Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: Fc1cc2c(Nc3ccc(OCc4ccccn4)c(Cl)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.65 g, 10.0 mmol), thionyl chloride (30 ml) and a catalytic amount of DMF (3 drops) was stirred under reflux for 2 h 30 min to give a homogeneous mixture. It was evaporated under reduced pressure at 40° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-chloro-4-(pyridin-2-ylmethoxy)aniline (2.58 g, 11.0 mmol) in dry DMA (15 ml). The residue of 3-chloro-4-(pyridin-2-ylmethoxy)aniline was washed down with more DMA (2×5 ml). The reaction mixture was stirred at room temperature for 18 h. It was poured into water (300 ml). The pH was adjusted to ca. 9 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether (300 mL). The solid was collected by filtration and washed with water (4×50 mL). It was stirred with hot (ca. 50° C.) acetone (300 mL) for 15 min. The insoluble materials was filtered off and the filtrate was evaporated under reduced pressure to give N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (203) (3.18 g, 83%) as a yellow/orange solid, mp 216-219° C.; 1H NMR δ [(CD3)2SO] 10.04 (s, 1H), 8.94 (s, 1H), 8.69 (s, 1H), 8.63-8.57 (m, 1H), 8.22 (br s, 1H), 8.08 (d, J=2.6 Hz, 1H), 7.85 (td, J=7.7, 1.8 Hz, 1H), 7.75 (dd, J=9.0, 2.6 Hz, 1H), 7.59 (br d, J=7.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.32 (d, J=9.0 Hz, 1H), 5.31 (s, 2H). Anal. Calcd for C19H13ClFN5O.0.9H2O: C, 57.34; H, 3.75; N, 17.60. Found C, 57.46; H, 3.82; N, 17.63.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:29])[NH:22][C:23]([CH3:28])=[CH:24][C:25]=2[CH2:26]O)=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:50]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:29])[NH:22][C:23]([CH3:28])=[CH:24][C:25]=2[CH2:26][Br:50])=[O:17])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(CO)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(CBr)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.9 %

Procedure:
To a stirred solution of 6-bromo-1-cyclopentyl-N-((4-(hydroxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.6 g, 1.3 mmol) in DCM (5 mL), triphenylphosphine (0.54 g, 2.06 mmol) was added at 0° C. followed by carbon tetrabromide (0.684 g, 2.262 mmol) at the same temperature. Reaction mixture was stirred at room temperature for 2 h. On completion, the reaction mixture was purified by column over silica gel to afford intermediate 6-bromo-N-((4-(bromomethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-cyclopentyl-1H-indazole-4-carboxamide (0.4 g, 58.8%). To a solution of this intermediate in DMF, respective amine (5 equiv.) was added and reaction stirred for overnight at room temperature. On completion, reaction mixture was poured into water and extracted with 15% MeOH/DCM. The combined organic layers were dried over sodium sulfate and concentrated to obtain crude material which was purified by prep HPLC affording 6-bromo-1-cyclopentyl-N-((4-((dimethylamino)methyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (19.2% yield). LCMS: 486.05 (M+1)+; HPLC: 99.59% (@ 254 nm) (Rt; 5.723); 1H NMR (DMSO-d6, 400 MHz) δ 11.65 (s, 1H), 8.83 (s, 1H), 8.36 (s, 1H), 8.20 (s, 1H), 7.62 (s, 1H), 6.07 (s, 1H), 5.23-5.18 (m, 1H), 4.41 (d, 2H, J=4 Hz), 3.37 (m, 2H), 2.16 (s, 6H), 2.15-2.05 (m, 5H), 1.99-1.91 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: [CH2:1]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH:9]1[NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C>C(#N)C.ClCCl>[NH2:33][CH2:32][CH2:31][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH2:10][CH:9]([NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22])[CH:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)NC1Cc2ccc(O)cc2C1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)NC1Cc2ccc(OCCN)cc2C1Cc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A suspension of ethyl 1-benzyl-6-hydroxy-2,3-dihydro-1H-inden-2-ylcarbamate (620 mg, 1.991 mmol) and caesium carbonate (1298 mg, 3.98 mmol) in acetonitrile (15 ml) was stirred at 80° C. under argon for 1 h, cooled down to 50° C. and tert-butyl 2-bromoethylcarbamate (669 mg, 2.99 mmol) dissolved in acetonitrile was slowly added. Stirred at 80° C. for 2 h. Evaporated acetonitrile, re-dissolved in dichloromethane, washed with water, co-extracted aqueous layer twice with dichloromethane and the combined organic layers were dried, filtered and evaporated and purified by flash silica gel chromatography on 40 g SiO2-cartridge using 30% ethyl acetate in cyclohexane to afford the titled compound as a brown oil. m=624 mg
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([N:15]2[CH2:19][CH2:18][S:17][C:16]2=[S:20])=[O:14])=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:21]([N:23]1CCS[C:24]1=S)=[O:22].CN.C(O)(C)C.CO>ClCCl>[CH3:1][O:2][C:3]1[C:12]([C:13]([N:15]2[CH2:19][CH2:18][S:17][C:16]2=[S:20])=[O:14])=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][C:4]=1[C:21]([NH:23][CH3:24])=[O:22]
Reactant: CNC(=O)c1cc(C(=O)N2CCSC2=S)c(OC)c(C(=O)N2CCSC2=S)c1
Agent: CN
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: CNC(=O)c1cc(C(=O)NC)c(OC)c(C(=O)N2CCSC2=S)c1

