Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[N:11]=[C:10]([CH2:16][OH:17])[CH:9]=1.C(N(CC)CC)C.O>C(Cl)Cl.CS(C)=O>[Cl:7][C:8]1[CH:13]=[C:12]([CH:14]=[O:15])[N:11]=[C:10]([CH:16]=[O:17])[CH:9]=1
Reactant: OCc1cc(Cl)cc(CO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=Cc1cc(Cl)cc(C=O)n1
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
Oxalyl chloride (126.93 g, 154 mmol) and CH2Cl2 (80 mL) were placed in a 1 L, 3-neck round bottomed flask. The solution was cooled to −60° C. To the cooled solution, DMSO (24 mL) in CH2Cl2 (80 mL) was added over a 5 minutes period via dropping funnel. After 10 minutes, 4-chloro-2,6-dihydroxymethyl pyridine (12.13 g, 69.9 mmol) in DMSO (40 mL) was added over 5 minutes, also via dropping funnel. After 20 min., triethylamine (200 mL) was added and the reaction was stirred at −60° C. for an additional 5 minutes. The reaction mixture was then allowed to reach room temperature. Water (400 mL) was added to the flask. The aqueous mixture was extracted with several portions of CH2Cl2 and the organic fractions were added together, dried over Na2SO4, filtered and concentrated. The crude product was eluted through a silica gel (Aldrich 200-400 mesh, 60 Å) column with CH2Cl2 to give 8.20 g (69% yield) of pure 4-chloropyridine-2,6-dicarboxaldehyde as a bright yellow solid. 1H NMR (300 MHz, CDCl3) δ 10.12 (s), 8.11 (s). 13C NMR (CD3OD, 100 MHz) δ 191.26, 154.24, 147.55, 125.53•mp=163° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.ClCCl.CN(C)C=O.[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[NH:30][CH:29]=C3)[CH:24]=1)=[O:19])[CH3:16]>C(OCC)(=O)C>[CH2:15]([O:17][C:18]([C:20]1[CH:21]=[N:22][N:23]([C:25]2[CH:33]=[C:32]3[C:31](=[CH:27][CH:26]=2)[NH:30][CH:29]=[C:2]3[CH:1]=[O:5])[CH:24]=1)=[O:19])[CH3:16]
Reactant: CCOC(=O)c1cnn(-c2ccc3[nH]ccc3c2)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc3[nH]cc(C=O)c3c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.56 mL, 6.6 mmol) was added to anhydrous dichloromethane (50 mL), N,N-dimethylformamide (0.51 mL, 6.6 mmol) was added thereto at 0° C., and the mixture was stirred for 30 min at 0° C. To this reaction solution was added a mixture of 1-(1H-indol-5-yl)pyrazole-4-carboxylic acid ethyl ester (1.40 g, 5.47 mmol) obtained in Preparation 1 and dichloromethane (50 mL). The mixture was stirred under reflux for 1 h at room temperature, and the solvent was removed. Tetrahydrofuran (100 mL) and 20% aqueous ammonium acetate solution (100 mL) were added, which was then heated for 30 min while being stirred under reflux. After completion of the reaction, the reaction solution was cooled. Ethyl acetate was added and the mixture was washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:34]=[CH:33][C:20]4[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]>Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:34]=[CH:33][C:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCNCC4)no2)cc1Cl
Yield: 163.7 %

