Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:18](Cl)=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:8]([F:20])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH:21]1(B(O)O)[CH2:23][CH2:22]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:5][C:6]1[C:18]([CH:21]2[CH2:23][CH2:22]2)=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:8]([F:20])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1cc(F)c(C(=O)OC(C)(C)C)cc1C1CC1
Temperature: 130 °C
Yield: 64 %

Procedure:
To a solution of tert-butyl 4-butoxy-5-chloro-2-fluorobenzoate (0.23 g, 0.76 mmol), cyclopropylboronic acid (0.10 g, 1.14 mmol), potassium phosphate (0.64 g, 3.10 mmol) and tricyclohexylphosphine tetrafluoroborate (0.05 g, 0.15 mmol) in toluene (3 mL) and water (0.3 mL) under a nitrogen atmosphere was added palladium acetate (0.005 g, 0.076 mmol). The reaction mixture was heated at 130° C. for 30 minutes in the microwave then cooled to ambient temperature. Water (20 mL) was added and the mixture extracted with ethyl acetate (2×15 mL). The combined organics were washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) afforded tert-butyl 4-butoxy-5-cyclopropyl-2-fluorobenzoate (0.15 g, 67%), which was used directly in the next step. To a solution of this compound (0.15 g, 0.48 mmol) in dichloromethane (2 mL), was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was triturated in diethyl ether (10 mL) and the solid was filtered, rinsed with diethyl ether (2×10 mL) and dried to give the title compound (0.048 g, 40%). 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J=8.3 Hz, 1H), 6.56 (d, J=12.7 Hz, 1H), 4.08-3.95 (m, 2H), 2.18-0.39 (m, 14H).
Reaction SMILES: [Na][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O1CCCC1.[O-]S(C(F)(F)[F:29])(=O)=O.[O-]S(C(F)(F)F)(=O)=O.F[N+]12CC[N+](F)(CC1)CC2>C(#N)C.C(OCC)C>[F:29][C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCOC(=O)C([Na])(C(=O)OCC)c1ccccc1
Agent: F[N+]12CC[N+](F)(CC1)CC2
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(=O)C(F)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
A cold (-10° C.) solution of diethyl sodio(phenyl)-malonate in anhydrous tetrahydrofuran [prepared in conventional fashion from sodium hydride (2.5 mmol) and diethyl phenylmalonate (0.5 g, 2.1 mmol) in THF (15 cm3)] was added slowly to a cold (-10° C.) stirred solution of 1,4-difluoro-1,4-diazoniabicyclo[2.2.2]octane bistriflate (0.95 g, 2.12 mmol) in dry acetonitrile (50 cm3) under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and then diluted with diethyl ether (100 cm3). The mixture was then washed with 0.5M oxalic acid (30 cm3), 10% aqueous potassium hydrogen carbonate (30 cm3), and saturated brine (30 cm3) (in that order), dried (MgSO4), filtered, and the filtrate evaporated under reduced pressure to provide diethyl fluoro(phenyl)-malonate (65% yield) with correct NMR parameters.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:12][Mg+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])([CH3:12])[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: C[Mg+]
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Agent: [Br-]
Product: CC(C)(O)c1cnc(Cl)c(Cl)c1

Procedure:
1-(5,6-Dichloro-pyridin-3-yl)-ethanone from step (a) above (300 mg, 1.58 mmol) reacted with MeMgBr (0.79 mL, 2.4 mmol, 3.0 M in ether, Aldrich) under the conditions of Example 154b to give the title compound. MS (ESI, pos. ion) m/z: 206 (M+1).
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]([O:18]CC)=[O:17])[CH:12]=[N:11]2)[CH:5]=1.[OH-].[Na+]>C(O)C>[F:21][CH:2]([F:1])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[N:11]2)[CH:5]=1
Reactant: CCOC(=O)c1cnn(-c2cc(OC(F)F)n(C)n2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)cnn1-c1cc(OC(F)F)n(C)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A mixture of 1.25 g (4.16 mmol) Ethyl 1-(5-difluoromethoxy-1-methyl-3-pyrazolyl)-5-methyl-4-pyrazolecarboxylate, 20 ml ethanol and 0.97 ml aqueous sodium hydroxide (45%) was stirred for 1 hour at 80° C. The reaction solution was concentrated to a half and acidified with hydrochloric acid (37%). The precipitate was suction filtered off, washed with water and dried.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=2)[N:6]=1)=[O:4].[NH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([F:30])[CH:29]=3)[N:6]=[C:5]([C:3]([NH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncc(F)c2)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 25 °C
Yield: 38.6 %

