Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:19][CH3:20])[CH:9]=[CH:10][C:11]=2[NH:15][C:16](=[O:18])[CH3:17])[CH2:6]1)(=[O:3])[CH3:2].CC(C)=[O:23].S([O-])([O-])(=O)=O.[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>O>[C:1]([NH:4][CH:5]1[CH2:6][C:7]2[C:12](=[C:11]([NH:15][C:16](=[O:18])[CH3:17])[CH:10]=[CH:9][C:8]=2[O:19][CH3:20])[C:13](=[O:23])[CH2:14]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(NC(C)=O)c2c1CC(NC(C)=O)CC2
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc(NC(C)=O)c2c1CC(NC(C)=O)CC2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
190 mg of the compound prepared in (3) above was suspended into a mixture of 16 ml of acetone and 4 ml of 15% aqueous solution of magnesium sulfate, and to the solution was added 543 mg of potassium permanganate, followed by stirring for 1.5 hours at room temperature. After the addition of 150 ml of water, the reaction mixture was extracted with chloroform. The extract was waxed with saturated brine and dried over magnesium sulfate. After removal of the solvent, the residue was crystallized in ethyl acetate and hexane to produce 124 mg of the title compound.
Reaction SMILES: CN(C)C=O.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[CH:14][C:13]1=[O:24].[Br:25]N1C(=O)CCC1=O>O>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:15]=[C:14]([Br:25])[C:13]1=[O:24]
Reactant: O=c1ccc(-c2ccccn2)cn1-c1ccccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccn1
Yield: 54.3 %

Procedure:
2 ml of a dimethylformamide solution containing 0.07 g of 1-(2-pyridyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one was incorporated with 0.07 g of N-bromosuccinic acid imide, under stirring and ice-cooling. After stirring the mixture at room temperature for 2 hours, it was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=3:1), to give 0.05 g of the title compound as a pale brown powder.
Reaction SMILES: [CH:1]1([N:7]2[CH:11]([CH3:12])[CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.Cl[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=O.[Cl-].[NH4+].C(N(CC)CC)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C1COCC1.O>[CH2:25]([CH:9]1[CH2:10][CH:11]([CH3:12])[N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]1=[O:13])[C:24]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:23]=1
Reactant: CC1CCC(=O)N1C1CCCCC1
Reactant: O=Cc1ccccc1Cl
Agent: CC(C)[N-]C(C)C
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1CC(Cc2ccccc2)C(=O)N1C1CCCCC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Charge a flask with 1-cyclohexyl-5-methyl-pyrrolidin-2-one (U.S. Pat. No. 6,743,819, 500 mg, 2.8 mmol), dissolve in THF (30 mL) and cool to −78° C. under nitrogen. Add LDA (2M, 1.7 mL, 3.3 mmol) and stir at −78° C. for 10 minutes. Add 2-chlorobenzaldehyde (500 mg, 3.6 mmol) and warm to room temperature. Pour into saturated aqueous ammonium chloride and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Dissolve the residue in THF (30 mL) and add triethylamine (360 mg, 3.6 mmol) and methanesulfonyl chloride (380 mg, 3.3 mmol). Stir at room temperature for 2 hours and filter. Add DBU (440 mg, 3.6 mmol) to the filtrate and stir overnight. Pour the reaction into water and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Purify residue over silica gel (5:1 hexanes:ethyl acetate). Dissolve the residue in methanol (10 mL) and add 10% palladium on carbon (40 mg) and stir under a balloon of hydrogen for 3 days. Filter through celite® and concentrate. Purify over silica gel (9:1 hexanes:ethyl acetate) to afford two separable isomers.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[N:17][C:16]([CH3:20])=[C:15]([C:21](=[O:23])[NH2:22])[N:14]=2)=[CH:9][C:8]=1[F:24])(=O)=O.[F:27][C:28]1[CH:29]=[C:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])[CH:31]=[CH:32][C:33]=1B1OC(C)(C)C(C)(C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>COCCOC.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].C(Cl)Cl.O>[C:21]([C:15]1[N:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:33]3[CH:32]=[CH:31][C:30]([CH2:43][C:44]([O:46][CH3:47])=[O:45])=[CH:29][C:28]=3[F:27])=[C:8]([F:24])[CH:9]=2)[C:18]([CH3:19])=[N:17][C:16]=1[CH3:20])(=[O:23])[NH2:22]
Reactant: Cc1nc(C)c(-c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)nc1C(N)=O
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2F)c(F)c1
Temperature: 90 °C
Yield: 75.8 %