Procedure:
A solution of 1,1-dimethylethyl 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 42) (950 mg, 1.963 mmol) in hydrochloric acid (a 4M solution in dioxane, 10 ml, 40.0 mmol) and 1,4-dioxane (10 ml) was stirred at room temperature for 5 hours (a precipitate had formed). The reaction mixture was filtered and washed with dioxane (˜5 ml), and the solid dried under vacuum (pistol) overnight to yield the title compound (711 mg, 1.607 mmol, 82% yield) as a white solid. δH (CDCl3, 400 MHz): 10.17 (2H, br s), 8.25 (1H, d), 8.06 (1H, dd), 7.98-8.03 (2H, m), 7.33 (1H, d), 7.06 (1H, d), 4.72 (1H, sept), 3.35-3.47 (8H, m), 1.46 (6H, d). MS (ES): C21H2235ClN3O2 requires 383; found 384 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15]C)=O)(=[O:10])=[O:9])[CH:2]=1.[CH3:21][CH:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[CH3:21][CH:22]([CH3:26])[CH2:23][CH2:24][NH:25][C:13](=[O:15])[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=1[S:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:9])=[O:10]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Reactant: CC(C)CCN
Product: CC(C)CCNC(=O)c1ccccc1S(=O)(=O)Nc1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
The title compound was prepared according to procedures described above, using methyl 2-[(pyridin-3-ylamino)sulfonyl]benzoate and 3-methylbutylamine. The title compound was further purified by dissolving 2.0 g in ethyl acetate (20 mL) and heating to reflux. When compound had fully dissolved the resultant solution was left to cool very slowly to room temperature. The resulting crystals were left to stand at RT for 30 min, after which time they were filtered using a funnel, washed with cold ethyl acetate (20 mL), and dried under high vacuum for 16 h to afford the title compound as a white crystalline solid (1.67 g, 84%). 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H) 8.26-8.43 (m, 2H) 7.60-7.68 (m, 2H) 7.45-7.59 (m, 2H) 7.39 (t, 1H) 7.12-7.21 (m, 1H) 6.08-6.17 (m, 1H) 3.52 (q, 2H) 1.67-1.79 (m, 1H) 1.57 (q, 2H) 0.98 (d, 6H).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].[CH3:15][CH:16]([CH3:21])[CH2:17][C:18](Cl)=[O:19].Cl>CN(C)C=O>[CH3:15][CH:16]([CH3:21])[CH2:17][C:18]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)=[O:19]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(C)CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CC(C)CC(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 70 °C
Yield: 84.7 %

Procedure:
Aluminum trichloride (10.7 g, 7.5 mmole) was placed in a round bottom flask under nitrogen at room temperature. Dimethylformamide (1.7 mL) was added dropwise, which produced an exothermic reaction. The reaction stood for 15 minutes before the addition of oxindole (1 g, 7.5 mmole) followed by 3-methyl-butanoyl chloride (0.96 g, 8 mmole). The reaction was heated to 70° C. for 60 minutes. The reaction was poured onto crushed ice (100 g) with concentrated hydrochloric acid added (10 mL). The aqueous layer was extracted with EtOAc (100 mL). The organic layer was washed with a saturated NaCl (aqueous) solution, dried over MgSO4. The volatiles were removed in vacuo to afford the desired compound (1.38 g, 85%). 1H NMR (DMSO-d6): d 10.71 (s, 1H); 7.82 (d, J=8, 1H); 7.77 (s, 1H); 6.86 (d, J=8, 1H); 3.51 (s, 2H); 2.76 (d, J=7, 2H); 2.13-2.05 (m, 1H ); 0.88 (d, J=7, 6H) ESI-MS: m/z 216 (m−H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[N+:12]([O-])=O>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[CH:4][C:3]=1[NH2:12]
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(F)c(N)cc1N
Reaction time: 24 h
Yield: 87.5 %