Procedure:
A mixture of 1-benzyl-5-(5-fluoro-pyridin-3-yl)-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (23 mg, 0.056 mmol), β-alanine (495 mg, 5.6 mmol) and NaOMe solution (9 mL, 4.4 mmol) was refluxed for 16 h. After cooling to r.t., solvent was evaporated. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stilling until pH about 3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc/hexanes+2% AcOH). The product isolated was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 10 mg of the title compound. MS: (+) m/z 463.35 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]([CH3:17])=[CH:6]2)=[O:2].CC(=CC)C.P([O-])(O)(O)=[O:24].[Na+].[Cl-].[Na+].Cl>O.C(O)(C)(C)C>[CH3:16][O:15][C:13]([C:8]1[C:7]([CH3:17])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]([OH:24])=[O:2])[CH:4]=2)[N:9]=1)=[O:14]
Reactant: O=P([O-])(O)O
Reactant: COC(=O)c1nc2ccc(C=O)cc2cc1C
Agent: CC=C(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)c1nc2ccc(C(=O)O)cc2cc1C
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a mixture of water (0.8 ml) and tert-butyl alcohol (3 ml) were added methyl 6-formyl-3-methylquinoline-2-carboxylate (140 mg) , 2-methyl-2-butene (190 mg) and sodium dihydrogenphosphate (105 mg) in water bath. To the mixture was added dropwise sodium chloride (244 mg) and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was cooled in an ice bath, adjusted to pH 4 with 1M hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1, V/V) followed by crystallization from methanol-isopropyl ether to give 2-methoxycarbonyl-3-methylquinoline-6-carboxylic acid (121 mg) as crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][C:9]([S:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:8][C:7]=1[CH3:18])=[O:5])[CH3:2].CS(O)(=O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:18][C:7]1[C:8]2[C:15](=[O:17])[CH2:14][CH2:13][S:12][C:9]=2[CH2:10][CH2:11][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C1=C(C)C=C(SCCC(=O)O)CC1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCOC(=O)C1=C(C)C2=C(CC1)SCCC2=O
Temperature: 20 °C
Yield: 79.5 %

Procedure:
A mixture of ethyl-4-β-carboxyethylthio-2-methyl-1,3-cyclohexadiene-1-carboxylate (121.3 g, 0.449 mole) in toluene is stirred at 20° C., treated sequentially with 5.0 ml methanesulfonic acid and portionwise over a 5 minute period with trifluoroacetic anhydride (94.3 g, 0.449 mole) and allowed to stir at ambient temperatures for 18 hours. The resultant reaction mixture is quenched with a 1:1 mixture of ethyl acetate and water and stirred for 15 minutes. The phases are separated. The organic phase is washed with water and concentrated in vacuo to give a residue. Crystallization of the residue from isopropanol/heptane affords the title product as a yellow solid, 90.1 g, (79.5% yield), mp 99°-100° C., identified by 1HNMR and mass spectral analyses.
Reaction SMILES: [CH2:1]([C:13]1[CH:52]=[CH:51][C:16]([C:17]([C:19]2[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[C:25]([C:31](=O)[C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:34][CH:33]=3)=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=O)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H][H]>[Pd].O1CCCC1>[CH2:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][C:25]2[CH:24]=[C:20]([C:21]([OH:23])=[O:22])[C:19]([CH2:17][C:16]3[CH:15]=[CH:14][C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:52][CH:51]=3)=[CH:27][C:26]=2[C:28]([OH:30])=[O:29])=[CH:33][CH:34]=1)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCCCCCCCCc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(CCCCCCCCCCCC)cc3)cc2C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(CCCCCCCCCCCC)cc3)cc2C(=O)O)cc1

