Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[O:11][CH2:12][C:13](=[O:20])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[CH:7][CH:8]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][N:28]=2)[C:23]([CH:30]=O)=[CH:22]1.N1CCCCC1>C(O)C>[NH:21]1[C:29]2=[N:28][CH:27]=[CH:26][CH:25]=[C:24]2[C:23]([CH:30]=[C:12]2[O:11][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:13]2=[O:20])=[CH:22]1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: CCOC(=O)C1=C(Nc2cccc(OC)c2)OCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C1=C(Nc2cccc(OC)c2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of ethyl 2-[(3-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.28 g, 1.0 mmol) which similarly prepared according to the procedure described in the Example 2, First step and 7-azaindole-3-carboxaldehyde (0.15 g, 1.2 mmol) in ethanol (4.0 mL), piperidine (0.12 mL, 1.2 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with ethanol and diisopropyl ether then dried to afford the titled compound (0.17 g, y. 29%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:38]([OH:40])=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:46](=[O:53])([O:50][CH2:51]I)[S:47][CH2:48][CH3:49]>O.C(Cl)Cl>[C:46](=[O:53])([S:47][CH2:48][CH3:49])[O:50][CH2:51][O:39][C:38](=[O:40])[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:24][C:22](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCSC(=O)OCOC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a mixture of dipeptide 51 (969 mg, 1.69 mmol) in H2O (3.25 mL) and CH2Cl2 (3.25 mL) was added NaHCO3 (294 mg, 3.50 mmol) and TBAHSO4 (572 mg, 1.69 mmol). After stirring for 15 min, S-ethyl O-iodomethyl carbonothioate (322 mg, 1.30 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 2.5 h and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on silica gel, using a gradient of 0-50% EtOAc in CH2Cl2 as eluent to provide compound 52 (818 mg, 91%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 1.30-1.53 (m, 8H), 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.60-1.75 (m, 2H), 1.82-1.90 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 3.06-3.14 (m, 4H), 4.04-4.10 (m, 1H), 4.58-4.64 (m, 1H), 4.70 (bs, 2H), 5.18-5.21 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.90 (d, J=5.6 Hz, 1H) 6.67 (bd, J=6.8 Hz, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:2].[N-:37]=[N+:38]=[N-:39].[Na+].N(CC)(CC)CC.Cl>O1CCOCC1>[N:2]1[NH:37][N:38]=[N:39][C:1]=1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: N#CCc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ccc(Cc4nn[nH]n4)cc3)CC2)C1

