Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1CC[CH2:17][CH2:16]1.O.ICC>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([CH2:16][CH3:17])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCI
Product: CCC1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 100 °C

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5 g, 25.1 mmol), pyrollidine (5 ml) and p-toluenesulfonic acid (25 mg) in benzene (100 ml) was heated at reflux for 16 h with azeotropic distillation of water. The resulting enamine solution was cooled to rt and concentrated. The crude enamine was dissolved in acetonitrile (50 ml); iodoethane (4.67 g, 30.1 mmol) was added and the mixture was heated at 100° C. for 0.5 h, cooled to rt and concentrated. The mixture was dissolved in ethyl acetate (200 ml), washed with 1 N hydrochloric acid, saturated aqueous sodium bicarbonate, and brine. The extract was dried over magnesium sulfate, filtered and concentrated. The crude compound was purified by silica gel chromatography (80% hexanes/20% ethyl acetate) to afford 3-ethyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (680 mg).
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CC(C)=O>[P:7]([N:16]=[N+:17]=[N-:18])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1

Procedure:
Following the procedure of Baldwin and Washburn, J. Org. Chem., 30, 3860 (1965), 6.99 g (0.0297 mole) of diphenylphosphinyl chloride and 2.09 g (0.032 mole) of sodium azide were stirred in 40 ml of anhydrous acetone under a nitrogen atmosphere for 48 hours. The sodium chloride and unreacted sodium azide was removed by gravity filtration and the acetone solvent removed in vacuo. The crude diphenylphosphinic azide was analyzed for Cl content and in all cases only trace quantities (less than .1%) were found. The colorless diphenylphosphinic azide was purified by distillation to yield 6.31 g (87%) boiling at 138°-140° C./0.05 mm; literature value 137°-140° C./0.05 mm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([N:17]=[N+]=[N-])[CH2:15][S:16][C@H:11]12)=[O:8].[O:35]1[CH:39]=[CH:38][CH2:37][CH2:36]1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[O:21])=[C:14]([N:17]=[C:36]3[CH2:37][CH2:38][CH2:39][O:35]3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: C1=COCC1
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N=C3CCCO3)CS[C@H]12

Procedure:
A mixture of 852 mg. of p-nitrobenzyl 7β-(2-thienylacetylamino)-3-azido-3-cephem-4-carboxylate and 20 ml. of 2,3-dihydrofuran was heated at the reflux temperature (54°-55° C.) for 15 minutes. The mixture was evaporated to dryness and the residue chromatographed over 8 g. of silica gel (toluene) using 400 ml. of 5% ethyl acetate in toluene vs. 400 ml. of ethyl acetate. Multiple fractions were collected and fractions containing the product were pooled and evaporated to dryness to give 559 mg. of the title compound.
Reaction SMILES: C([N:11]1[CH2:18][C@@H:17]([F:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.[BrH:20].CCOCC>C(O)(=O)C>[BrH:20].[F:19][C@@H:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: O=C(O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(O)[C@@H]1C[C@H](F)CN1
Reaction time: 1 h