Procedure:
To a solution of compound 6A in dichloromethane, a mixture of 1 mL methylamine solution (40% wt in water, d=0.902) and isopropanol (10 mL) was added dropwise over 48 h. The reaction mixture was applied directly onto a gradient flash silica column (1-5% methanol in dicholoromethane). The desired product was obtained as a thick, yellow oil. Yield 2.9 g (68% based on methylamine).
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3](N)[CH:2]=1.[OH2:9]>CC(O[Na])=O>[C:1]1([OH:9])[C:6]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(N)cc1
Reactant: O
Agent: CC(=O)O[Na]
Product: Oc1cccc2ccccc12
Reaction time: 1 h

Procedure:
A 0.5 mg/ml solution of a first compound (p-phenylenediamine, "A") and a 0.5 mg/ml solution of a second compound (1-naphthol, "B") was prepared by dissolving the compound in the appropriate amount of 0.1 M CH3COONa, pH 5.5, buffer. A total volume of 100 ml was used in each LOM beaker. 100 ml "A" was added to one beaker and 50 ml "A" and 50 ml "B" were combined to form 100 ml in a second beaker. Swatches of the materials listed above were wetted in DI water and soaked in the precursor solutions. A Myceliophthora thermophila laccase ("MtL") with an activity of 690 LACU/ml (80 LACU/mg) was added to each beaker at a concentration of 12.5 mg/l. The LOM beakers were sealed and mounted in the LOM. After 1 hour at 42 RPM and 30° C., the LOM was stopped. The spent liquor was poured off and the swatches were rinsed in cold tap water for about 15 minutes. The swatches were dried at room temperature and CIELAB values were measured for all of the swatches using the Macbeth ColorEye 7000. The results are given in Tables 12 and 13.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[CH:9]=[N:8]1.[OH-].[Li+]>C1COCC1.CO.O>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(Cn2cc(-c3c[nH]c4ncc(-c5ccc(C6CCNCC6)cc5)cc34)cn2)c1
Yield: 511.1 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperidin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (170 mg, 0.026 mmol) was hydrolyzed by lithium hydroxide (12 mg, 0.264 mmol) in THF/methanol/water (10/5/2.5 ml) to yield 60 mg (40% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.54 (s, 2H), 8.229-8.227 (d, 1H), 7.959-7.957 (d, 1H), 7.73-7.70 (m, 3H), 7.44-7.41 (d, 2H), 7.38-7.23 (m, 1H), 7.12-7.09 (d, 1H), 7.08-7.00 (m, 2H), 5.43 (s, 2H), 3.55-3.50 (d, 2H), 3.21-3.13 (m, 2H), 3.05-2.93 (m, 1H), 2.16-2.11 (d, 2H), 2.02-1.89 (m, 2H). MS: m/z=452.5 (M+1), HPLC: 96.75% in method A.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12](O)(=O)[CH2:13][OH:14].N>>[N+:9]([C:5]1[CH:6]=[C:7]2[N:8]=[C:12]([CH2:13][OH:14])[NH:1][C:2]2=[N:3][CH:4]=1)([O-:11])=[O:10]
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Reactant: O=C(O)CO
Agent: N
Product: O=[N+]([O-])c1cnc2[nH]c(CO)nc2c1
Temperature: 145 °C
Reaction time: 0.62 h
Yield: 57.9 %

