Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[C:8]([C:10]1[C:11]([F:24])=[N:12][C:13]2[C:18]([C:19]=1[F:20])=[CH:17][C:16]([N+:21]([O-])=O)=[CH:15][CH:14]=2)#[N:9].[H][H]>[Pd].O1CCCC1>[NH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([F:24])[C:10]([C:8]#[N:9])=[C:19]2[F:20]
Reactant: N#Cc1c(F)nc2ccc([N+](=O)[O-])cc2c1F
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(F)nc2ccc(N)cc2c1F
Yield: 74 %

Procedure:
130 parts of anhydrous sodium sulfate were suspended in a solution of 305 parts of 3-cyano-2,4-difluoro-6-nitro-quinoline in 3,400 parts of tetrahydrofuran. 30 parts of a hydrogenation catalyst (10% palladium on carbon) were added, which was followed by hydrogenation at 40° C. and 3 bar. After the uptake of hydrogen had ended, the suspension was filtered, and the clear solution was added to 6,000 parts of ice-water. The resulting precipitate was filtered off with suction, washed and dried. This gave 198 parts of 6-amino-3-cyano-2,4-difluoroquinoline, corresponding to a yield of 74%.
Reaction SMILES: [NH2:1][C:2]1([C:15]([F:18])([F:17])[F:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[O:19]=[C:20]1[NH:25][C:24]2[CH:26]=[C:27]([CH:30]=O)[CH:28]=[CH:29][C:23]=2[S:22][CH2:21]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>CN(C=O)C>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][C:2]([NH:1][CH2:30][C:27]2[CH:28]=[CH:29][C:23]3[S:22][CH2:21][C:20](=[O:19])[NH:25][C:24]=3[CH:26]=2)([C:15]([F:18])([F:16])[F:17])[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1ccc2c(c1)NC(=O)CS2
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(F)(F)F)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc3c(c2)NC(=O)CS3)(C(F)(F)F)CC1

Procedure:
A mixture of 4-amino-1-(tert-butoxycarbonyl)-4-(trifluoromethyl)piperidine (3 e) (1 equiv.), 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carbaldehyde (1n) (1.1 equiv.), and Na2SO4 in DMF is stirred until the imine has formed, then is filtered through a sintered glass funnel. The filtrate is concentrated to dryness in vacuo, and the residue is dissolved in EtOH. NaBH4 (1 equiv.) is added, and the reaction is stirred until the imine is consumed. The solvent is removed in vacuo and the residue is taken up in dilute HCl. The mixture is neutralized with dilute NaOH and extracted with CH2Cl2. Drying (Na2SO4), concentration, and flash chromatography on silica gel gives the title compound.
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].C(C1C=CC=CC=1B(O)O)(O)=O.C1(B(O)O)C=CC=CC=1.CCN1C=[N+](C)C=C1.[Cl-]>CC(N(C)C)=O>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCn1cc[n+](C)c1
Agent: O=C(O)c1ccccc1B(O)O
Agent: OB(O)c1ccccc1
Solvent: CC(=O)N(C)C
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 120 °C

Procedure:
Glucose (49.5 mg, 275 μmol), 2-carboxyphenylboronic acid (45.9 mg, 277 μmol) or other phenylboronic acid (as indicated) and MgO (36.6 mg, 908 μmol) were mixed in DMA or [EMIM]Cl (500 mg). The reaction mixture was heated at 120° C. for 4 h. At 1-h intervals, aliquots of the reaction mixture were removed for analysis by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([NH:8][C:9](=O)[CH3:10])[C:5](=O)[CH3:6].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.FC(F)(F)C(O)=O>C(#N)CCC>[CH3:10][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([CH3:6])=[C:4]([C:3]([O:2][CH3:1])=[O:12])[N:8]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(NC(C)=O)C(C)=O
Solvent: CCCC#N
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(C)n(-c2ccccc2)c1C
Yield: 46 %