Procedure:
A solution of 4-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-fluorophenyl trifluoromethanesulfonate (Intermediate 6-4; 302 mg, 0.77 mmol) and methyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (Intermediate 6-2; 226 mg, 0.77 mmol) and potassium phosphate, tri-basic (196 mg, 0.92 mmol) in DME (10 mL), methanol (5 mL) and water (2.5 mL) was thoughroughly degassed. The mixture was treated with PdCl2(dppf)-DCM adduct (31.4 mg, 0.04 mmol), degassed again and the atmosphere replaced with nitrogen before being heated to 90° C. for 4 hours. The reaction mixture was allowed to cool to room temperature and then evaporated. The crude product was partitioned between EtOAc (75 mL), and saturated brine (75 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 70% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,2′-difluorobiphenyl-4-yl)acetate (240 mg, 76%) as a cream solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][O-].[K+].S(=O)(=O)(O)O.C(O)C>C(OCC)(=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:12]=2)[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CCOC(=O)C(Cl)=C[O-]
Reactant: Nc1ncc(C(F)(F)F)cc1Br
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2c(Br)cc(C(F)(F)F)cn12
Temperature: 90 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (3.0 g), potassium 2-chloro-3-ethoxy-3-oxoprop-1-en-1-olate (5.4 g), sulfuric acid (0.80 mL) and ethanol (60 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, and washed with water. The aqueous layer was neutralized with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solvent of IPE and hexane, and the obtained solid was collected by filtration to give the title compound (2.6 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)[CH:2]=C.I([O-])(=O)(=O)=[O:16].[Na+].C1COCC1.CO>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O.O>[N:13]1[C:14]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][CH2:1][CH:2]=[O:16])[CH:10]=[CH:11][CH:12]=1
Reactant: C=CCOc1cccc2cccnc12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: O=CCOc1cccc2cccnc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.4 %

Procedure:
A solution of osmium tetroxide (2.1 mmol) in tert-butanol (26 mL) was added to a stirred mixture of 8-allyloxyquinoline (3.7 g, 20 mmol), sodium periodate (15 g, 70 mmol), THF (90 mL), methanol (4 mL) and water (2 mL). The mixture was stirred at room temperature for 20 h, then was extracted with dichloromethane (100 mL). The aqueous layer was basified with the addition of sodium hydrogen carbonate then was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with 20% w/w sodium sulfite solution (200 mL), then dried over sodium sulfate and evaporated in vacuo to give the title compound (1.1 g, 30%) as an amber oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.[C:29](=[O:31])=[O:30]>C(OCC)C.C1COCC1>[C:1]([O:5][C:6]([NH:7][C:8]1[C:13]([C:29]([OH:31])=[O:30])=[CH:12][C:11]([Cl:14])=[N:10][CH:9]=1)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1C(=O)O
Temperature: -10 °C
Reaction time: 2 h

Procedure:
A solution of (6-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (4.19 g) in diethyl ether (150 mL) was cooled to −78° C. and N,N,N′,N′-tetramethylethylendiamine (6.60 g) was added. After slow addition of n-butyl lithium solution (1.32 M in hexane, 41.6 mL) over a time period of 10 minutes, the mixture was allowed to warm up to −10° C., stirred at this temperature for 2 hours and then was re-cooled to −78° C. The mixture was poured slowly into a stirred mixture of crushed dry ice in THF and stirred for 30 minutes. The mixture was concentrated on a rotary evaporator and water was added to the residue. The aqueous layer was washed 2× with MTB-ether and acidified with 6N hydrochloric acid to pH ˜3. The formed precipitate was filtered off, washed with water, ethyl acetate and dried in vacuum to afford 2.46 g of the title compound of the formula
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[SH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][CH:2]2[CH2:6][CH2:5][O:4][C:3]2=[O:7])=[CH:10][CH:11]=1
Reactant: O=C1OCCC1Br
Reactant: OCc1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCCC1Sc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
3-bromo-dihydrofuran-2(3H)-one (2.35 g, 14.3 mmol) was added to a solution of (4-mercaptophenyl)methanol (2.00 g, 14.0 mmol) and triethylamine (2.4 mmol, 17 mmol). The reaction was stirred at room temperature overnight, then was diluted with CH2Cl2 and washed sequentially with saturated NH4Cl and NaCl solutions. The organics were dried over MgSO4 and concentrated under reduced pressure to provide the product as a viscous oil (2.3 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH:20]=[O:21])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc(-c2cccs2)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(-c2ccc(Cl)s2)s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.7 %