Procedure:
The cis-N-carbobenzyloxy-4-fluoro-L-proline (5.5 g., 0.021 mole) is treated with 28 ml. of hydrogen bromide in acetic acid (30-32%), stoppered loosely, and stirred for one hour. Ether (300 ml.) is added to the yellow mixture and when the crystalline product has settled the ethereal liquor is decanted and the material washed with 300 ml. of fresh ether by decantation. The product is finally heated in the steam bath with 70 ml. of methyl ethyl ketone, cooled for two hours, washed with cold methyl ethyl ketone and with ether, and dried in vacuo. The yield of nearly colorless solid, cis-4-fluoro-L-proline, hydrobromide is 3.8 g. (86%), m.p. 189°-191° (dec.), [α]D26 -19° (c=1, methanol).
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.Cl[C:33]1[CH:38]=[C:37]([N:39](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:36]2[N:56]=[CH:57][C:58]([C:59]3[CH:60]=[N:61][C:62]4[C:67]([CH:68]=3)=[CH:66][CH:65]=[CH:64][CH:63]=4)=[C:35]2[N:34]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:39][C:37]1[N:36]2[N:56]=[CH:57][C:58]([C:59]3[CH:60]=[N:61][C:62]4[C:67]([CH:68]=3)=[CH:66][CH:65]=[CH:64][CH:63]=4)=[C:35]2[N:34]=[C:33]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:2])=[O:20])=[CH:10][CH:9]=2)[CH:38]=1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cc(-c2ccc(CC(=O)O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 100 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid methyl ester (0.576 mmol, 160 mg), K3PO4 (0.864 mmol, 183 mg), and PdCl2(dppf).CH2Cl2 (0.029 mmol, 24 mg) was added to a solution of (5-Chloro-3-quinolin-3-yl-pyrazolo[1,5-a]pyrimidin-7-yl)-bis-(2-trimethylsilanyl-ethoxymethyl)-amine (0.288 mmol, 160 mg) in dioxane (2 mL). To this suspension was added distilled H2O (0.2 mL). The resulting solution was stirred at 100° C. under an argon atmosphere for 18 hours. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in 2:1 MeOH:H2O (1.5 mL) and was treated with 2N NaOH(aq) (1.0 mL). The resulting solution was stirred at room temperature for 18 hours. Aqueous hydrochloride solution (1.0 N, 4 ml) was added to the reaction mixture and the resulting solution was stirred at 65° C. for 2 h. The reaction mixture was concentrated and purified by prep-LC to afford the title compound (70 mg, 62% yield): LC/MS RT=3.21 min. Mass calculated for, M+H 396.14, observed 396.14.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([I:9])[CH:3]=1.[Si]([O:17][CH2:18][CH:19]=O)(C(C)(C)C)(C)C.FC(F)(F)C(O)=O.[BH3-]C#N.[Na+]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:19][CH2:18][OH:17])=[C:4]([I:9])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: Nc1cnc(Cl)cc1I
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OCCNc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 12 h
Yield: 190.5 %

Procedure:
To a solution of 6-chloro-4-iodopyridin-3-amine (6.5 g, 25.5 mmol) in CH3OH (1500 mL) was added 2-(tert-butyldimethylsilyloxy)acetaldehyde (18.0 g, 103 mmol). Then trifluoroacetic acid (150 mL) and NaBH3CN (8.0 g, 127 mmol) were added slowly at 0° C. The mixture was allowed to warm to 25° C. and the stirring was continued for an additional 12 hours. The mixture was concentrated under reduced pressure and treated with NaOH (3M) to pH=8. The aqueous layer was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. The solvent was concentrated in vacuo to afford crude product 2-(6-Chloro-4-iodopyridin-3-ylamino)ethanol (14.5 g), that was used in the next step without further purification.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)([CH3:3])[CH3:2].[C:9]1([OH:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>>[C:9]1([O:19][CH2:5][CH:6]([OH:8])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)N1CC(O)C1
Reactant: Oc1cccc2ccccc12
Agent: [K+]
Agent: [OH-]
Product: CC(C)NCC(O)COc1cccc2ccccc12
Temperature: 160 °C
Yield: 76 %

Procedure:
To a mixture of 11.5 parts of 1-(iso-propyl)-3-azetidinol and 15.8 parts of α-naphthol 0.2 part of potassium hydroxide was added, and the mixture was heated under nitrogen gas at 160° C. for 20 hours. The reaction mixture was cooled and then extracted with ether. The ether extract was washed with 2 N-NaOH aqueous solution and then with water. The liquor was dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was recrystallized from cyclohexane or subjected to distillation under reduced pressure. As a result, 19.6 parts of 1-(α-naphthoxy)-3-(isopropylamino)-2-propanol having a melting point of 94°-96° C. and a boiling point of 158°-159° C. under 2.5 mm Hg were obtained. The yield was 76%. The results of infra-red spectrum analysis of the product are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:43])(=[O:42])[CH3:41]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:43])(=[O:42])[CH3:41]
Reactant: CC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: CC(=O)[O-]
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
Nilotinib base (1.5 g, 2.83 mmol) in glacial acetic acid (5 mL, 3.3V) was heated to 40° C. leading to dissolution. A precipitate was observed after stirring the solution at 40° C. for about 10 min. The mixture was then sonicated at 40° C. for 1 h leading to a clear solution. The solution was then allowed to cool to room temperature while stirring. A precipitate formed and was filtered to give Nilotinib acetate form V as a white solid.
Reaction SMILES: OCC([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)[OH:8])[OH:6])=O.O=[CH:14][C@@H:15]([C@H]([C@@H]([C@@H](CO)O)O)O)O>>[CH:11]([C:9]1[CH:15]=[CH:14][O:8][C:7]=1[CH:5]=[O:6])=[O:12]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=Cc1ccoc1C=O