Procedure:
A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (1.0 g, 5 mmol) and 10% Pd/C (200 mg) in MeOH (20 ml) was hydrogenated at 23° C. for 24 h. The reaction mixture was filtered through celite and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate-hexane) gave 4-fluoro-6-methyl-benzene-1,3-diamine (613 mg, 87%).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([N:14]1[C:18]2[N:19]=[C:20]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[NH:21][C:22](=[O:23])[C:17]=2[CH:16]=[N:15]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.CS(C)=[O:42]>ClCCl>[C:3]([CH:4]([N:14]1[C:18]2[N:19]=[C:20]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=3)[NH:21][C:22](=[O:23])[C:17]=2[CH:16]=[N:15]1)[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:42])[CH3:2]
Reactant: CS(C)=O
Reactant: COc1ccc(Cc2nc3c(cnn3C(CCO)CCCc3ccccc3)c(=O)[nH]2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cc2nc3c(cnn3C(CCCc3ccccc3)C(C)=O)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
151 mg (0.35 mmol) of 1-[1-(-hydroxy-ethyl)-4-phenyl-butyl]-6-(4-methoxy-benzyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one are dissolved in 1 ml of DMSO and 3.5 ml of dichloromethane, and the solution is cooled to 0° C. 0.485 ml of triethylamine and 245 mg of SO3/pyridine complex are added, and the mixture is stirred for 15 hours at room temperature. The mixture is diluted with 20 ml of dichloromethane, extracted with 1N HCl and saturated NaHCO3 solution, the extract is dried over Na2SO4, and the solvent is removed in vacuo. Purification by chromatography (PE-EA=2:1) gives 115 mg (76%), M.p.: 129° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=2)([CH3:15])[CH2:13][O:12]S1(=O)=O)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:25]([O:27][C:28](=[O:36])[C@:29](O)([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:36])[C@:29]([O:12][CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[N:17]=1)([NH:10][C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH3:15])([CH3:34])[C:30]([F:32])([F:33])[F:31])[CH3:26]
Reactant: CCOC(=O)[C@@](C)(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C(C)(c2cccc(Br)n2)COS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@](C)(OCC(C)(NC(=O)OC(C)(C)C)c1cccc(Br)n1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., NaH (0.508 g of a 60% dispersion in mineral oil, 12.69 mmol) was added to a solution of 4-(6-bromo-pyridin-2-yl)-4-methyl-2,2-dioxo-2lambda*6*-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (3.84 g, 9.76 mmol) and (R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (2.54 g, 13.67 mmol) in DMF (10 ml, soln. predried over 4 Å mol. sieves). The reaction mixture was allowed to stir at rt for 30 min, then at 60° C. for 17 h. The reaction mixture was quenched with H2O and diluted with 1N aq. HCl and EtOAc. The phases were separated and the aq. phase was twice reextracted with EtOAc. The combined org. phases were washed with brines, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (cyclohexane: EtOAc, gradient 0-5 min 100:0, 5-30 min 90:10, 30-40 min 90:10, 40-50 min 80:20, 50-55 min 80:20) yielded the title compound (diastereomer mixture) as a clear oil. HPLC RtH4=1.39 min; ESIMS: 499, 501 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1nccc2ccccc12
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2nccc3ccccc23)CC1
Yield: 100.1 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (Example 1, Step 4, 150 mg, 0.51 mmol) was reacted with 1-chloroisoquinoline (100 mg, 0.61 mmol) to afford the title compound (215 mg), a white solid, in 51% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5](C(O)=O)[NH:6]2.Cl>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2
Reactant: O=C(O)c1cc2c(Cl)cc(Cl)cc2[nH]1
Agent: [Cu]
Agent: Cl
Solvent: c1ccc2ncccc2c1
Product: Clc1cc(Cl)c2cc[nH]c2c1
Yield: 93.9 %

Procedure:
Dissolve 4,6-dichloro-indole-2-carboxylic acid (1.0g, 4.35mmol) in quinoline (25mL). Add copper powder (100mg) and heat to 220° C. for 3 hours. Pour the resulting black solution into cold concentrated hydrochloric acid (300mL) and extract into ethyl ether (500mL). Filter, wash with 1M hydrochloric acid (2×200mL), water (100mL) and dry (MgSO4). Evaporate the solvent in vacuo to give a brown oil (0.76g). Purify by silica gel chromatography (17% ethyl acetate/hexane) to give the title compound as an amber oil (0.66g, 81%). 1H NMR (CDCl3 /TMS): 6.56-6.59 ppm (1H, m), 7.10-7.13 ppm (2H, m), 7.16-7.18 ppm (1H, m). 13C NMR (CDCl3), ppm: 101.48, 110.16, 120.24, 125.77, 125.94, 126.54, 122.79, 106.54.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([NH:20][N:21]=[C:22]([NH2:24])[CH3:23])([CH3:19])[CH3:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([N:24]=[C:22]([NH:21][NH:20][CH:17]([CH3:19])[CH3:18])[CH3:23])=[O:15])[N:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: CC(N)=NNC(C)C
Reactant: O=C(O)c1c[nH]c(-c2ccc(Cl)cc2F)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1c[nH]c(-c2ccc(Cl)cc2F)n1)NNC(C)C