Procedure:
A solution of 133 grams of 2,5-bis(4-dodecylbenzoyl)terephthalic acid and 1 L of tetrahydrofuran was treated with 8 grams of 10% palladium on carbon (as a catalyst) and heated to 65° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The mixture was filtered through Celite™ diatomaceous earth filter agent to remove the catalyst. The filtrate was concentrated in vacuo to give a solid. The solid was triturated with ethyl acetate, and the residue was dried to give 2,5-bis(4-dodecylbenzyl)terephthalic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([CH:15]1[CH2:18][N:17](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.ClCCl.[Pd]>[C:1]([O:5][C:6](=[O:32])[N:7]([CH:15]1[CH2:18][NH:17][CH2:16]1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CNC1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
To a solution of (1-Benzhydryl-azetidin-3-yl)-benzyl-carbamic acid tert-butyl ester (0.43 g, 1 mmol) in a mixture of methanol (18 ml) and dichloromethane (2 ml) was added ammonium formate (1.3 g, 20 mmol), and 0.15 g of 10% Pd/C. The mixture was stirred at reflux for 18 h. After cooling to room temperature, it was filtered through Celite. The solvents were evaporated, and the residue was washed with hexanes and then extracted with dichloromethane. The dichloromethane solution was evaporated to give 0.24 g of a white solid; m.p. 144-145° C.; MS (ES) m/z 263.0 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:10].C1C=C[NH+]=CC=1.[Br:17][Br-]Br.C(OCC)C>C(O)(=O)C>[BrH:17].[Br:10][CH2:2][C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1cnccn1
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(CBr)c1cnccn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of acetylpyrazine (10 g, 81.88 mmol) in acetic acid (70 mL) is added hydrogen bromide (38% acetic acid solution, 16 mL) followed by pyridinium bromide perbromide (28 g, 83.17 mmol) which is added in a single portion. The reaction is stirred at room temperature for approximately 1.5 hours. A suspension is formed during this time. Diethyl ether is added (500 mL) and the resulting precipitate is collected by filtration. The isolated product is washed with acetonitrile and diethyl ether and is dried under vacuum to give a pale brown solid (23.2 g, quantitative yield). 1H NMR (d6-DMSO) δ 9.19 (1H, m), 8.95 (1H, m), 8.84 (1H, m), 5.02 (2H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[C:1]([O:5][C:6](=[O:14])[CH2:7][CH2:8][N:9]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH2:10][CH2:11][O:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: COCCNCCC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A solution of 2.23 g (0.011 mole) of 3-(2-methoxy-ethylamino)-propanoic acid tert-butyl ester in 20 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 20 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-85:15) gave 3.3 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methoxy-ethyl)-amino]-propanoic acid tert-butyl ester (IV-40).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[CH2:4].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K]>CN(C)C=O>[C:7]1(=[O:17])[N:11]([CH2:5][C:3](=[CH2:4])[CH2:2][Cl:1])[C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=C(CCl)CCl
Agent: [K]
Solvent: CN(C)C=O
Product: C=C(CCl)CN1C(=O)c2ccccc2C1=O
Temperature: 50 °C