Procedure:
A solution of N-({1-[4-(4-cyanomethyl-phenyl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 21, 250 mg, 0.50 mmol), sodium azide (Aldrich, 160 mg, 2.50 mmol), and Et3N HCl salt (350 mg, 2.50 mmol) in dioxane (5 mL) was heated in a sealed tube to 120° C. overnight. The solvent was removed in vacuo and the residue was purified on a silica gel column using a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:13]=[C:12](Br)[C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])=O.[NH4+]>[Pd].CCO.CCOC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:13]=[CH:12][C:11]2[C:15]([CH3:18])=[N:16][S:17][C:10]=2[C:9]=1[OH:19])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2c(C)nsc2c1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCOC(=O)c1ncc2c(C)nsc2c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A mixture of 4-Bromo-7-hydroxy-3-methyl-isothiazolo[4,5-c]pyridine-6-carboxylic acid butyl ester (0.19 mmol), 10% Pd/C (33 mg), ammonium formate (9.7 mmol), and EtOH/EtOAc (1:1, 1.9 mL) was refluxed with stirring for 4 h. After cooling to r.t. the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Eluting with 0-20% EtOAc/CH2Cl2 gave the title compound (35.4 mg) as a white solid: MS (m/z) 267.2 (M+1).
Reaction SMILES: C(O)(=O)C.S(=O)(=O)(O)O.[C:10]1([O:16][CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O[CH2:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23]>O>[CH3:17][O:16][C:10]1[CH:15]=[CH:14][C:13]([CH2:19][NH:20][C:21](=[O:24])[CH2:22][Cl:23])=[CH:12][CH:11]=1
Reactant: O=C(CCl)NCO
Reactant: COc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(CNC(=O)CCl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
Into an ice-cooled mixture of 80 ml of acetic acid and 20 ml of 95% sulfuric acid, 16 g of anisol and 12.4 g of N-hydroxymethyl-2-chloroacetamide (refer to Beilsteins, Handbuch der Organischen Chemie, Vol. 2, 200) were added under agitation, and after stirring the reaction mixture for 30 min, it was left stand still for 2 days. Then, the reaction mixture was poured into iced water and the thus deposited white crystals were collected by filtration. The crystals were recrystallized from an aqueous ethyl alcoholic solution to obtain 8.7 g of the object product in a yield of 41%. The product melted at 101°-102° C., and showed infrared absorption peaks at 3320 cm-1 (due to NH), 1640 cm-1 (due to C=O) and 1260 cm-1 (due to --O--), respectively.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].Cl.[CH2:16]([O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3C=C(O)[C:38]([Cl:42])=[CH:37][C:36]=3[F:43])=[N:29][CH:30]=[N:31]2)=[CH:26][C:25]=1[O:44][CH3:45])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:12]([O:11][C:8]1[C:38]([Cl:42])=[CH:37][C:36]([F:43])=[C:35]([CH:9]=1)[NH:34][C:28]1[C:27]2[C:32](=[CH:33][C:24]([O:23][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:25]([O:44][CH3:45])[CH:26]=2)[N:31]=[CH:30][N:29]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(Nc3cc(O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(Nc3cc(OC(C)=O)c(Cl)cc3F)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
Triethylamine (216 ml, 1.5 mmol) and then acetic anhydride (133 ml, 1.4 mmol) were added to a stirred suspension of 7-benzyloxy-4-(4-chloro-2-fluoro-5-hydroxyanilino)-6-methoxy quinazoline hydrochloride (600 mg, 1.4 mmol) in methylene chloride (7 ml). The mixture was stirred at ambient temperature for 3 hours and insoluble material removed by filtration. Volatiles were removed from the filtrate by evaporation and the residue purified by flash chromatography eluting with methylene chloride/methanol (100/0 increasing in polarity to 97/3) to give 4-(5-acetoxy-4-chloro-2-fluoroanilino)-7-benzyloxy-6-methoxyquinazoline (340 mg, 52%) as a solid.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:10].C(OC)(C)(C)C>C(O)(C)C>[ClH:10].[C:1]1([CH:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: CC(N)c1ccccc1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
At room temperature 122 g of (R)-1-phenylethylarnine (1.0 mol) was dissolved in 30 mL of isopropanol. The solution was stirred and cooled to 0° C. Then, a previously prepared solution of 100 mL of 37% hydrochloric acid (118 g, 1.2 mol) in 320 mL of isopropanol was added during 1 hour. The solution was stirred at 0° C. for an additional 40 minutes, and then it was concentrated on a rotary evaporator (16 mbar, bath 45° C.) to a volume of 300 mL. The translucent gel which had formed was transferred into a 1.5 1 flask, then, under stirring, 250 mL of tert-butyl-methyl-ether was slowly added. Crystals started to form and the suspension was stirred at 0° C. for 3 hours. The product was collected by filtration, washed with 100 mL of tert-butyl-methyl-ether and dried at 30° C./16 mbar for 4 hours to yield 133 g (84%) of 1-phenylethylamine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10](O)([CH3:12])[CH3:11]>C(OCC)(=O)C.C(O)(=O)C>[CH:10]([C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:12])[CH3:11]
Reactant: COc1cccc(C)c1C(C)(C)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1cccc(C)c1C(C)C
Yield: 98.9 %

