Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH3:12][O:13][C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=[C:16](S(C)(=O)=O)[N:15]=1>O1CCOCC1>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:16]2[N:15]=[C:14]([O:13][CH3:12])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:17]=2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(OC(F)F)cc1
Reactant: CCOC(=O)c1cnc(S(C)(=O)=O)nc1OC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2ccc(OC(F)F)cc2)nc1OC
Temperature: 150 °C
Yield: 70.9 %

Procedure:
A mixture of 4-(difluoromethoxy)aniline (0.285 mL, 2.305 mmol) and ethyl 4-methoxy-2-(methylsulfonyl)pyrimidine-5-carboxylate (0.4 g, 1.537 mmol) in dioxane was heated in the microwave at 150° C. for 50 min. The mixture was then cooled to room temperature and concentrated. The residue was purified by flash chromatography on silica gel using 5-50% ethyl acetate in hexanes. The desired fractions were concentrated to give ethyl 2-((4-(difluoromethoxy)phenyl)amino)-4-methoxypyrimidine-5-carboxylate as an orange solid (0.37 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.83 (s, 1H), 7.67-7.58 (m, 2H), 7.37 (br. s., 1H), 7.20-7.09 (m, 2H), 6.74-6.12 (m, 1H), 4.35 (q, J=7.0 Hz, 2H), 4.08 (s, 3H), 1.38 (t, J=7.0 Hz, 3H). LCMS: R.T.=0.96; [M+H]+=340.1.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[S:7][C:8]2[CH:14]([CH3:15])[CH2:13][C:12]([CH3:17])([CH3:16])[CH2:11][C:9]=2[N:10]=1>C(OCC)(=O)C>[CH3:16][C:12]1([CH3:17])[CH2:11][C:9]2[N:10]=[C:6]([N:5]=[C:1]=[O:2])[S:7][C:8]=2[CH:14]([CH3:15])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: CC1CC(C)(C)Cc2nc(N)sc21
Solvent: CCOC(C)=O
Product: CC1CC(C)(C)Cc2nc(N=C=O)sc21

Procedure:
A saturated solution of phosgene in ethyl acetate (200 ml) and 2-amino-5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothiazole (6.0 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture was heated at reflux for a period of about 5 hours. After this time the reaction was stripped of solvent and unreacted starting materials to yield the desired product 5,5,7-trimethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl-isocyanate dimer as a brown crystalline solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[C:10]([C:19]([F:22])([F:21])[F:20])=[N:11][N:12]([CH3:18])[C:13]=2[O:14][CH:15]([F:17])[F:16])=[N:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[S:6][C:5]([S:7]([CH2:8][C:9]2[C:10]([C:19]([F:22])([F:20])[F:21])=[N:11][N:12]([CH3:18])[C:13]=2[O:14][CH:15]([F:17])[F:16])=[O:31])=[N:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncc(Br)s2)c1OC(F)F
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)(F)F)c(CS(=O)c2ncc(Br)s2)c1OC(F)F

Procedure:
The 5-bromo-2-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-thiazole obtained in this manner (4.0 g, 9.429 mmol) is initially charged in 100 ml of toluene. With stirring, 3-chloroperbenzoic acid (1.976 g, 8.015 mmol, 77% pure) is then added a little at a time, and the mixture is stirred at room temperature for a further 4 hours. For work-up, the reaction mixture is washed successively with water, aqueous NaHSO3 solution, aqueous NaHCO3 solution and finally with NaCl solution. The organic phase is dried over magnesium sulfate, filtered off and concentrated. The residue is triturated with n-heptane, filtered off and dried. The racemic 5-bromo-2-({[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfinyl)-1,3-thiazole obtained (3.75 g) is purified by preparative chiral HPLC (column: Chiralcel® OD; mobile phase: n-hexane/2-propanol 90:10; flow rate: 0.6 ml/min; column temperature: 25° C.) and separated into the enantiomers. This gives 1.505 g (36.2% of theory) of 5-bromo-2-[(S)-{[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfinyl]-1,3-thiazole (Rt=10.258 min) and 1.305 g (31.4% of theory) of 5-bromo-2-[(R)-{[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfinyl]-1,3-thiazole (Rt=12.557 min).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([Br:16])[CH:13]=[N:12]1)C1C=CC=CC=1.Cl>C(O)C>[OH:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([Br:16])[CH:13]=[N:12]1
Reactant: Brc1cnn(CCOCc2ccccc2)c1
Agent: Cl
Solvent: CCO
Product: OCCn1cc(Br)cn1
Yield: 71.7 %