Procedure:
Scheme 15 shows the synthesis of 5-(2-(4-chloro-2-fluorophenyl)-1H-imidazol-4-yl)-1-isopropyl-3-methyl-1H-1,2,4-triazole 44 from 4-chloro-2-fluorobenzonitrile 38. Addition of hydroxylamine to the nitrile of 38 gave 4-chloro-2-fluoro-N-hydroxybenzimidamide 39. Michael addition of 39 to ethyl propiolate gave ethyl 3-(4-chloro-2-fluorobenzimidamidooxy)acrylate 40. Heating 40 in diphenyl oxide gave cyclized imidazole, ethyl 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylate 41. Saponification of the ester of 41 with aqueous sodium hydroxide in tetrahydrofuran gave 2-(4-chloro-2-fluorophenyl)-1H-imidazole-4-carboxylic acid 42. Reaction of 42 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 2-(4-chloro-2-fluorophenyl)-N-(1-(2-isopropylhydrazinyl)ethylidene)-1H-imidazole-4-carboxamide 43 which cyclizes upon heating to give 44.
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.[Li]CCCC.[F:15][C:16]([F:36])([F:35])[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[N:23]=[CH:22]2)=[O:18].Cl>CCOCC.C1COCC1>[F:36][C:16]([F:15])([F:35])[C:17]([C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[N:23]=[CH:22]2)([C:5]1[S:4][CH:3]=[N:7][CH:6]=1)[OH:18]
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: C[Si](C)(C)c1nccs1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1cncs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 2-trimethylsilanyl-thiazole (157 mg, 1.00 mmol) in dry ether (2 mL) was added n-BuLi (440 μL, 2.5 M in hexanes, 1.10 mmol). After 30 minutes, a solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (154 mg, 0.50 mmol) in dry ether (2 mL) was added. After 1 hour, the mixture was warmed to room temperature, quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl ether. The combined organic layers was washed with 10 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 202 mg of the crude product. To a solution of crude product (100 mg) in THF (2 mL) was added 2 M HCl (1 mL) and the mixture was stirred overnight. The mixture was then quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The mixture was purified over SiO2 using ethyl acetate-hexanes (0-100% gradient) to afford 38.4 mg (39% over two steps) of the title compound. MS m/z 394.26 (MH+).
Reaction SMILES: C(O[C:5]1([CH3:16])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.C1(C)C=CC=CC=1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+]>C(O)(=O)C>[C:24]([O:27][CH:9]1[CH2:8][C:7](=[O:10])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:5]1[CH3:16])(=[O:26])[CH3:25]
Reactant: CCCCCC1C(=O)C=CC1(C)OC(C)=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCC1=C(C)C(OC(C)=O)CC1=O
Yield: 170.1 %

Procedure:
In the same apparatus as in Example 1, 3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone (22.4 g), toluene (60 ml), acetic acid (10 ml) and sodium acetate (4 g) were charged and heated for 10 hours with agitation. After the completion of the reaction, acetic acid was evaporated off under reduced pressure. The residue was extracted with toluene (70 ml) and water (50 ml) and treated as in Example 1 to obtain 4-acetoxy-2-n-pentyl-3-methyl-2-cyclopentenone (18.6 g). Yield, 83%, B.P., 125°-135° C./0.2-0.5 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[N:19][CH:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br.C(=O)([O-])O.[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[N:19][CH:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(C(=O)N2CCOc3cnccc32)cc1Cl
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: O=C(c1ccc(O)c(Cl)c1)N1CCOc2cnccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.7 %

Procedure:
In a 10 ml flask, (3-chloro-4-methoxy-phenyl)-(2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-methanone (134 mg, 0.441 mmol) was dissolved in dichloromethane (5 ml), and the mixture was cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (2.2 ml, 2.2 mmol) was added thereto and stirred at room temperature for 16 hours. After neutralizing with saturated solution of sodium hydrogen carbonate to pH 8 to 9, the mixture was adjusted to pH 6 again by using 1N hydrochloric acid and extracted with dichloromethane. The combined organic layer was washed with saturated saline solution and dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of methanol:dichloromethane=1:20. The fractions containing the product were collected and evaporated to obtain the target compound 34 as white solid (65 mg, 50.9%).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]=[C:8]([N:14]4[C:18]([CH:19]([CH3:21])[CH3:20])=[N:17][CH:16]=[N:15]4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:19]([C:18]1[N:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[N:34][NH:35][CH:36]=5)[CH:23]=[CH:22][C:5]=4[C:6]=3[N:7]=2)[N:15]=[CH:16][N:17]=1)([CH3:21])[CH3:20]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)c1ncnn1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1ncnn1-c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 20.1 %