Procedure:
A solution of 2-(2-methoxy-6-methylphenyl)-2-propanol (0.50 g, 2.77 mmol) in ethyl acetate-acetic acid (9:1, 10.0 mL) at room temperature was stirred under a H2 atmosphere for 16 h. The mixture was filtered through a Celite plug and the solvent was removed under reduced pressure. The residue was dissolved in hexanes and washed with water. The organic layer was dried MgSO4, filtered and concentrated under reduced pressure to afford 2-iso-propyl-3-methylanisole (0.45 g, 100%) as colorless oil, which was used for the next step without further purification: 1H NMR (300 MHz, DMSO-d6): δ 7.01 (dd, J=12.0 Hz, 11.7 Hz, 1H), 6.78 (d, J=12.0 Hz, 1H), 6.70 (d, J=11.7 Hz, 1H), 3.74 (s, 3H), 3.28 (m, 1H), 2.26 (s, 3H), 1.24 (d, J=10.8 Hz, 6H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate-hexanes (1:9); Rf=0.80.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][CH:19]=[N:20]4)[N:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1COCC1>CC(O)=O>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH2:17][CH2:18][CH2:19][NH:20]4)[N:11]=2)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2nc(-c3cccc4ncccc34)no2)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCCN4)no2)cc1
Yield: 48.6 %

Procedure:
To a solution of the product of Step C (0.069 g; 0.219 mmol) in AcOH (1 ml) and anhydrous THF (1.5 ml) NaBH3CN (3×0.07 g; 3.34 mmol) was added portion wise over a period of 2 h, while the temperature of the reaction mixture was kept <15° C. The solvents were removed in vacuo and the residue was diluted to 15 ml with EtOAc, washed with 5% NaOH, H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of CF3CO2H and EtOH (2 ml+2 ml), refluxed for 1 h and re evaporated. The residue was treated with NH4OH saturated CH2Cl2 (5 ml) and evaporated under reduced pressure. The residue was purified by FCC (SiO2, CH2Cl2) to give the title compound (0.034 g; 48%), as colourless solid. 1H-NMR (CDCl3) 0.95 (tr, 3H, J=7.4 Hz); 1.61-1.75 (m, 2H); 1.91-2.0 (m, 2H); 2.66 (tr, 2H, J=7.8 Hz); 3.09 (tr, 2H, J=6.5 Hz); 3.29-3.33 (m, 2H); 3.8 (broad s, 1H); 6.6 (dd, 1H, J=1, 8 Hz); 7.07 (tr, 1H, J=7.9 Hz); 7.3-7.35 (m, 3H); 8.1 (d, 2H, J=8.3 Hz).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[S:6])[CH:2]=[CH2:3].Br[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[CH2:1]([NH:4][C:5]1[S:6][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:7]=1)[CH:2]=[CH2:3]
Reactant: C=CCNC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: C=CCNc1nc(C(=O)OCC)cs1

Procedure:
The reaction described in Preparation 42 was repeated but using 20 g of allylthiourea, 37 g of ethyl bromopyruvate and 200 ml of ethanol, giving the title compound as a pale yellow powder.
Reaction SMILES: Cl[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[CH:2]=[CH:3][C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CNC
Reactant: CCCCCC(=O)C=CCl
Product: CCCCCC(=O)C=CN(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of dimethylamine (560 ml, 40% aqueous) is cooled to 5° C. 1-Chloro-1-octen-3-one (192 g) is added and the mixture stirred at room temperature for 20 min. The solution is then saturated with potassium carbonate and extracted with ether. The organic layer is washed 3 × with sat. sodium chloride solution, dried over sodium sulfate, concentrated and distilled to give the title compound, b.p. 94°-96° C/0.2mm.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]2=[N:22][NH:23][C:24](=[O:25])[N:13]2[CH:12]=1)(C)(C)C>CC#N.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=2)[C:14]2=[N:22][NH:23][C:24](=[O:25])[N:13]2[CH:12]=1
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc(Cl)ccc12
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NC/C=C/c1cn2c(=O)[nH]nc2c2cc(Cl)ccc12