Procedure:
1-(2-Benzyloxyethyl)-4-bromopyrazole (1.078 g) was dissolved in ethanol (20 ml). After adding conc. hydrochloric acid (15 ml), the resultant mixture was stirred at 80° C. for 10 hr. After allowing to cool, it was concentrated under reduced pressure followed by the addition of a saturated aqueous solution of sodium bicarbonate. Then the resultant mixture was extracted with ethyl acetate and the organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (525 mg) as a colorless oil (yield: 71%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:39]1[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Product: COC(=O)c1c(-c2ccc(S(C)(=O)=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 4-(methanesulfonyl)phenylboronic acid. A colorless powder (63 mg).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=O>CN1C(=O)CCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([C:12]2[N:9]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:8][CH:11]=2)=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: NC(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(-c2coc(-c3ccccc3)n2)cc1
Temperature: 135 °C
Reaction time: 0.5 h

Procedure:
a mixture of benzamide (3.7 g, 31 mmol), 2-bromo-1-(4-nitrophenyl)ethanone (5.00 g, 20 mmol) and 2.5 mL NMP heated in a 135° C. oil bath. After 30 minutes a precipitate developed. Another 2 mL of NMP was added to dissolve the precipitate. The reaction was heated for a total of 2 hours then removed from the oil bath. The reaction mixture solidified upon cooling. 30-40 mL acetonitrile was added to the solid and the resulting mixture was heated to 90° C. The resulting solution was removed from the oil bath and a precipitate developed upon cooling. The precipitate was collected by filtration (3.4 g, 62%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:11][S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:62])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([O:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:62])(=[O:7])=[O:6])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)Oc1ccon1
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)Oc1ccon1

Procedure:
3-(3-Chloropropylsulfonylamino)-1-hexadecylthio-2-(3-isoxazolyloxy)propane IIIj1 is allowed to react and worked up by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH2:51][CH3:52])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.[C@H:62]1([C:69](O)=[O:70])[CH2:65][C@@H:64]([C:66]([OH:68])=[O:67])[CH2:63]1>CN(C=O)C.O.C(#N)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH2:51][CH3:52])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:69]([C@@H:62]2[CH2:65][C@H:64]([C:66]([OH:68])=[O:67])[CH2:63]2)=[O:70])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: CCOc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Reactant: O=C(O)[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](C(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.8 %

Procedure:
HATU (226 mg, 0.59 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-ethoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (200 mg, 0.49 mmol), DIEA (0.169 mL, 0.99 mmol) and cis-cyclobutane-1,3-dicarboxylic acid (214 mg, 1.48 mmol) in DMF (2.0 mL) at room temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 20→90% ethyl acetate/hexane), and then preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)) to give the title compound (74.8 mg, 0.141 mmol, 28.5%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[C:16]([CH3:24])[CH:17]=[C:18]([C:21](O)=[O:22])[CH:19]=2)[NH:14][CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[CH2:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:10][C:11]1([CH3:37])[C:20]2[C:15](=[C:16]([CH3:24])[CH:17]=[C:18]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:19]=2)[NH:14][CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:26]=2)[CH2:12]1
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1cc(C(=O)O)cc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)NS(=O)(=O)C2CC2)cc2c1NC(c1cccc(N3CCOCC3)c1)CC2(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.3 %

