 (s,3), 7.74 (s,1), 7.96 (d,1), 8.28 (s,1), 8.45 (d,1), 12.28 (s,1); MS: m/z=404(M+1).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])#[N:2].[I-].C[N:15](C)N(C)C>CS(C)=O>[C:1]([C:3]1([NH2:15])[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:4]1[NH2:5])#[N:2]
Reactant: CN(C)N(C)C
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N
Agent: [I-]
Solvent: CS(C)=O
Product: N#CC1(N)C=CC([N+](=O)[O-])=CC1N
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.8 %

Procedure:
To a solution of 2-cyano-5-nitroaniline (435 mg, 2.67 mmol) in dimethylsulfoxide (25 ml) was added tetramethylhydrazine iodide(534 mg, 2.67 mmol) and sodium t-pentoxide (880 mg, 8.01 mmol). The mixture was stirred at room temperature for 12 hrs., the reaction was quenched with 10% HCl. Precipitated solids were filtered and the remaining solution was extracted with ethyl acetate, the solvent was evaporated and chromatography of the resulting solid on silica gel(25%EtOAc/Hexane) gave the desired product (254 mg, 53%). 1H NMR (CD3COCD3): δ7.49 (d, 1H), 7.03 (bs, 2H), 6.80 (d, 1H), 5.78(bs, 2H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][CH2:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)[CH3:2].[CH3:23][C:24]([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:25][CH2:26]CCO.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[CH2:21][O:22][CH:5]1[O:4][CH2:1][CH2:2][CH2:26][CH:25]=[C:24]([CH3:23])[CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)CCCC(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)COC(OCCCC=C(C)CCCC(C)CCCC(C)CCCC(C)C)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.7 %

Procedure:
Under a nitrogen atmosphere, 80.0 g (0.251 mol) of β-xylose tetraacetate and 106 g (0.327 mol) of 5,9,13,17-tetramethyloctadec-4-en-1-ol was dissolved in dry acetonitrile (0.30 L), and stirred for 30 min. After the solution was cooled to 0° C., 38 mL (0.30 mol) of boron trifluoride diethyl etherate complex was added. The reaction mixture was allowed to warm up to room temperature while being stirred overnight before addition of 70 mL (0.50 mol) of triethylamine at 0° C. The resulting solution was diluted with ethyl acetate, and washed with water, 3M hydrochloric acid (twice), saturated sodium bicarbonate aqueous solution (twice), and saturated brine, successively, and dried over magnesium sulfate. After filtration, the filtrate was concentrated to obtain 161.95 g of the title compound as a crude product. A part of the crude product was purified by silica gel column chromatography (hexane/ethyl acetate 85:15). The results of NMR analysis of the resulting compound are as shown below.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:55](=[O:56])[N:14]2[C:15]([C:39]([O:41][CH:42]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])=[C:16]([CH:19]=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:57][C:58]1[N:59]=[CH:60][S:61][C:62]=1[CH:63]=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH:42]([O:41][C:39]([C:15]1[N:14]2[C:55](=[O:56])[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C@H:13]2[S:18][CH2:17][C:16]=1[CH:19]=[CH:63][C:62]1[S:61][CH:60]=[N:59][C:58]=1[CH3:57])=[O:40])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: Cc1ncsc1C=O
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)CS[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ncsc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Yield: 59.4 %

Procedure:
Benzhydryl 7-(phenoxyacetamido)-3-(triphenylphosphoran-diylmethyl)-3-cephem-4-carboxylate (1.55 g ) and 4-methylthiazol-5-carboaldehyde (0.305 g) were dissolved in methylene chloride (20 ml), to which aqueous saturated sodium bicarbonate (20 ml) was added at ambient temperature. The resultant mixture was stirred for 17 hours at ambient temperature. The mixture was allowed to stand until it separated into the aqueous phase and organic solvent phase. The aqueous phase was removed and washed with methylene chloride (20 ml), and the washings (in methylene chloride) were combined with the organic solvent phase separated. The combined solution was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure. The solid residue obtained was purified chromatographically on a column of silica gel (Wako gel C-300) (40 g) as developed with benzene-ethyl acetate (5:1) as the development solvent. The entitled compound, 7-(phenoxyacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid benzhydryl ester (0.741 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.ICI.[Sm].O1CC[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([OH:7])[CH2:18][CH2:17]2)[CH:9]=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: COC(=O)c1cccc(Cl)c1
Agent: [Sm]
Solvent: ICI
Product: OC1(c2cccc(Cl)c2)CC1
Temperature: -10 °C

Procedure:
A solution of methyl 3-chlorobenzoate (0.27 g, 1.58 mmol) and diiodomethane) in anhydrous tetrahydrofuran was added slowly to a vigorously stirred and heated (50° C.) slurry of samarium powder (1.0 g, 6.65 mmol) in tetrahydrofuran over 1.5 hours. After complete addition, the reaction mixture was stirred for 1 hour, than cooled (−10° C.), quenched with 1 N hydrochloric acid over 30 min. The reaction mixture was extracted with ether, dried, filtered and concentrated. Purification by silica gel chromatography (1:1 hexanes in dichloromethane) afford 100 mg of 1-(3-chlorophenyl)cyclopropanol.