Procedure:
Remarkably, catalyst activity was found to be closely related to the stereo property of the NHC ligands. 1-CrCl2 catalyzed the dehydration fructose and glucose with HMF yields of 65% and 66%, respectively (Table 1). Catalyst with the isopropyl-substituted NHC ligand, 2-CrCl2, showed similar efficiency as 1-CrCl2. In contrast, the HMF yields from sugars were significantly increased using chromium catalysts with the more bulky NHC ligands, such as 3-7. 6-CrCl2 system provided a HMF yield as high as 96% from fructose. It also gave a HMF yield of 81% from glucose, which was a record high efficiency for glucose feedstock. There was no difference in yield for the metal catalysts with saturated vs. unsaturated NHC ligands. The catalysts with the most bulky NHC ligand, 1,3-bis(2,6-diisopropylphenyl)imidazolylidene 6 and 1,3-bis(2,6-diisopropyl)phenylimidazolinylidene 7 provided the highest yields. To better understand the details of this reaction, bidentate ligand 8 was examined. Interestingly, catalyst 8-(Cr)2 gave a good HMF yield (81%) from glucose, while 8-(Cr)1 showed a poor HMF yield (14%). These results suggested that an over-crowded complex would have a lower activity in binding with substrates and initiating the reaction. Control reaction without catalyst showed a very low HMF yield (less than 40% and 1% from fructose and glucose, respectively). The reaction temperature was investigated between 80° C. and 100° C. for both fructose and glucose. Lower temperature led to a lower HMF yield: higher temperature gave rise to byproducts, mainly diformylfuran (DFF) (see FIG. 1).
Reaction SMILES: O[N:2]=[CH:3][C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1>C(OC(=O)C)(=O)C>[C:3]([C:4]1[S:8][C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:5]=1)#[N:2]
Reactant: COC(=O)c1ccc(C=NO)s1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(C#N)s1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A solution of methyl 5-((hydroxyimino)methyl)thiophene-2-carboxylate (440 mg, 2.4 mmol) in acetic anhydride (10 mL) was refluxed for 16 h. After completion, the reaction mixture was cooled to room temperature, concentrated under reduced pressure and the residue was dissolved in diethyl ether. The organic layer was washed with 10% aqueous NaOH solution, water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield methyl 5-cyanothiophene-2-carboxylate (5-cyano-thiophene-2-carboxylic acid methyl ester) (400 mg, yield 90%) which was carried through without any further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (d, J=4.2 Hz, 1H), 7.60 (d, J=4.1 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: [NH3:1].Cl[C:3]1([C:16]2[C:17]([O:22][CH2:23][CH3:24])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][C:4]1=[O:15].[Na+].[Cl-]>ClCCl>[NH2:1][C:3]1([C:16]2[C:17]([O:22][CH2:23][CH3:24])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][C:4]1=[O:15]
Reactant: N
Reactant: CCOc1ncccc1C1(Cl)C(=O)Nc2cc(F)c(C#N)cc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOc1ncccc1C1(N)C(=O)Nc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.4 ml (17.0 mmol) of a 7N methanolic ammonia solution were added dropwise to a cooled solution of 1.13 g (3.41 mmol) of 3-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 20 ml of dichloromethane under a nitrogen atmosphere, and the reaction mixture was then stirred at room temperature overnight. The reaction mixture was mixed with saturated NaCl solution and extracted with ethyl acetate (3×). The combined organic phases were dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. The residue was mixed with 20 ml of diethyl ether. After stirring for 5 min, a white solid precipitated and was filtered off and dried in a vacuum oven. 800 mg of the title compound were obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccccc2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(OCC(=O)O)ccc1OCc1ccccc1
Yield: 97.7 %