Procedure:
Solid 2,3-Diamino-5-nitropyridine (prepared according to J. Med. Chem. 1997, 40, 3679-3686; 610 mg, 0.0040 mol) and solid glycolic acid (750 mg, 0.0099 mol) were combined in a sealed tube (left open) and heated to 145° C. and stirred for approx. 30-45 min (solid fuses together, liquifies then re-solidifies). After allowing to cool to rt the solid was extracted with 1N HCl. The aqueous mixture was concentrated under vacuum to leave a crude solid that was basified using conc. NH3 solution. The ammonia solution was concentrated under vacuum to leave a crude solid that was dry-loaded on to silica and purified by column chromatography (using the ISCO system) to give a solid (450 mg) that was used directly in the next step.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1([C:10](OCC)=[O:11])[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[BH4-].[Na+]>CCO>[OH:11][CH2:10][C:7]1([C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH2:8][CH2:9]1
Reactant: CCCNC(=O)C1(C(=O)OCC)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCNC(=O)C1(CO)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.7 %

Procedure:
To a solution of ethyl 1-(propylcarbamoyl)cyclopropanecarboxylate (Example 198d) (1.65 g, 8.27 mmol) in EtOH (70 mL) was added NaBH4 (0.97 g, 25.64 mmol) at rt. The obtained mixture was stirred at rt over 2 days, quenched with 1.5M HCl and concentrated under reduced pressure. The concentrated mixture was extracted with EtOAc (4×70 mL), the combined extract was washed with saturated NaHCO3 and brine, and was dried over MgSO4. The filtrate was evaporated and the residue was purified by chromatography on silica gel using the solvent gradient hexanes→hexanes/EtOAc (1:9), to furnish 1.14 g (88%) of the product as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ 7.49 (broad s, 1H), 5.09 (broad s, 1H), 3.49 (s, 2H), 3.05 (q, J=6.4 Hz, 2H), 1.41 (hex, J=7.6 Hz, 2H), 0.86-0.91 (m, 2H), 0.83 (t, J=7.2 Hz, 3H), 0.55-0.60 (m, 2H).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].C([Li:14])CCC>C1(C)C=CC=CC=1>[CH2:1]([N-:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:2]([CH3:4])[CH3:3].[Li+:14]
Reactant: [Li]CCCC
Reactant: CC(C)CNCC(C)C
Solvent: Cc1ccccc1
Product: CC(C)C[N-]CC(C)C
Product: [Li+]

Procedure:
Following the process disclosed in application Ser. No. 374,740, 0.22 moles of diisobutyl amine was added to 100 ml of a 2.2M solution of n-butyl lithium in toluene. A clear solution of lithium diisobutylamide was obtained.
Reaction SMILES: C[N:2](C)[NH:3][C:4]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])=[O:5].Cl[C:19](Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.O.Cl[CH2:32][Cl:33]>>[Cl:33][C:32]1[N:6]([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])[C:4](=[O:5])[N:3]([CH3:19])[N:2]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccccc1NC(=O)NN(C)C
Reactant: ClCCl
Solvent: O
Product: COC(=O)c1ccccc1-n1c(Cl)nn(C)c1=O
Temperature: 10 °C

Procedure:
To a solution containing 61.5 g of the title compound of Step A dissolved in 1300 mL of dichloromethane under a nitrogen atmosphere was added 154 g of triphosgene portionwise with external cooling to maintain the reaction temperature at 0-20° C. The reaction mixture was then heated at reflux for approximately 24 h and then was cooled to 0° C. The reaction mixture was poured into water. The organic layer was separated and washed with water and saturated aqueous sodium chloride. The organic layer was then dried over magnesium sulfate, filtered and the filtrate was then evaporated to obtain 35.49 g of a white solid. This solid was purified by column chromatography on silica gel eluting with 2:1 hexane/ethyl acetate. Collection and evaporation of the fractions containing only the most polar component (according to thin layer chromatography on silica gel, 1:1 hexane/ethyl acetate mixture as the development solvent) yielded 12.2 g of the title compound of Step B as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.BrC1C=C[C:15]([OH:18])=CC=1.C(OC(OCC)CBr)C>>[O:6]1[CH:7]=[CH:8][C:4]2[CH:3]=[C:2]([CH:15]=[O:18])[CH:10]=[CH:9][C:5]1=2
Reactant: Brc1ccc2occc2c1
Reactant: Oc1ccc(Br)cc1
Agent: CCOC(CBr)OCC
Product: O=Cc1ccc2occc2c1