Procedure:
To a solution of 5-chloro-[2,2′]bithiophene (1.06 g, 5.28 mmol) in 12 mL of THF at −78° C. is added n-BuLi (4.4 mL of a 1.6M solution in hexanes, 6.99 mmol). After 15 minutes, DMF (0.97 mL, 14 mmol) is added and the resulting solution is allowed to warm to 0° C. After 15 min, the solution diluted with EtOAc and quenched with saturated NaHCO3 solution. The organic solution is washed with H2O and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude product is purified by flash column chromatography eluting with a gradient of 10% Et2O/hexanes to 20% Et2O/hexanes to yield the title compound (0.89 g, 3.89 mmol) as a white solid. 1H NMR (CDCl3, 300 MHz) δ9.87 (s, 1H), 7.70 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 6.91 (d, 1H).
Reaction SMILES: N12CCCCC1C=NCCC2.[CH3:12][O:13][C:14](=[O:47])/[C:15](/[N:20]1[CH:23]([S:24]S(C2C=CC(C)=CC=2)(=O)=O)[CH:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21]1=[O:46])=[C:16](/[O:18][CH3:19])\[CH3:17]>O1CCCC1.C(Cl)Cl>[CH3:12][O:13][C:14]([C@@H:15]1[N:20]2[C:21](=[O:46])[C@@H:22]([NH:35][C:36](=[O:45])[CH2:37][O:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:23]2[S:24][CH:17]=[C:16]1[O:18][CH3:19])=[O:47]
Reactant: COC(=O)/C(=C(\C)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C1=NCCCN2CCCCC12
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)[C@H]1C(OC)=CS[C@@H]2[C@H](NC(=O)COc3ccccc3)C(=O)N12

Procedure:
302 mg (2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene are added to a solution of 534 mg (1 mmol) of a mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-methoxy-isocrotonic acid methyl ester and 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoacetidin-1-yl]-3-methoxy-crotonic acid methyl ester in the ratio of about 4:1, in 20 ml of tetrahydrofurane, whilst stirring. The mixture is then stirred for 40 minutes, diluted with 70 ml of methylene chloride and washed successively with dilute hydrochloric acid, with water, with dilute aqueous sodium bicarbonate solution and again with water. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 15 g of acid-washed silica gel using toluene/ethyl acetate, 2:1 followed by 1:1, resulting in the elution of, first, pure 7β-phenoxyacetamido-3-methoxy-ceph-2-em-4α-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70, 5.90 and 8.25μ, followed by pure 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85, 5.90 and 7.10μ, in the form of colourless foams.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)/[C:17](=[N:21]/[OH:22])/[CH2:16][CH2:15][CH2:14]2)=[CH2:10].[CH2:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31](OC)=O)=[CH:29][C:28]=1[C:37]([F:40])([F:39])[F:38])[CH:24]([CH3:26])[CH3:25].S(Cl)(Cl)=O>C1COCC1.N1C=CC=CC=1>[CH2:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31]2[O:22][N:21]=[C:17]3[C:18]4[C:13]([CH2:14][CH2:15][C:16]=23)=[CH:12][C:11]([CH:9]=[CH2:10])=[CH:20][CH:19]=4)=[CH:29][C:28]=1[C:37]([F:38])([F:39])[F:40])[CH:24]([CH3:26])[CH3:25]
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: COC(=O)c1ccc(CC(C)C)c(C(F)(F)F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1ccc(CC(C)C)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.5 %