Procedure:
Using the procedure of Step D of Example 16, 3.2 g of the product of Step B and 5 ml of 2N sodium hydroxide and then 5 ml of hydrochloric acid were reacted to obtain 2.85 g of the expected product.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH3:18])[C:12]=2[F:19])=[CH:8][C:7]([Cl:20])=[CH:6][C:3]=1[C:4]#[N:5].C1C(=O)N([Br:28])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:28][CH2:18][C:13]1[C:12]([F:19])=[C:11]([O:10][C:9]2[C:2]([Cl:1])=[C:3]([CH:6]=[C:7]([Cl:20])[CH:8]=2)[C:4]#[N:5])[C:16]([Cl:17])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2Cl)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1Cl
Yield: 51.6 %

Procedure:
2,5-dichloro-3-[(6-chloro-2-fluoro-3-methylphenyl)oxy]benzonitrile (1.01 g, 3.06 mmol) and NBS (0.544 g, 3.06 mmol) were combined in carbon tetrachloride (30 mL) with a catalytic amount of AIBN (0.025 g, 0.153 mmol) and stirred at reflux for 16 h. The reaction mixture was washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by chromatography on 80 g silica gel eluted with 0 to 10% Et2O in hexanes to give the 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-2,5-dichlorobenzonitrile (0.647 g, 1.580 mmol, 51.7% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.03 (d, J=2.20 Hz, 1H), 7.53-7.64 (m, 2H), 7.29 (d, J=1.92 Hz, 1H), 4.75 (s, 2H).
Reaction SMILES: C([C@@H:8]1[CH2:12][O:11]C(=O)N1)C1C=CC=CC=1.C([Li])CCC.[N:19]([CH:22]([C:24]1[CH:25]=[C:26]([C:30](=[O:32])[CH3:31])[CH:27]=[CH:28][CH:29]=1)C)=C=O>C1COCC1>[CH3:31][C:30]1([C:26]2[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=2)[C:22]#[N:19])[O:32][CH2:8][CH2:12][O:11]1
Reactant: CC(=O)c1cccc(C(C)N=C=O)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2cccc(C#N)c2)OCCO1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 155.4 %

Procedure:
(R)-4-benzyloxazolidin-2-one 18 (212.6 mg, 1.19 mmol) was dissolved in dried 100 mL round-bottom flask containing anhydrous THF (8 mL) under N2 atmosphere. Cooled to −78° C. 2.5M solution of n-butyl lithium in hexanes (0.9 mL, 1.2 mmol) was added dropwise. Continuing the same temperature, 16 (2.4 mmol) was added to the reaction mixture and allowed to stir for 15 min. Then reaction mixture was warmed from −78° C. to 0° C. and allowed to stir for 30 min. The reaction mixture was quenched with aq. NH4Cl. The solvent was removed in vacuo, extracted with DCM and washed with brine, dried (MgSO4), filtered, and concentrated. The crude product was isolated by column chromatography eluting with (EtOAC/n-hexane, 20:80) to yield 19 (350 mg, 80%) as a brown semisolid. 1H NMR (CDCl3, 400 MHz) δ 2.77 (t, J=12 Hz, 1H), 3.29 (d, J=12.8 Hz, 1H), 4.23 (m, 2H), 4.35 (d, J=18.4 Hz, 1H), 4.47 (d, J=18.4 Hz, 1H), 4.67 (m, 1H), 7.16-7.30 (m, 7H), 7.40 (dd, J, =4 Hz, J2=2.4 Hz, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([Cl:16])[CH:10]=2)=O)C.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24].C(=O)(O)[O-].[Na+]>>[N:24]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:25][C:4]=1[C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([Cl:16])[CH:10]=2
Reactant: CCOC(=O)c1cc2ccc(Cl)cc2[nH]c1=O
Reactant: Nc1ccccc1N
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1[nH]c2cc(Cl)ccc2cc1-c1nc2ccccc2[nH]1
Temperature: 200 °C