Procedure:
A suspension of 8-bromo-2-(5-isopropyl-[1,2,4]triazol-1-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (84 mg, 0.21 mmol), 4,4,5,5-tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (62 mg, 0.32 mmol), tetrakis(triphenylphosphine) palladium (0) (24 mg, 0.021 mmol) and sodium carbonate (45 mg, 0.42 mmol) in acetonitrile (6 mL) and water (3 mL) under nitrogen was heated at 140° C. for 25 mins under microwave irradiation. More tetrakis(triphenylphosphine) palladium (0) (24 mg, 0.021 mmol) was added, and heating was pursued for 30 mins at 150° C. The reaction mixture was diluted with ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and purified twice by flash chromatography (SiO2, gradient 50 to 75% ethyl acetate in cyclohexane, then 60% ethyl acetate in cyclohexane) to afford 484 as an off-white solid (16 mg, 20%). LCMS (Method C): RT=10.30 min, [M+H]+=379. 1H NMR (DMSO-d6): 12.98 (1H, bs), 8.28 (1H, bs), 8.18 (1H, d, J=8.3 Hz), 8.16 (1H, s), 7.99 (1H, bs), 7.46 (1H, dd, J=8.3, 1.8 Hz), 7.34 (1H, d, J=1.8 Hz), 4.38 (2H, t, J=5.0 Hz), 4.13-4.01 (1H, m), 3.37 (2H, t, J=5.0 Hz), 1.43 (3H, s), 1.41 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O-:8])=[CH:4][CH:3]=1.[Na+].[CH3:10][C:11]([C:14]([CH2:16]Br)=[O:15])([CH3:13])[CH3:12]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:16][C:14](=[O:15])[C:11]([CH3:13])([CH3:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CBr
Reactant: [O-]c1ccc(Cl)cc1
Agent: [Na+]
Product: CC(C)(C)C(=O)COc1ccc(Cl)cc1

Procedure:
226 g (1 mol) of 1-(4-chlorophenoxy)-3,3-dimethylbutan-2-one (obtained from sodium 4-chlorophenolate and α-bromopinacolone; in this respect, see German Patent Specification No. 2,201,063), together with 120 g (1.07 mols) of glycerol, 19 g (0.1 mol) of p-toluenesulphonic acid monohydrate and 30 ml of butanol, are dissolved in 1,000 ml of toluene, and the mixture is heated under reflux for 16 hours in a water separator. After the mixture has been cooled, the toluene phase is washed with 4 times 250 ml of water, dried over magnesium sulphate, filtered, and evaporated down in vacuo. 186 g (65.4% of theory) of 2-(t-butyl)-2-(4-chlorophenoxymethyl)-4-hydroxymethyl-1,3-dioxolane of boiling point b.p. 0.1 : 161° C.-163° C. are obtained by distillation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][C:8]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[C:1]([O:5][C:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([CH:23]=[O:24])=[CH:9][C:8]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Br)ccc1C(=O)OC(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1C(=O)OC(C)(C)C
Temperature: -95 °C
Reaction time: 1.25 h

Procedure:
A solution of 4-bromo-2-methyl-benzoic acid tert-butyl ester (Example I1) (75 g) in dry tetrahydrofuran (750 ml) was cooled to −100° C. A solution of butyl lithium (“BuLi”) (1.6 M in hexane) (163 ml) was added dropwise at −100° C. N,N-Dimethylformamide (1.14 ml) was added at −100° C. The reaction mixture was stirred at −95° C. for 75 minutes. The reaction was quenched by addition of aqueous ammonium chloride (saturated) (8 ml) at −90° C. The mixture was stirred for 10 minutes at −90° C., warmed to 0° C. and poured on a mixture of ice and water. The mixture was allowed to warm to ambient temperature and then extracted twice with ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate, and concentrated to give 4-formyl-2-methyl-benzoic acid tert-butyl ester (60.3 g) as yellow oil. 1H-NMR (CDCl3, 400 MHz): 10.03 (s, 1H), 7.93 (d, 1H), 7.75 (m, 2H), 2.65 (s, 3H), 1.65 (s, 9H).