Procedure:
Part C: To a magnetically stirred solution of 2-acetylamino-3-oxo-butyric acid methyl ester (5 gram, 28.9 mmol) in butyronitrile was added aniline (3.42 ml) and trifluoroacetic acid (2.89 ml) and the resulting mixture was heated at reflux for 45 minutes. The butyronitrile was removed in vacuo at room temperature and the resulting residues was taken up dichloromethane and washed twice with an aqueous potassium carbonate solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (diethyl ether/acetone=4/1 (v/v)) to give methyl 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylate (3.0 gram, 46% yield). 1H-NMR (400 MHz, CDCl3): 2.22 (s, 3H), 2.33 (s, 3H), 3.91 (s, 3H), 7.18-7.22 (m, 2H), 7.51-7.59 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:47]=[CH:46][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]4[CH2:45][CH2:44]4)=[O:42])[N:39]=3)[CH:36]=2)=[C:28]([F:48])[CH:27]=1.C(=O)([O-])O.[Na+]>O1CCCC1.CN(C)C=O>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:46]=[CH:47][C:26]([NH:25][C:16]([C:5]5[C:6](=[O:15])[N:7]([C:8]6[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=6)[C:2]([CH3:1])=[CH:3][CH:4]=5)=[O:18])=[CH:27][C:28]=4[F:48])=[CH:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1cccc(-n2c(C)ccc(C(=O)O)c2=O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(-n2c(C)ccc(C(=O)Nc3ccc(Oc4ccc5nc(NC(=O)C6CC6)cn5c4)c(F)c3)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution (3 mL) of 6-methyl-1-(3-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (120 mg, 0.50 mmol) in tetrahydrofuran were added oxalyl dichloride (130 mg, 1.0 mmol) and N,N-dimethylformamide (1 drop), and the mixture was stirred at room temperature for 1 hr. The mixture was concentrated under reduced pressure, and the solvent was evaporated. N,N-Dimethylformamide (3.0 mL) and a solution (2.0 mL) of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (130 mg, 0.40 mmol) in N,N-dimethylformamide were successively added, and the mixture was stirred at room temperature for 5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate and collected by filtration to give the title compound (150 mg, 69%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[H-].[Na+].[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1ccc2[nH]cc(CCN3CCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CCN3CCCC3)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-3-(2-pyrrolidinylethyl)-1H-indole (Example 2, 9.10 g, 31 mmol) in tetrahydrofuran (100 mL) cooled to 0° C., were added sodium hydride (12.4 g, 310 mmol) and p-toluenesulfonyl chloride (6.10 g, 32 mmol). The resulting mixture was stirred at room temperature for 3 h, poured into water (200 mL) and extracted into ethyl acetate (200 mL). The organic phase was washed with water (200 mL) and then poured onto a silica gel column which was eluted with ethyl acetate followed by methanol. The title compound was obtained as a yellow syrup (11.7 g, 90%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[H-].[Na+].[CH3:14]I.[NH4+].[Cl-].Cl>CN(C=O)C.CC(=O)OCC>[N+:9]([C:3]1[C:4](=[O:8])[N:5]([CH3:14])[CH:6]=[CH:7][C:2]=1[OH:1])([O-:11])=[O:10]
Reactant: O=c1[nH]ccc(O)c1[N+](=O)[O-]
Reactant: CI
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1ccc(O)c([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To 4-hydroxy-3-nitro-1H-pyridin-2-one (300 mg, 1.9 mmol) in DMF (5 mL) was added NaH (176 mg, 4.4 mmol, 60% in mineral oil) at 0° C. under N2. After stirring at 0° C. for 30 min, CH3I (272 mg, 1.9 mmol) in DMF (5 mL) was added dropwise, and the mixture was stirred for 2 h at 25° C. Saturated aqueous NH4Cl was added, the pH was adjusted to ˜3 with 1N HCl and EA extractive work up gave a residue that was triturated with MeOH (0.5 ml): EA (10 mL): PE (5 mL). After filtration, the trituratate was evaporated to give the title compound (300 mg, 91%) as a yellow solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.75 (d, J=7.2 Hz, 1H), 6.17 (d, J=7.2 Hz, 1H) 3.54 (s, 3H). LCMS: 171.0 (M+1)+
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9](C(OC(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][NH:9][C@H:8]([C:18]([NH:26][CH2:25][CH2:24][N:23]([CH2:27][CH3:28])[CH2:21][CH3:22])=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: CCN(CC)CCN
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: C=CCON=C1CN[C@H](C(=O)NCCN(CC)CC)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)-imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, and N1,N1-diethyl-1,2-ethanediamine the title compound was obtained in 78% purity by LC/MS. MS(ESI+): m/z=283.0.
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.[H-].[Na+].Cl[C:20]1[C:21]([CH3:29])=[CH:22][C:23]2[N:24]([N:26]=[CH:27][N:28]=2)[N:25]=1.Cl>O1CCCC1>[CH2:15]([C:10]([CH2:13][CH3:14])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:20]1[C:21]([CH3:29])=[CH:22][C:23]2[N:24]([N:26]=[CH:27][N:28]=2)[N:25]=1)[CH3:16]
Reactant: CCC(CC)(CO)CS(=O)(=O)N=CN(C)C
Reactant: Cc1cc2ncnn2nc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(COc1nn2ncnc2cc1C)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 1.38 g of 3-(N,N-dimethylamino-methylene)aminosulfonyl-2,2-diethyl-1-propanol in 30 ml of tetrahydrofuran was added 0.23 g of 60% sodium hydride in oil and the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added 0.74 g of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine and the mixture was refluxed with stirring for 1 hour. After cooling, the reaction mixture was adjusted to pH 6 with 1N-hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was washed with water and dried and the solvent was distilled off. To the residue was added 14 ml of 6N-hydrochloric acid and the mixture was stirred at 110° C. for 30 minutes. After cooling, 100 ml of water was added to the reaction mixture and the resulting crystals were recovered by filtration and recrystallized from methanol to provide 1.16 g of the title compound. m.p. 208°-209° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH2:11][OH:12])=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:17]([O:12][CH2:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[CH:8][C:9]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:4]([OH:6])=[O:5])(=[O:19])[CH3:18]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1CO
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl

Procedure:
1.3 g of 2-chloro-3-hydroxymethyl-4-methanesulfonyl benzoic acid and 30 ml of acetic anhydride, was refluxed for 3 hours under heating. The reaction mixture was concentrated under reduced pressure. Then, 50 ml of water was added thereto and warmed for 1 hour. Precipitated solid was collected by filtration, washed with water and dried to obtain 1.35 g of the desired product. Melting point: 219°-223° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:13][OH:14])[CH2:8][CH2:7][CH2:6]2.C([Li])CCC.[C:20]1([C:26]2[C:30]([C:31]([F:34])([F:33])[F:32])=[C:29]([C:35](OC)=O)[O:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1=[N:13][O:14][C:35]([C:29]3[O:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:30]=3[C:31]([F:34])([F:32])[F:33])=[C:8]1[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=NO
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
To 6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 2, 0.328 g, 1.715 mmol) in 3 mL of THF, cooled to 0° C. was added butyllithium (1.372 mL, 3.43 mmol) dropwise over a period of 3 min. The contents were stirred at 0° C. for 30 min. A solution of methyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (Intermediate 3, 0.31 g, 1.14 mmol) dissolved in 2 mL of THF was added over a period of 3 min. The pale yellow reaction mixture was allowed to come to room temperature and stirred for 20 min. To the reaction mixture was added 0.5 mL of conc. sulfuric acid dropwise over a period of 3 min. at 0° C. and the contents were allowed to come to room temperature over a period of 10 min., then stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. Dioxane (5 mL) was added and the contents were heated at 100° C. for 1.5 h, and at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (25 mL) and water (10 mL). The ethyl acetate layer was washed with sat. aq. sodium bicarbonate (15 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography using hexane/ethyl acetate to yield 7-methoxy-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (0.125 g, 0.303 mmol, 26.5% yield) as pale yellow solid. LC/MS M+1=413.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][NH:6][C:7](=[S:12])[NH:8][NH:9][CH:10]=O.[O-]CC.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][N:6]1[CH:10]=[N:9][N:8]=[C:7]1[SH:12]
Reactant: O=CNNC(=S)NCc1cccc(F)c1
Agent: CC[O-]
Agent: [Na+]
Product: Fc1cccc(Cn2cnnc2S)c1
Yield: 41.8 %

