Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][NH2:21])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: NCCc1cccc(F)c1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Br)cc1NCCc1cccc(F)c1
Temperature: 80 °C

Procedure:
A mixture of 4-bromo-2-fluoronitrobenzene (500 mg, 2.27 mmol), 2-(3-fluorophenyl)ethylamine (411 mg, 2.95 mmol), and potassium carbonate (1.0 g, 7.24 mmol) in 7 mL N,N-dimethylformamide was heated at 80° C. for 1 hour. The mixture was diluted with ethyl acetate, rinsed with brine (three times), dried over magnesium sulfate, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14]C)=[CH:12][C:6]([C:7]([O:9][CH2:10]C)=[O:8])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.Cl.S(Cl)(Cl)=O>[OH-].[Na+]>[OH:14][C:13]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([N+:16]([O-:18])=[O:17])=[C:6]([CH:12]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCOC(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Yield: 66 %

Procedure:
Ethyl 4,5-dimethoxy-2-nitrobenzoate (10.22 g, 40.04 mmol) was refluxed in 20% aqueous NaOH (50 mL) for 2 days. The solution was cooled, acidifed to pH 2 using concentrated HCl, and the resulting solid filtered, washed with water and dried. The solid was dissolved in methanol (90 mL) and thionyl chloride (3.1 mL, 42.75 mmol) cautiously added. After refluxing for 3 days, the solution was cooled, concentrated and diluted with dichloromethane (280 mL). The organic phase was washed with water (200 mL) and the aqueous layer further extracted with dichlormethane (100 mL). Organic layers were combined, dried (MgSO4) and concentrated to give the title compound as a yellow solid (6.00 g, 66%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:31])=[N:27][CH:28]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)S(O)(=O)=O.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([NH:29][C:30]([NH:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[O:31])=[N:27][CH:28]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(NC(=O)Nc4ccccc4)nc3)n2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2ccc(NC(=O)Nc3ccccc3)nc2)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 47 %

Procedure:
A solution of 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-phenylurea (0.0707 g, 0.108 mmol) and trifluoromethanesulfonic acid (TCI) (0.02 mL, 0.225 mmol) in 1 mL of TFA was stirred at rt for 3 h then heated to 50° C. and stirred for 3 h. Then the mixture was heated at 75° C. overnight. Saturated sodium bicarbonate was added slowly to quench the reaction and the resulting precipitate was collected by filtration. The crude product was purified by preparative HPLC using Phenomenex, Gemni NX 5 micron C18 150×30 mm column (10%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The resulting fraction was concentrated to dryness in vacuo. Saturated sodium bicarbonate was added to the residue and the resulting yellow precipitate was collected by filtration, washed with water and dried in a vacuum oven to give 1-(5-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)pyridin-2-ylamino)pyridin-2-yl)-3-phenylurea (0.0210 g, 47% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.87 (s, 1H); 10.28 (br. s., 1H); 9.30 (s, 1H); 8.71-8.84 (m, 2H); 8.34 (dd, J=4.60, 1.86 Hz, 8.22 (dd, J=9.00, 2.74 Hz, 1H); 7.87 (br. s., 1H); 7.74 (br. s., 1H); 7.47-7.58 (m, 3H); 7.31 (t, J=7.92 Hz, 2H); 7.01 (t, J=7.43 Hz, 1H); 6.92 (dd, J=7.83, 4.69 Hz, 1H); 2.44 (s, 3H). m/z (ESI, +ve ion) 414.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1>CN(C)C=O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)=[CH:13][CH:12]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(COc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To prewashed NaH (3×20 ml hexane) (2.52 g active NaH, 105 mmol) in dimethylformamide (DMF) (50 ml) is added 3-hydroxypyridine (10.0 g, 105 mmol) in DMF (50 ml) with cooling over 0.5 hour. The reaction mixture is stirred at RT for 1 hour and is then cooled to 15°. To this is rapidly added 4-chlorobenzyl chloride (16.25 g, 99.8 mmol) in 5 ml of DMF. The reaction is allowed to warm to RT, and is then poured into ice and extracted with chloroform (3×). The chloroform layers are combined, washed with water and with brine, dried over calcium sulfate and rotoevaporated. The crude product is poured into ice and extracted with ether (3×). The combined ether layers are washed with water and with brine, and dried over calcium sulfate to give 3-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])=[O:8].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]([F:21])([F:22])[F:23])=[O:8]
Reactant: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)ccc1C(F)(F)F)c1cc(Br)ccc1OC(=O)N1CCOCC1
Yield: 89.4 %