Procedure:
tert-butyl[(2E)-3-(9-chloro-3-oxo-2,3-dihydro[1,2,4]triazolo[3,4-a]isoquinolin-6-yl)prop-2-en-1-yl]carbamate (3-10) was dissolved in CH3CN (10 mL) with 0.1% TFA present. The resulted solution was irradiated in microwave at 150° C. for 5 minutes. LCMS showed only product. The crude mixture was purified with reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA) to afford the desired product 3-11. 1H NMR (500 MHz, CD3OD) δ 8.29 (d, 1H, J=2.9 Hz), 7.90 (d, 1H, J=8.5 Hz), 7.78-7.64 (m, 2H), 7.14 (d, 1H, J=16.5 Hz), 6.30 (dt, 1H, J=16.5 , 7.0 Hz), 3.83 (d, 2H, J=7.0 Hz). LRMS m/z (M+H) 275.1 found, 275.1 required.
Reaction SMILES: O[CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:9][CH:10]=1.P(Br)(Br)[Br:23]>C(COC)OC.C(OCC)(=O)C>[Br:23][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH2:11][CH:12]([O:18][CH:19]([CH3:21])[CH3:20])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(Cc1cccc(C#CCO)c1)OC(C)C
Reactant: BrP(Br)Br
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(C#CCBr)c1)OC(C)C
Reaction time: 8 h

Procedure:
184 mg of Ethyl 3-[3-(3-hydroxy-1-propynyl)phenyl]-2-isopropoxypropanoate was dissolved in 4 ml of dimethoxyethane, and 50 μl of phosphorous tribromide was added. After stirring was continued at room temperature overnight, the reaction mixture was diluted with ethyl acetate and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was distilled off. Then, the residue was purified by silica gel column chromatography, to give 209 mg of the title compound in the 20:1 hexane-ethyl acetate fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCCl>[Br:14][CH2:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Cl)ccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(Cl)ccc1CBr
Temperature: 75 °C
Yield: 69.2 %

Procedure:
A mixture of ethyl 5-chloro-2-methylbenzoate (3.20 g, 16.1 mmol), N-bromosuccinimide (3.15 g, 17.7 mmol) and benzoyl peroxide (0.39 g, 1.61 mmol) in 1,2-dichloroethane (90 mL) was heated to 75° C. in an oil bath for 4 h. After this time, the mixture was cooled to room temperature and the organic layer was washed with water (45 mL) and brine (45 mL). The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (silica, 1:20 ethyl acetate/hexanes) afforded ethyl 2-(bromomethyl)-5-chlorobenzoate (3.09 g, 68%) as a clear oil: 1H NMR (500 MHz, CDC13) 7.94 (d, J=2.5 Hz, 1H), 7.46 (dd, J=8.5, 2.5 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 4.91 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H); ESI MS m/z 279 [(M+2)+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([NH:9][S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[C:4]([N:9]([CH3:26])[S:10]([CH:13]2[CH2:14][CH2:15]2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=S(=O)(Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F)C1CC1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)S(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)cyclopropane-sulfonamide (see Example 2) (283.9 mg, 0.61 mmol) in 3 ml anhydrous THF was added at −78° C. a 1M solution of LHMDS (0.6 ml, 0.6 mol) and the solution was stirred for 10 min at this temperature. Then, methyl iodide (0.8 ml, 1.824 g, 12.9 mmol) was added and the mixture was warmed to room temperature and stirred for 7 h. The solvent was removed and the residue extracted using EtOAc and brine. The organic fractions were dried using Na2SO4 and the solvent was removed. The obtained crude product was purified using flash-column chromatography (Si, EtOAc/Hexanes 1:2, Rf=0.45). Yield: 205 mg, 70%). 1H-NMR (500 MHz, CDCl3): δ=7.41-7.39 (d, 1H, J=10 Hz), 7.30-7.29 (d, 1H, J=8.0 Hz), 7.23-7.20 (m, 1H), 6.98-6.93 (q, 1H, J=8.5 Hz), 6.60 (s, 1H, br), 6.51-6.47 (m, 1H), 3.23 (s, 3H), 2.46-2.42 (m, 1H), 1.19-1.16 (m, 2H), 1.04-1.02 (m, 2H); m/z=481 [M−1]−.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[C:22][C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=1)[CH:28]=O>>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[C:22][C:23]1[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27](/[CH:28]=[CH:2]/[C:1]([C:4]2[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=2)=[O:3])[CH:30]=1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1C#Cc1ccccc1N
Yield: 82.6 %