Procedure:
The crude 4-(3'-fluorobenzyl)-1-formyl-3-thiosemicarbazide (1.3 g) was refluxed overnight in a solution of sodium ethoxide (from sodium (0.3 g) in ethanol (25 ml)). The reaction was filtered, evaporated to dryness, and diluted with water. The aqueous solution was acidified to pH 3-4 with 10% hydrochloric acid, and the precipitate was collected by filtration and recrystallized from ethanol-water to yield 0.5 g (41%) of 4-(3'-fluorobenzyl)-1,2,4-triazole-3-thiol, m.p.: 124°-125° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([O-:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.OS(O)(=O)=O>CC(O)=O.O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[C:5]([C:22]([OH:24])=[O:23])=[CH:6][N:7]2[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)[O-])cn2CCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2CCc1ccccc1
Temperature: 0 °C
Yield: 96.3 %

Procedure:
To a suspension of 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylate (458 mg, 1.21 mmol) in a mixture of AcOH (1.8 mL) and water (1.5 mL), was added H2SO4 (0.3 mL), the whole mixture was heated under reflux for 1 h. The reaction mixture was poured into ice-water and the resulting precipitates were collected by filtration. The filtered precipitates were suspended in water, filtered, and dried in vacuo to give 5-amino-6,7-difluoro-1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecarboxylic acid (401 mg, 95%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)C(N)c1cccc(C(F)(F)F)c1
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cccc(C(F)(F)F)c1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(3-trifluoromethylphenyl)acetate (prepared from 2-(hydroxyimino)-2-(3-trifluoromethylphenyl)acetic acid [CAS 179811-81-5] using General Procedures G and R above), the title compound was prepared as a solid (mp=133-134° C.). The product was purified by tituration from EtOAc/hexanes.
Reaction SMILES: CO.[Na].CO[C:6](=[O:17])[C:7]1[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:9]([O:11]C)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1>C1C=CC=CC=1>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:26]2[C:6](=[O:17])[C:7]3[C:8](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:9]2=[O:11])=[O:27])=[CH:21][CH:20]=1
Reactant: COC(=O)c1ccccc1C(=O)OC
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Na]
Solvent: c1ccccc1
Solvent: CO
Product: O=C(c1ccc(Br)cc1)C1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (8.5 ml) was treated with sodium (4.8 g) in benzene (90 mL). The reaction mixture was refluxed overnight, allowed to cool to room temperature, and treated with phthalic acid dimethyl ester (38.84 g) and 1-(4-bromophenyl)ethanone (39.81 g) in benzene (50 mL). Distillation of the reaction mixture was performed at 80° C. overnight to remove methanol. The reaction mixture was poured into diluted HCl and filtered. The filter cake was collected and recrystallized from ethanol to provide the title compound.
Reaction SMILES: [N:1]([CH2:4][CH:5]([CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[OH:6])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH:5]([CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[OH:6]
Reactant: CC1(C)OCC(C(O)CN=[N+]=[N-])O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OCC(C(O)CN)O1
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 9.36 g of 2-azido-1-(2,2,-dimethyl-1,3-dioxolan-4-yl)ethanol in 150 ml of methanol is combined with 900 mg of palladium/charcoal catalyst (10%). The hydrogenation is conducted for 1 hour under normal pressure. The mixture is then filtered off from the catalyst and washed with methanol. The combined solutions are concentrated to dryness under vacuum. The remaining oil is crystallized from ethanol/ether, thus obtaining 6.29 g (78% of theory) of 2-amino-1-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol in white needles, mp 94°-96° C.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][C@H:24]([C:34]([O:36][CH3:37])=[O:35])[CH2:25][CH2:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].Cl.ClC(OCC(C)C)=O>>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][C@H:24]([C:34]([O:36][CH3:37])=[O:35])[CH2:25][CH2:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 88 %