Procedure:
Using 5-bromo-2-hydroxy-N-[2,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.CCOCC>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:21])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2c(Br)cncc2c1
Solvent: CCOCC
Solvent: ClCCl
Product: [O-][n+]1cc(Br)c2ccc(Cl)cc2c1
Temperature: 25 °C

Procedure:
4-bromo-7-chloroisoquinoline (3-6)(1 g, 4.12 mmol, 1.0 equiv.) was dissolved in anhydrous CH2Cl2 (8.2 mL) and treated with mCPBA (1.622 g, 9.40 mmol, 2.3 equiv.). The reaction mixture was stirred at room temperature, forming 3-7 as a white precipitate. Following dilution with Et2O, the solid was collected and used without further purification in the next step. LRMS m/z (M+H) 260.1 found, 259.9 required.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[C:8](C)[CH:9]=1)(=[O:3])[NH2:2].NC1C=C(C=C(OC)C=1)[C:30](N)=[O:31].COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[C:8]([O:31][CH3:30])[CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Nc2cc(C)cc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: COc1cc(N)cc(C(N)=O)c1
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1cc(NC(C(=O)O)c2ccc(OC)c(OC)c2)cc(C(N)=O)c1

Procedure:
Using a procedure analogous to that described for the preparation of 89D, 93D was reacted with 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate to give 93E. 1H NMR (400 MHz, CD3OD) δ ppm 3.73 (s, 3H) 3.80 (s, 3H) 3.81 (s, 3H) 5.07 (s, 1H) 6.39 (t, J=1.98 Hz, 1H) 6.75 (s, 1H) 6.81 (s, 1H) 6.92 (d, J=8.35 Hz, 1H) 7.07 (dd, J=8.35, 1.76 Hz, 1H) 7.11 (d, J=1.76 Hz, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:21])[CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH3:13].Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>O1CCCC1.[Cl-].[NH4+]>[CH2:12]([O:14][C:15](=[O:21])[CH:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[C:17](=[O:20])[CH2:18][CH3:19])[CH3:13]
Reactant: CCOC(=O)CC(=O)CC
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: CCOC(=O)C(Cc1ccc(OC)cc1)C(=O)CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of potassium tert-butoxide (5.4 g), tetrahydrofuran (80 mL), tert-butanol (0.1 mL) and 3-oxopentanoic acid ethyl ester (5.0 g) at 0° C. was treated with a solution of 1-chloromethyl-4-methoxybenzene (4.7 mL) in tetrahydrofuran (20 mL), and the resulting mixture was stirred at 0° C. for 30 minutes, and then at room temperature for 24 hours. The mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of pentane and ethyl acetate (1:0 to 0:1 by volume), followed by distillation under reduced pressure (150° C., 1 mbar) gave title compound as a colourless oil (3.0 g). 1H NMR analysis showed that the product existed as a mixture of keto and enol isomers.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[NH:4][N:3]=1.C[O-].[Na+].Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14]>CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][N:4]2[N:3]=[C:2]([CH3:1])[O:6][C:5]2=[O:7])=[CH:16][CH:17]=1
Reactant: O=C(CCl)c1ccc(F)cc1
Reactant: Cc1n[nH]c(=O)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[O-]
Agent: [Br-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1nn(CC(=O)c2ccc(F)cc2)c(=O)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of 5-methyl-3H-1,3,4-oxadiazol-2-one (2.77 g, 27.7 mmol) in MeOH (25 mL) is added 25 wt % NaOMe solution in methanol (6.4 mL, 27.9 mmol) and the mixture is stirred at rt for 10 min. The mixture is concentrated in vacuo and the residue is added to a solution of 2-chloro-4′-fluoroacetophenone (4.71 g, 27.3 mmol) and tetrabutylammonium bromide (0.174 g, 0.54 mmol) in CHCl3 (16 mL). The mixture is heated to reflux for 2.5 h under N2. The reaction mixture is then allowed to cool and stirred overnight at