Procedure:
To a suspension of 60% sodium hydride (664 mg, 16.6 mmol) in N,N-dimethylformamide (5 mL) was added cyclopropanesulfonic acid amide (2.01 g, 16.6 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A66. A solution of 4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (0.9 g, 2.37 mmol) and 1,1′-carbonyldiimidazole (768 mg, 4.74 mmol) in N,N-dimethylformamide (5 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B66. Solution B66 was added to Solution A66 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid [4,4,8-trimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (107 mg, 9%) as a brown solid: MS (ESI) M+1=484.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:3]=1.O.[N:25]([O-])=[O:26].[Na+]>CC(O)=O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:5]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:3]=1[N:25]=[O:26]
Reactant: Nc1cc(N2CCOCC2)nc(OCCOc2ccccn2)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(OCCOc2ccccn2)nc(N2CCOCC2)c1N=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
6-Amino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine (1.90 g, 6.00 mmol, 1.0 equiv.) was dissolved in 8 mL HOAc, and 8 mL H2O was added. The solution was cooled to 0° C., and NaNO2 (0.414 g, 6.00 mmol, 1.0 equiv.) was added. The reaction mixture was stirred at 0° C. for 1 hour. Water (20 mL) was added to dilute the slurry, and the solid was collected by filtration, washed with water, EtOAc (2 mL), then dried to yield 6-amino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlino-5-nitroso-pyrimidine (1.47 g, 4.25 mmol, 85% yield) as blue solid. The nitroso compound (1.385 g, 4.00 mmol, 1.0 equiv.) was treated with 5 mL water and enough 2 N HCl so that a clear dark blue solution was formed. Na2S2O4 (2.79 g, 16.00 mmol, 4.0 equiv.) was added in three portions, and the solution was stirred at room temperature for 1 hour. The resulting clear yellow solution was carefully neutralized with cold 2 M NaOH solution, and subjected to EtOAc extraction. 5,6-Diamino-2-[2-(pyridin-2-yloxy)-ethoxy]-4-morphlinopyrimidine (0.80 g, 2.41 mmol, 60%) was obtained as light yellow solid after usual workup.
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=CC=1S([O-])=O.[Na+].[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](Cl)=[C:23]([N+:28]([O-])=O)[CH:22]=1)(=[O:20])=[O:19].P([O-])([O-])([O-])=O.[H][H]>O>[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[CH:22]=1)(=[O:19])=[O:20]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Nc1cccc(S(=O)(=O)CCO)c1
Temperature: 85 °C

Procedure:
102.6 g of moist paste of 2-chloro-5-nitrophenyl 2-hydroxyethyl sulphone from Example 1 [or an equimolar amount of 4-chloro-3-nitrophenyl 2-hydoxyethyl sulphone] are stirred into 250 ml of water and 50 ml of the phosphate buffer solution described under Example 2. A small amount of a nonionic emulsifier and 5 g of palladium-oncharcoal catalyst are added. Hydrogenation with hydrogen is then carried out in an autoclave at 70° C. and approximately 40 bar. The reduction is monitored by chromatography. After the hydrogenation, and after releasing the pressure and flushing the reactor, the product is heated to 85° C. and clarified via a pressure filter. The filter is cooled to 0° C. and the crystalline 3-aminophenyl 2-hydroxyethyl sulphone is isolated by filtration. 53 g of single-substance product are obtained after drying.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:32]=[N:31][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:35][CH:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1cccnc1C(F)(F)F
Product: C[C@@H](c1ccc(-c2ccc(C(F)(F)F)nc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 2-trifluoromethylpyridine-3-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 3 tR=1.36 min, m/z=459.3; 1H NMR (CDCl3) 1.40 (m, 1H), 1.51 (m, 3H), 1.63 (m, 1H), 1.70-1.98 (m, 3H), 2.11-2.33 (m, 3H), 2.95 (m, 1H), 3.50-3.63 (m, 2H), 5.66 (m, 1H), 6.97 (m, 4H), 7.20 (m, 2H), 7.29 (m, 2H), 7.67 (m, 1H), 7.87-7.90 (m, 1H), 8.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:17]C>Br>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:17]
Reactant: COc1ccc2c(-c3ccccn3)noc2c1Cl
Agent: Br
Product: Oc1ccc2c(-c3ccccn3)noc2c1Cl

Procedure:
7-chloro-6-methoxy-3-(2-pyridyl)-1,2-benzisoxazole (24.4 g) is refluxed for 1.5 hours in 450 ml of 48% HBr. The precipitated hydrobromide salt is filtered off, washed with ether and neutralized with 10% NaHCO3 solution. The free base is filtered off and dried, giving 7-chloro-6-hydroxy-3-(2-pyridyl)-1,2-benzisoxazole, mp 209°-211° C.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18](=[O:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([CH3:27])[CH:11]=1.CN(CN(C)C)C>O>[CH3:8][O:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18](=[O:26])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH2:1])=[C:12]([CH3:27])[CH:11]=1
Reactant: COc1cc(C)c(C(=O)Cc2ccccc2)cc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)CN(C)C
Solvent: O
Product: C=C(C(=O)c1cc(OC)c(OC)cc1C)c1ccccc1