Procedure:
A mixture of 3-chloro-2-chloromethyl-1-propene (6.55 g, 50 mmol) and potassium phthalimide (5.6 g, 30 mmol) in anhydrous dimethylformamide (200 ml) was heated two days at 50° C. Then the mixture was concentrated in vacuo and, after usual work-up, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (4.2 g, 78%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:33]2[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=2)=[C:3]([CH3:28])[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)c(-c2cnn(C)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 43.9 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.72 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.44 g, 43%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1)/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: O=Cc1cc(Cl)cc(C(F)(F)F)c1
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(Cl)cc(C(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (100 mg, 0.404 mmol) in toluene 5 mL was added 3-chloro-5-(trifluoromethyl)benzaldehyde 48 (84.4 mg, 0.404 mmol). PTSA (153.9 mg, 0.809 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h. The reaction mass was diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 49, which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-2-(3-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 49 was eluted at 35% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:20]([CH:24]=2)[C:21](O)=[O:22])(=[O:15])=[O:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1.C(N(C(C)C)CC)(C)C>ClCCl>[N:7]1([S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[C:20]([CH:24]=2)[C:21]([NH:39][C:35]2[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=2)=[O:22])(=[O:15])=[O:14])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: O=C(O)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Reactant: Nc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cc(S(=O)(=O)N2CCOCC2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of oxalyl chloride (0.06 ml, 0.66 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 5-(4-morpholinylsulfonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 66; 250 mg, 0.66 mmol) in dichloromethane (5 ml) at 0° C. The reaction mixture was stirred at 25° C. for 0.5 h. The organic phase was evaporated in vacuo to give the crude acyl chloride as a yellow solid. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (62.3 mg, 0.66 mmol) and diisopropylethylamine (0.12 ml, 0.66 mmol) in dichloromethane (20 ml) under nitrogen at 0° C. The reaction mixture was stirred at 25° C. for 1 h. The organic phase was washed with water (25 ml) three times and saturated brine (10 ml) two times, dried over sodium sulfate, and evaporated in vacuo to give the crude product as a orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH3:11])[C:3]=1[C:4]#[N:5].[Br:12]Br>C(Cl)(Cl)(Cl)Cl.ClCCl.[Fe].II>[Br:12][C:9]1[C:2]([Cl:1])=[C:3]([C:6]([S:10][CH3:11])=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: CSc1cccc(Cl)c1C#N
Reactant: BrBr
Agent: [Fe]
Agent: II
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CSc1ccc(Br)c(Cl)c1C#N
Temperature: 30 °C
Yield: 45.5 %

Procedure:
Iron powder (0.5 g) and iodine (0.05 g) were added to a solution of 2-chloro-6-(methylsulphenyl)benzonitrile (10.0 g) in a mixture of carbon tetrachloride and dichloromethane. The mixture was warmed to 30° C. and bromine (9.5 g) was added. The mixture was heated at 55° C. for 5 hours. It was cooled, washed with aqueous sodium bisulphite, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was redissolved in a mixture of carbon tetrachloride and dichloromethane and treated with iron powder (0.5 g) and iodine (0.05 g). Bromine (6.5 g) was added and the mixture was heated at 55° C. for 5 hours. It was cooled and washed with sodium bisulphite, water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by column chromatography eluted with a mixture of ethyl acetate and n-hexane to give 3-bromo-2-chloro-6-(methylsulphenyl)benzonitrile (6.51 g) as an orange solid NMR (CDCl3) 2.5(s,3H) 7.0(d, 1H) 7.65(d, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[CH:9]=[CH:10][S:11][C:4]=2[S:3]1(=[O:13])=[O:12].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl>CS(C)=O>[OH:8][C:7]1[N:2]([CH3:1])[S:3](=[O:13])(=[O:12])[C:4]2[S:11][CH:10]=[CH:9][C:5]=2[C:6]=1[C:22](=[O:23])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[CH:16][CH:17]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CN1C(=O)Cc2ccsc2S1(=O)=O
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2ccsc2S1(=O)=O
Temperature: 0 °C

Procedure:
1.8 g (8.3 mmol) of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide are stirred for 24 hours at room temperature under nitrogen with 1.6 g (8.3 mmol) of p-bromophenylisocyanate and 0.84 g (8.3 mmol) of triethylamine in 20 ml of absolute dimethyl sulfoxide. Thereafter, the mixture is poured into 50 ml of 2-N hydrochloric acid and 20 g of ice. The separated precipitate is filtered off under suction and washed neutral with water. The filter residue is taken up in 200 ml of methylene chloride, dried over sodium sulfate, stirred with 1 g of active carbon and filtered. The filtrate is extracted with four 100 ml portions of semi-saturated sodium carbonate solution, each of the organic phases being re-extracted with a small amount of methylene chloride. The combined aqueous phases are acidified to pH 1 with concentrated hydrochloric acid. The separated product is extracted with three 100 ml portions of methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated, whereby the product crystallizes out. For purification, the product is recrystallized from ca 30 ml of methanol to give 3-hydroxy-2-methyl-4-(4-bromophenylcarbamoyl)-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide of melting point 197°-199° C.