ambient temperature. The resultant slurry is filtered through qualitative filter paper and the filtrate is concentrated to obtain a liquid. This liquid is further filtered through a pad of silica gel, eluting with 1:1 EtOAc/DCM. The filtrate is concentrated in vacuo to afford 3-[2-(4-fluoro-phenyl)-2-oxo-ethyl]-5-methyl-3H-1,3,4-oxadiazol-2-one (˜100%). MS: 237 (M+H); 1H NMR (300 MHz, CDCl3) δ 7.90-8.10 (m, 2H), 7.10-7.22 (m, 2H), 5.08 (s, 2H), 2.29 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:21][O:22][CH2:23][CH2:24][N:25]1[C:29]2=[N:30][CH:31]=[CH:32][CH:33]=[C:28]2[N:27]=[C:26]1S(C)(=O)=O.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:11])[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:26]4[N:25]([CH2:24][CH2:23][O:22][CH3:21])[C:29]5=[N:30][CH:31]=[CH:32][CH:33]=[C:28]5[N:27]=4)=[CH:14][CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1c(Oc2ccc(-c3nn(C)c4cc(F)cnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a stirred solution of 4-(6-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (37 mg) in DMF (4 mL) was added NaH (60% in oil, 4.02 mg) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from EtOH/hexane to give the title compound (28.0 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: Cc1ccnc(Br)c1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4c(F)ccnc4F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12j and 2-bromo-4-methylpyridine
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)([F:4])[F:3].ClC1C=CC=C(C(OO)=[O:19])C=1.[OH-].[Na+]>ClCCl>[F:1][C:2]([F:4])([F:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:19]
Reactant: FC(F)(F)c1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: [O-][n+]1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
5.1 g (35 mmol) of trifluoromethylpyridine were dissolved at room temperature in 100 ml of dry dichloromethane, admixed with 17.3 g of m-chloroperbenzoic acid and stirred at room temperature for 72 h. Thereafter, the mixture was admixed with 1 N sodium hydroxide solution and extracted four times with dichloromethane; the combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was taken up in water, stirred and filtered, and the filtrate was concentrated under reduced pressure. 65.3 was obtained in 47% yield. 1H NMR: 8.46, d, 1H, 7.96, d, 1H, 7.7, m, 1H, 7.5, m, 1H.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15]([OH:17])=O)[CH3:2].S(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:15]([Cl:20])=[O:17])[CH3:2]
Reactant: CCOc1nc2c(cnn2CC)nc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCOc1nc2c(cnn2CC)nc1C(=O)Cl

Procedure:
40 g. of 6-ethoxy-1-ethyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid (0.17 mol.) and 300 ml. of thionyl chloride are refluxed for 21/2 hours. After removal of the excess thionyl chloride under vacuum, the 6-ethoxy-1-ethyl-1 H- pyrazolo[3,4-b]-pyrazine-5-carbonyl chloride is treated with hexane, filtered off and then dried at 60°, yield 41.5 g. (96%), m.p. 86°-87°.
Reaction SMILES: C([N:4]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:26][C:27]3[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([NH2:38])[C:28]=3[C:29](=[O:31])[CH:30]=2)=[CH:21][C:20]=1[F:39])[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18])(=O)C.Cl.[OH-].[Na+]>O1CCOCC1>[NH2:38][C:32]1[C:28]2[C:29](=[O:31])[CH:30]=[C:25]([C:22]3[CH:23]=[CH:24][C:19]([NH:4][CH2:5][CH2:6][CH2:7][N:8]4[C:12](=[O:13])[C:11]5=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]5[C:9]4=[O:18])=[C:20]([F:39])[CH:21]=3)[O:26][C:27]=2[C:35]([F:36])=[CH:34][C:33]=1[F:37]
Reactant: CC(=O)N(CCCN1C(=O)c2ccccc2C1=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCN4C(=O)c5ccccc5C4=O)c(F)c3)cc(=O)c12
Yield: 87.4 %