Procedure:
240 ml of acetic anhydride are added dropwise in the course of 20 minutes at room temperature, while stirring, to a mixture of 135.0 g (0.50 mole) of 1-(4,5-dimethoxy-2-methylphenyl)-2-phenyl-1-ethanone and 250 ml of bis-(di-methylamino)-methane, the temperature being held at 40° by cooling with an ice bath. The reaction mixture is stirred at 40° for a further hour and is then poured into a 2 kg mixture of ice and water, during which the crude product crystallises. After stirring for 15 minutes at 15° the crude product is filtered off, the filtered material is washed with cold water and then dried for 18 hours at 30° under approximately 100 mbar, yielding 1-(4,5-dimethoxy-2-methylphenyl)-2-phenyl-2-propen-1-one having a melting point of 57°-59°.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)CCC>C1(C)C=CC=CC=1.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:5][C:6]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A mixture of t-butylacetyl chloride (1 ml, 7.2 mmol), 2-(tributylstannyl)thiophene (2.4 ml, 7.56 mmol) and PdCl2(PPh3)2 (98 mg, 0.14 mmol) in toluene (50 ml) was heated at reflux until the starting material disappeared. After cooling at room temperature, the brown-black solution was diluted with ether and washed with a 0.1 N aqueous HCl solution. The organic phase was separated and stirred vigorously with a 10% w/v aqueous KF solution for 30 minutes. After filtration, the layers were separated and the organic one washed with water, brine, dried over MgSO4 and concentrated. The residual brown oil was chromatographied on silica gel (hexane/AcOEt 97/3) to give 3,3-dimethyl-1-(2-thienyl)-1-butanone 10 as a colorless oil (810 mg, 62%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][N:22]1[C:26](=[O:27])[C:25]([CH:31]=[CH:32][CH3:33])([CH:28]=[CH:29][CH3:30])[C:24]([CH:37]=[CH:38][CH3:39])([CH:34]=[CH:35][CH3:36])[C:23]1=[O:40].C(N(CC)CC)C>CN(C)C=O>[C:7]([O:21][N:22]1[C:26](=[O:27])[C:25]([CH:31]=[CH:32][CH3:33])([CH:28]=[CH:29][CH3:30])[C:24]([CH:34]=[CH:35][CH3:36])([CH:37]=[CH:38][CH3:39])[C:23]1=[O:40])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC=CC1(C=CC)C(=O)N(O)C(=O)C1(C=CC)C=CC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC=CC1(C=CC)C(=O)N(OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)C1(C=CC)C=CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
0.14 mole of triphenylchloromethane and 0.14 mole of N-hydroxy tetrapropenylsuccinimide are dissolved in 100 milliliters of dimethylformamide. 50 milliliters of triethylamine are added and the mixture is stirred overnight at room temperature. The solvent is then removed under vacuum and the reaction product is water washed until salt free and then dried. A yield of 90% of N-trityloxy tetrapropenylsuccinimide is recovered.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](=[O:33])[CH2:15][C:16]2[C:30]([CH3:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:17]=2[C:18]([N:20]=[S:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:19])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1.OO.C(=O)([O-])[O-:37].[Na+].[Na+].C(Cl)Cl>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:14](=[O:33])[CH2:15][C:16]2[C:30]([CH3:31])=[CH:29][C:28]([Cl:32])=[CH:27][C:17]=2[C:18]([N:20]=[S:21]2(=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[O:19])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)cc(C(=O)N=S2CCCCC2)c1CC(=O)c1cc(Br)nn1-c1ccccc1Cl
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(Cl)cc(C(=O)N=S2(=O)CCCCC2)c1CC(=O)c1cc(Br)nn1-c1ccccc1Cl
Reaction time: 18 h

Procedure:
0.2 g 2-{2-[5-Bromo-2-(2-chloro-phenyl)-2H-pyrazol-3-yl]-2-oxo-ethyl}-5-chloro-3-methyl-N-(tetrahydro-1lambda*4*-thiopyran-1-ylidene)-benzamide (0.35 mmol) were dissolved in 10 ml acetic acid. 4 mg Sodium wolframate dihydrate were added. 45 mg of a 30% solution of hydrogenperoxide was added dropwise and the resulting solution was stirred for 18 h. The reaction mixture was poured into a saturated aqueous sodium carbonate solution, methylene chloride was added and the organic pase was subsequently washed with water and saturated aqueous sodium carbonate. The organic solvent was dried and the solvent removed. Column chromatography yielded 0.07 g of the desired product, compound I.4-22.