Procedure:
benzo[b]furan-5-carboxaldehyde was prepared from 5-bromobenzo[b]furan (prepared from 4-bromophenol and bromoacetaldehyde diethyl acetal by the general method described in J. Chem. Soc. Perkin 1, 1972, 556) following essentially the same procedure as that described in (b) above. Benzo[b]furan-5-carboxaldehyde was obtained as an oil. Pmr spectrum (CDCl3 ; δ in ppm): 6.90 (1H, d); 7.55-7.93 (3H, m); 8.15 (1H, d); 10.08 (1H, s).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([OH:7])[CH:2]=1.CN(C1CCCCC1)C.[CH3:17][N:18]1[C:23](Cl)=[N:22][C:21]([CH3:25])=[N:20][S:19]1(=[O:27])=[O:26]>C(Cl)Cl>[CH3:17][N:18]1[C:23]([O:7][C:3]2[CH:4]=[N:5][CH:6]=[CH:1][CH:2]=2)=[N:22][C:21]([CH3:25])=[N:20][S:19]1(=[O:27])=[O:26]
Reactant: Oc1cccnc1
Reactant: CC1=NS(=O)(=O)N(C)C(Cl)=N1
Solvent: ClCCl
Solvent: CN(C)C1CCCCC1
Product: CC1=NS(=O)(=O)N(C)C(Oc2cccnc2)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
17.1 parts of β-hydroxypyridine in 120 parts of methylene chloride and 19.1 parts of N,N-dimethylcyclohexylamine are introduced simultaneously, via 2 feeds, in the course of 15 minutes and at 15°-20° C., into a stirred solution of 29.3 parts of 2,5-dimethyl-3-chloro-2H-1,2,4,6-thiatriazine 1,1-dioxide in 150 parts of methylene chloride. The mixture is stirred for one hour at 25° C., after which the precipitate is filtered off under suction and the filtrate is washed with water and with dilute sodium carbonate solution, dried over magnesium sulfate, chromatographed over neutral aluminum oxide and then evaporated down under reduced pressure to give 26 parts (68.6% of theory) of 2,5-dimethyl-3-(pyrid-3-yloxy)-2H-1,2,4,6-thiatriazine 1,1-dioxide of melting point 137°-138° C. (compound No. 1).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]([CH3:17])[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.CO>[F:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[C:20]=1[C:21]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:2]=1[F:1])=[O:22]
Reactant: CN1CCC(N(C)c2cccc(N)c2F)CC1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cc(F)cc3F)c2F)CC1
Yield: 94 %

Procedure:
Heat a mixture of 2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 22, 60 mg) and 2,4,6-trifluorobenzoyl chloride (59 mg) in 1,4-dioxane (5 mL) for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a SCX column (10 g). After wash with methanol, elute the product with 2M NH3 in methanol, evaporate and purify on a silica gel column (4 g, solvent: dichloromethane-2M NH3 in methanol, gradient) to give 94 mg of the title compound: mass spectrum (electric spray) m/z=396 (M+1); 1H NMR (CDCl3): 7.96 (m, 1H), 7.84 (br s, 1H), 7.05 (m, 1H), 6.79 (m, 3H), 3.48 (d, 1H), 3.16 (m, 3H), 2.91 (br d, 2H), 2.74 (s, 3H), 2.27 (s, 3H), 1.97 (m, 2H), 1.84 (m, 2H), 1.72 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([OH:11])[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[O:29]1[CH:34]=[CH:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([O:11][CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][O:29]2)[CH:3]=1
Reactant: C1=COCCC1
Reactant: Oc1cc(Br)c2occc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1cc(OC2CCCCO2)cc2ccoc12
Temperature: 20 °C
Reaction time: 8 h