Procedure:
1.0 g of Compound 28 was dissolved in 12 ml of dioxane, 8 ml of concentrated hydrochloric acid was added and the mixture was heated at reflux for 4.3 hours. The reaction solution was cooled on ice and adjusted to pH 8 by addition of a 10N aqueous solution of sodium hydroxide thereto, and the precipitated crystals were collected by filtration to give 805 mg (87%) of Compound 29.
Reaction SMILES: [CH3:1][C@@H:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@H:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(O)(=O)C.[Zn]>[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@H:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[C@@H]1C(=O)c2ccccc2O[C@H]1c1ccccc1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: C[C@@H]1Cc2ccccc2O[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 30.4 %

Procedure:
Trans-3-methylflavanone (3.50 g.) was dissolved in acetic acid (120 ml) and concentrated hydrochloric acid (15 ml) and the solution added to amalgamated zinc prepared from zinc powder (25.0 g) and mercuric chloride (1.0 g). The mixture was stirred for 1 hr. at room temperature, then allowed to stand at room temperature for a further 16 hr. The zinc residue was filtered off, washing with acetic acid, and the filtrate and washings diluted with water and extracted with toluene. The extract was washed with saturated sodium bicarbonate solution, dried, and evaporated. The residue was recrystallised from methanol three times to yield the required trans-3-methylflavan (1.00 g., m.pt. 77°-78°). The configuration was confirmed by 1H n.m.r.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:15][C:14](=[O:16])[O:13][C:11]2=[O:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[CH2:1]([C:5]1[S:9][C:8]2[CH:10]([C:11]([OH:13])=[O:12])[CH2:15][C:14](=[O:16])[C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C2CC(=O)OC2=O)s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)Cc1cc2c(s1)C(C(=O)O)CC2=O
Temperature: 25 °C
Yield: 43.9 %

Procedure:
A solution of 5.2 g (0.022 mole) of (5-isobutyl-2-thienyl)succinic anhydride in 20 cc of nitrobenzene was added drop by drop to a solution of 8 g (0.06 mole) of aluminum chloride in 40 cc of nitrobenzene. The mixture was brought to 40C for 1 hour. After cooling to ambient temperature, the reaction mixture was poured into an ice-hydrochloric acid mixture, then extracted with methylene chloride. The organic solution was extracted with an aqueous sodium carbonate solution. The aqueous phase was acidified by dilute hydrochloric acid. The oil that separated was extracted with ethyl acetate. After elimination of the solvent under reduced pressure, the residue was purified by chromatography on a silica column (9/1/0.05 methylene chloride-methanol-acetic acid eluant). 2.3 g (yield=44%) of 2-isobutyl-4-oxo-5,6-dihydro-4H-cyclopenta[b]thiophene-6-carboxylic acid melting at 80° C. was obtained and used in the next stage without further purification. An analytical sample was obtained by recrystallization in a hexane-ethyl acetate mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:4]=1[CH2:5][NH:6][C:7](=[NH:12])[NH:8][C:9]([NH2:11])=[S:10].[F:19][C:20]([F:32])([F:31])[C:21]1[CH:30]=[CH:29][C:24]([C:25](=O)[CH2:26]Br)=[CH:23][CH:22]=1.C(O)(=O)C>O1CCOCC1>[CH3:18][O:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][NH:6][C:7]([NH:8][C:9]1[S:10][CH:26]=[C:25]([C:24]2[CH:29]=[CH:30][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:22][CH:23]=2)[N:11]=1)=[NH:12]
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: COc1cccc(OC)c1CNC(=N)NC(N)=S
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cccc(OC)c1CNC(=N)Nc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Yield: 52.9 %