Procedure:
Condensation of ZPheOH (3.00 g.) and HGlu(tBu)OMe hydrochloride salt (2.54 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-Glu(tBu)OMe in 88% yield. Debenzyloxycarbonylation of ZPhe-Glu(tBu)OMe (4.30 g.) by hydrogenation with palladium catalyst gave HPhe-Glu(tBu)OMe, which was not isolated but immediately condensed with BocPro-PheOH (3.12 g.) using dicyclohexylcarbodiimide and hydroxysuccinimide, affording BocPro-Phe-Phe-Glu(tBu)OMe in 22% yield. Hydrazinolysis of BocPro-Phe-Phe-Glu(tBu)OMe (1.09 g.) gave BocPro-Phe-Phe-Glu(tBu)NHNH2 in 58% yield.
Reaction SMILES: CO[C:3]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:14][C:13]=3[OH:26])[NH:11][C:7]=2[CH:6]=1)=[O:4].[CH3:29][NH2:30]>>[CH3:29][NH:30][C:3]([C:5]1[CH:28]=[CH:27][C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[C:16]([C:18]4[C:19]([O:24][CH3:25])=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:14][C:13]=3[OH:26])[NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Reactant: CN
Product: CNC(=O)c1ccc2nc(-c3cc(-c4cccnc4OC)ccc3O)[nH]c2c1
Temperature: 25 °C
Yield: 50 %

Procedure:
A suspension of 2-[2-hydroxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-3H-benzoimidazole-5-carboxylic acid methyl ester (37.5 mg, 0.1 mmol) in aqueous methylamine solution (40%, 2 mL) was heated at 140° C. in a Biotage Initiator Sixty microwave reactor for 15 min, cooled to the room temperature, and concentrated under reduced pressure. The residue was purified by chromatography (500:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (19 mg, 50%). 1H NMR (DMSO-d6) δ 2.84 (s, 3H), 3.92 (s, 3H), 7.11-7.17 (2H), 7.62-7.83 (4H), 8.10-8.29 (3H), 8.50 (br, 1H, NH). ESI-MS m/z 375.3 (MH+).
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17]([CH2:18][C@H:19]([CH2:21][CH2:22]2)[OH:20])=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH:3]([CH3:5])[CH3:4].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH3:5][CH:3]([C:2](=[O:1])[CH2:6][CH2:7][C@H:8]([C@@H:10]1[C@:28]2([CH3:29])[C@H:13]([C@H:14]3[C@H:25]([CH2:26][CH2:27]2)[C@:23]2([CH3:24])[C:17](=[CH:18][C:19](=[O:20])[CH:21]=[CH:22]2)[CH:16]=[CH:15]3)[CH2:12][CH2:11]1)[CH3:9])[CH3:4]
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Fucosterol is oxidized with ozone at low temperatures, and the resulting ozonide is reduced with an acetic acid/zinc system to form 24-ketocholesterol of the following formula ##STR15## in a yield of about 60 to 75%. The resulting 24-ketocholesterol is oxidized, for example, with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) under reflux of, for example, dioxane to form cholesta-1,4,6-triene-3,24-dione of the following formula ##STR16## and then this oxidation product is epoxidized at room temperature under alkaline conditions (pH about 7.5-9) using hydrogen peroxide, for example.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:21][C:20](=[O:22])[N:19]([C:23]2[CH:24]=[CH:25][C:26]3[S:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=3[CH:33]=2)[CH2:18]1)=[O:6]
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Product: COc1ccc(N)c(C(=O)NCCC[C@@H]2CN(c3ccc4c(c3)NC(=O)CS4)C(=O)O2)c1
Yield: 82 %

Procedure:
Starting from 2-amino-5-methoxybenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (180 mg; 82% yield).