Procedure:
Combine 7-bromo-5-hydroxybenzofuran (5.0 g, 0.0235 mol) with pyridinium para-toluenesulfonate (0.59 g, 0.1 equivalent) and dissolve in 60 mL dichloromethane under nitrogen. Add via syringe 3,4-dihydro-2H-pyran (3.2 mL, 1.5 equivalents) and stir at 20° C. overnight. Dilute with dichloromethane then extract with 1N sodium hydroxide and wash with brine. Dry over sodium sulfate, filtered, and then concentrate to afford the title compound as a brown oil.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)=[O:12]>>[CH3:1][S:2][C:3]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[O:12])[CH3:10])[CH:14]=1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CC(=O)c1cccc(N)c1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CSC(=C[N+](=O)[O-])Nc1cccc(C(C)=O)c1
Temperature: 140 °C
Yield: 64.9 %

Procedure:
A neat mixture of 1,1-bismethylthio-2-nitroethylene (6.5 g, 38.5 mmol, 10 eq) and 3-aminoacetophenone (0.5 g, 3.85 mmol, leq) was melted together and heated at 140° C. for four hours. The mixture was cooled to room temperature, then subjected to flash chromatography, eluting with 50% ethyl acetate/hexanes, to yield 0.63 g of a yellow powder as product. Yield=65%. NMR (300 MHz, CDCl3) δ 11.82 (bs, 1H), 7.95-7.91 (m, 2H), 7.59-7.48 (m, 2H), 6.73 (s, 1H), 2.65 (s, 3H), 2.41 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7](N)[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12].C(N(C(C)C)CC)(C)C.N1(C=O)CCCCC1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[S:6][CH:5]2[N:4]([C:8](=[O:9])[CH2:7]2)[CH:3]1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Agent: O=CN1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)SC2CC(=O)N2C1C(=O)O
Reaction time: 1 h
Yield: 22371.5 %

Procedure:
A mixture of 4-[3-(1H-imidazol-1-yl)propyl]-piperidine (1.5 g, 0.0078M) and dimethylformamide dimethylacetal (10 ml) was heated at 100° C. for 16 hrs. The excess of dimethylformamide dimethylacetal was removed to give 4-[3-(1H-imidazol-1-yl)propyl]-1-piperidinecarboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g, 0.0053M) and diisopropylethylamine (1.03 ml) in dry CHCl3 (9 ml) was added the above piperidinecarboxaldehyde in CHCl3 (5 ml) at 0° C. and stirred at that temperature for 1 hr, then at room temperature for 3 hrs. After the reaction, the solvent was removed and the residue dissolved in water (40 ml). The aqueous solution, washed with diethyl ether, was adjusted to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 column to give [2S-(2alpha,5alpha,6beta)]-6-[[4-[3-(1 H-imidazol-1-yl)propyl]-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid 1.2 mole hydrochloride monohydrate (0.87 g, 39% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[C:12]([NH2:20])(=[S:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:20]=[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[S:19][CH:2]=1
Reactant: Cc1ccncc1C(=O)CBr
Reactant: NC(=S)c1ccncc1
Product: Cc1ccncc1-c1csc(-c2ccncc2)n1
Yield: 27.5 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (428 mg) and thioisonicotinamide (153 mg), the title compound (77 mg) was obtained as colorless powder crystals.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1.O.O.[Sn](Cl)[Cl:17]>O.Cl>[ClH:17].[NH:5]([C:6]1[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[N:10][CH:11]=1)[NH2:1]
Reactant: COc1ccc(N)cn1
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(NN)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
A solution of sodium nitrite (3.795 g) in water (20 mL) was added dropwise to 5-amino-2-methoxypyridine (6.21 g) in concentrated hydrochloric acid (50 mL) over a period of 60 minutes with ice cooling, and the resultant mixture was stirred at a constant temperature for 30 minutes. Tin(II) chloride dihydrate (39.5 g) in concentrated hydrochloric acid (30 mL) was added dropwise to the reaction mixture at an internal temperature of about 10° C. for 30 minutes, followed by stirring for 2 hours at room temperature. Under cooling with ice, the reaction mixture was partitioned between sodium hydroxide (75 g) in water (300 mL) and diethyl ether. The aqueous layer was extracted with diethyl ether twice. Subsequently, the aqueous layer was saturated with sodium chloride, followed by extraction with diethyl ether. The organic layers were combined, and dried over sodium sulfate anhydrate, followed by filtration. 1M HCl in ethanol (50 mL) was added to the filtrate and the mixture was stirred. The solid that precipitated was collected by filtration, washed with diethyl ether, and dried, to thereby give the title compound (5.02 g, 57%).