Procedure:
Preparation took place analogously to Example 3 by reaction of 140 mg (0.52 mmol) N-[[(2,6-dimethoxybenzyl)amino](imino)methyl]thiourea with 140 mg (0.52 mmol) 4-(trifluoromethyl)phenacyl bromide. The educts were suspended in 3 ml dioxane, were added to 0.3 ml acetic acid and were heated for 40 minutes in the microwave (radiation 300 Watt). The mixture was subsequently concentrated and the crude product obtained was purified by chromatography on silica gel (dichloromethane/methanol 1-4%). Stirring of the yellow foam obtained with methyl tert.-butyl ether yielded 120 mg of a white amorphous solid.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21](O)[OH:22])[O:19][CH:20]=2)[CH:14]=1.[CH3:29][Al](C)C.[NH4+].[Cl-]>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[CH2:6][O:7][C:8](=[O:24])[NH:9][C:10]1[CH:11]=[N:12][N:13]([CH2:15][C:16]2[N:17]=[C:18]([CH:21]([OH:22])[CH3:29])[O:19][CH:20]=2)[CH:14]=1
Reactant: C[Al](C)C
Reactant: O=C(Nc1cnn(Cc2coc(C(O)O)n2)c1)OCc1ccccc1Cl
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(O)c1nc(Cn2cc(NC(=O)OCc3ccccc3Cl)cn2)co1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [1-(2-dihydroxymethyl-oxazol-4-ylmethyl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester (212 mg, 0.56 mmol) in CH2Cl2 (4.0 mL) was treated at 0° C. with trimethylaluminum (1.40 mL of a 2M solution in toluene, 2.80 mmol). The reaction mixture was then stirred at 0° C. for 1 h and at rt for 16 h. Sat. aq. NH4Cl was then added and the aq. layer was extracted with CH2Cl2 (3×10 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a pale yellow oil. TLC: rf (1:1 hept-EA)=0.28. LC-MS-conditions 02: tR=0.86 min, [M+H]+=377.17.
Reaction SMILES: [Cl:1][C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:20])[C:8]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1.[CH3:21]I.[H-].[Na+]>CC(N(C)C)=O.C(Cl)Cl.C(OCC)C>[Cl:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH2:16][CH3:17])([CH2:18][CH3:19])[CH2:9][N:10]2[CH:13]([CH3:15])[CH3:14])=[CH:4][N:3]=1
Reactant: CI
Reactant: CCC1(CC)CN(C(C)C)c2nc(Cl)ncc2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCC1(CC)CN(C(C)C)c2nc(Cl)ncc2N(C)C1=O
Temperature: 3 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 10-chloro-4,4-diethyl-2-propan-2-yl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 197; 2.7 g, 9.1 mmol) in DMA (50 mL) under nitrogen was added methyl iodide (0.627 mL, 10.0 mmol). The mixture was cooled on an ice/water bath to 3° C., and sodium hydride (60% mineral oil dispersion; 0.567 g, 11.8 mmol) added in one portion. The reaction was stirred overnight. The reaction was evaporated to dryness to afford a yellow solid, this was quenched with saturated NH4Cl(aq) (50 mL), extracted with DCM (3×100 mL), dried (MgSO4) and evaporated to yield a yellow solid. This was dissolved in a minimum amount of DCM, diethyl ether was added and the system was sonicated to afford an off white solid. (2.24 g, 80%)
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[C:7]([C:12]([OH:14])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:15]O.S(Cl)(Cl)=O>CO>[NH2:5][C:6]1[C:7]([C:12]([O:14][CH3:15])=[O:13])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccnc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ncccc1N

Procedure:
Methanol (75 mL) was cooled to 0° C. and treated dropwise with thionylchloride (3.5 mL, 48 mmol). 3-aminopyridine-2-carboxylic acid (0.9 g, 6.52 mmol, prepared as described by Sucharda, Chem. Ber. 1925, 1727) was added and the mixture brought to reflux. Over the next two days, two more MeOH/thionyl chloride mixtures were made and added to the reaction. The reaction was evaporated to dryness, then treated with thionyl chloride (5.7 mL, 78.3 mmole) in 75 mL of MeOH and refluxed for two more days. The reaction was evaporated to dryness and chromatographed on silica eluting with 9:1:1 EtOH/NH4OH(H2O to give methyl 3-aminopyridine-2-carboxylate as a yellow solid.