Procedure:
A mixture of 9-2 (30 mg, 0.12 mmol, 1 equiv) and 1,2-phenylenediamine (39 mg, 0.36 mmol, 3.0 equiv) in polyphosphoric acid (3 mL) was heated at 200° C. for 3 h. The hot reaction mixture was poured into ice water (20 mL), and the resulting mixture was allowed to stand until all polyphosphoric acid had dissolved. The acidic suspension was neutralized with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate (2×50 mL). The organic layer were dried over sodium sulfate and concentrated. The residue was suspended in ethyl ether (50 mL) aided by sonication, and the solids were filtered to afford 3-(benzoimidazol-2-yl)-7-chloro-quinolin-2-one (9-3) as a yellow solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.63 (br s, 1H), 12.53 (br s, 1H), 9.13 (s, 1H), 8.01 (d, 1H, J=8.5 Hz), 7.72 (m, 1H), 7.65 (m, 1H), 7.22 (br s, 1H), 7.35 (dd, 1H, J=8.5, 1.9 Hz), 7.21 (m, 2H); HRMS (electrospray FT/ICR) calculated for C16H11N3O [M+H]+ 296.0585, found 296.0590.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([NH2:11])[CH:5]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([N:11]=[CH:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)[CH:5]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: COC(=O)c1ccc(F)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(F)c(N=Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture solution of 3-amino-4-fluoro-benzoic acid methyl ester (26 g, 153.8 mmol), 3-bromo-benzaldehyde (28.5 g, 153.8 mmol) and p-toluenesulfonic acid (590 mg, 3.2 mmol) in toluene (200 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 3-[(3-bromo-benzylidene)-amino]-4-fluoro-benzoic acid methyl ester (51.7 g, quant.) as a pale-white solid: MS calcd. for C15H11BrFlNO2 337.16, obsd. (ESI+) [(M+H)+] 336.0 & 338.0.
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[S:5][C:6]([SH:9])=[N:7][N:8]=1.Br[CH:11]([CH2:17][CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>CO.O>[SH:9][C:6]1[S:5][C:4]([S:3][CH:17]([CH3:18])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:8][N:7]=1
Reactant: Sc1nnc(S)s1
Reactant: CCOC(=O)C(Br)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(C)Sc1nnc(S)s1
Reaction time: 3 h
Yield: 76.5 %

Procedure:
To a solution of 9.92 g of sodium hydroxide in 160 ml of methanol-water (10:1) was added 37.2 g of 2,5-dimercapto-1,3,4-thiadiazole to dissolve. Then 40 g of ethyl bromobutyrate was added to the solution followed by stirring for 3 hours. The reaction mixture was settled overnight. The formed solid was taken by filtration, washed with methanol-water (10:1) and dried under reduced pressure to obtain 41.5 g of ethyl 3-[(5-mercapto-1,3,4-thiadiazol-2-yl)thio]butyrate. Melting point: 107°~108° C. ##STR17##
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][CH2:22][OH:23]>CN(C)C=O>[OH:23][CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C=Cc1ccc(O)cc1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OCCO)cc1
Yield: 43.1 %

Procedure:
30 g (168 mmol) of methyl 3-(4-hydroxyphenyl)-acrylate (Example 1), 29 g (210 mmol) of anhydrous K2CO3 and a spatula tip of Kl were placed in 200 ml of dimethylformamide. 14.91 g (185 mmol) of 2-chloroethanol were added dropwise at 85° C. within 5 minutes while stirring. The batch was stirred at 85° C. for a further 3 days. Subsequently, the salts were filtered off and the filtrate was concentrated to dryness in a water-jet vacuum. 16.1 g of methyl (E)-3-[4-[2-hydroxyethoxy]-phenyl]-acrylate were obtained in the form of white crystals after recrystallization from i-propanol. ##STR17##