Procedure:
Ex-35D: 4-{3E-[5-(2-Amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonamide was prepared in a similar manner as Ex-1 using 4-acetylbenzenesulfonamide (Ex-35A) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C), 82.6% yield, yellow solid, mp 167–169° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.27 (d, J=8 Hz, 2H), 8.20(s, 1H), 8.01 (d, J=16Hz, 1H), 7.94 (d, J=8 Hz, 2H), 7.84 (d, J=16 Hz, 1H), 7.53 (s, 2H), 7.15–7.17 (m, 1H), 7.02–7.08 (m, 1H), 6.77 (s, 1H), 6.72 (d, J=8 Hz, 1H), 6.49–6.54 (m, 1H), 5.46 (br, 1H) 3.97 (s, 3H), 3.96 (s, 3H). MS m/z: 462 ([M+H]+, 100%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1/[CH:11]=[CH:12]/[CH2:13][OH:14].C(P(CCCC)CCCC)CCC.[CH2:28]([O:30][C:31](=[O:44])[C@@H:32]([O:41][CH2:42][CH3:43])[CH2:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)[CH3:29].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:28]([O:30][C:31](=[O:44])[C@@H:32]([O:41][CH2:42][CH3:43])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:14][CH2:13]/[CH:12]=[CH:11]/[C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:36][CH:35]=1)[CH3:29]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C/c1ccc2ccccc2c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc3ccccc3c2)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
Under an atmosphere of nitrogen, (E)-3-naphthalen-2-yl-prop-2-en-1-ol (190 mg, 0.8 mmol), tributylphosphine (323 mg, 1.6 mmol) and (S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (184 mg, 1.0 mmol) were successively dissolved in dry benzene (20 mL). Solid 1,1′-(azodicarbonyl) dipiperidine (403 mg, 1.6 mmol) was added at 0° C. with stirring. After 10 min. the reaction was warmed to room temperature and the stirring continued for 1 h. The reaction mixture was concentrated in vacuo and the product purified by flash column chromatography, eluting with heptane/ethyl acetate (3:2), to give 180 mg (55%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](=O)([O-])[O-].[K+].[K+].IC>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccc(C2CCNCC2)c1F
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CN1CCC(c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2,3-difluorophenyl)piperidine (0.2 g, 1.01 mmol) in acetonitrile (10 ml), was added potassium carbonate (0.28 g, 2.0 mmol) and 1-iodomethane (0.06 ml, 1.0 mmol) and the mixture was stirred at ambient temperature for 1 h. MS m/z (rel. intensity, 70 eV) 211 (M+, 78), 210 (bp), 2140 (8), 127 (12), 97 (11).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[NH:17][C:16](=[O:18])[NH:15][C:11]3=[N:12][C:13]=2[CH3:14])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Product: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(O)c([N+](=O)[O-])c1

Procedure:
It is further contemplated that 1,3-dihydro-6(4-hydroxyphenyl)-5-methyl-2H-imidazo[4,5-b]pyridin-2-one (Example 16) can be nitrated with nitric acid to obtain 6-(4-hydroxy-3-nitrophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one [I; Ar 3-O2N-4-HOC6H3, R1 and R3 =H, R5 =CH3 ], which in turn can be reduced by catalytic hydrogenation to obtain 6-(3-amino-4-hydroxyphenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one I; Ar =3-H2N-4-HOC6H3, R1 and R3 =H, R5 =CH3 ].