Procedure:
To the LDA solution was added 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 1, 0.25 g, 1.335 mmol) dissolved in 1 mL of THF dropwise over a period of 1 min. at 0° C. After 15 min., methyl 4-isobutyl-3-(trifluoromethyl)benzoate (Preparation 23B, 0.347 g, 1.335 mmol) dissolved in 1 mL of THF was added dropwise over a period of 1 min. at 0° C. and the contents were stirred at 0° C. for 10 min. The reaction mixture was partitioned between 1N hydrochloric acid (5 mL) and ethyl acetate (10 mL)-THF. The 1N hydrochloric acid layer was back extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were dried over sodium sulfate and concentrated under reduced pressure. The resulting yellow solid was azeotroped with toluene (5 mL). To the solid was added toluene (5.00 mL), followed by thionyl chloride (0.195 mL, 2.67 mmol) and 1 drop of pyridine. The contents were heated at 110° C. for 5 min. The dark reaction mixture was concentrated and partitioned between ethyl acetate (15 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate, concentrated and subjected to silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield 3-(4-isobutyl-3-(trifluoromethyl)phenyl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (0.305 g, 0.767 mmol, 57.5% yield) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:27]=1.O1CCCCC1[N:34]1[C:38](B(O)O)=[CH:37][CH:36]=[N:35]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>CN(C=O)C.O.C(OCC)(=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([NH:17][CH2:16][C:7]2([C:12]([F:15])([F:14])[F:13])[C:6]3[CH:27]=[C:2]([C:36]4[NH:35][N:34]=[CH:38][CH:37]=4)[CH:3]=[CH:4][C:5]=3[NH:10][C:9](=[O:11])[O:8]2)=[O:26])=[CH:20][CH:21]=1
Reactant: O=C1Nc2ccc(Br)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Reactant: OB(O)c1ccnn1C1CCCCO1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(-c3ccn[nH]3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-{[6-Bromo-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (4.0 g, 8.94 mmol), [1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]boronic acid (2.63 g, 13.42 mmol), a palladium chloride-1,1-bis(diphenylphosphino)ferrocene complex (654 mg, 0.894 mmol) and potassium phosphate trihydrate (4.76 g, 17.88 mmol) were suspended in DMF (27 mL) and water (2.7 mL), and the mixed solution was stirred at 120° C. for 15 minutes under microwave irradiation. After the reaction solution was left to cool, water (10 mL) and concentrated hydrochloric acid (5 mL) were sequentially added thereto, and the solution was stirred at room temperature for 2 hours. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed with water and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1). The resulting foamy solid was recrystallized from ethyl acetate-heptane, whereby the objective compound (2.70 g, 69.5%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl.O1CCOCC1>C(O)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([S:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)(=[O:22])=[O:21])=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ncc2ccc(Br)cc2n1
Reactant: Nc1ccc(S(=O)(=O)NCCCN2CCCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CC(C)O
Product: O=S(=O)(NCCCN1CCCC1)c1ccc(Nc2ncc3ccc(Br)cc3n2)cc1
Temperature: 120 °C

Procedure:
To a 0.1M suspension of 7-bromo-2-chloroquinazoline in isopropanol was added 4-amino-N-(3-(pyrrolidin-1-yl)propyl)benzenesulfonamide (1.1 eq), followed by the addition of 4.0M HCl in dioxane (1.1 eq). The reaction mixture was heated to 120° C. in an oil bath for 1 h. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the mixture was washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and concentrated. Desired product was a yellow color solid. ES/MS m/z 490/492 (MH+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:26]1[CH2:31][CH2:30][S:29][CH2:28][CH2:27]1>CC(C)=O.O>[CH3:1][S:2][C:3]1[N:8]=[C:7]([N:26]2[CH2:31][CH2:30][S:29][CH2:28][CH2:27]2)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:4]=1
Reactant: C1CSCCN1
Reactant: CSc1nc(Cl)c([N+](=O)[O-])c(NC2CCCCC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CSc1nc(NC2CCCCC2)c([N+](=O)[O-])c(N2CCSCC2)n1
Temperature: 25 °C

Procedure:
3.0 gm of 2-methylmercapto-4-chloro-5-nitro-6-cyclohexylamino-pyrimidine were dissolved in 30 ml of acetone, a solution of 1.38 gm of potassium carbonate in 1.5 ml of water was added, and the mixture was admixed with a solution of 1.2 gm of thiomorpholine in 10 ml of acetone. The resulting mixture was stirred at room temperature, whereby after a short time a voluminous, crystalline precipitate was formed which was further increased by addition of water. The mixture was suction-filtered and the filter cake, 2-methylmercapto-4-thiomorpholino-5-nitro-6-cyclohexylamino-pyrimidine, was recrystallized from isopropanol. Yield: 2.3 gm (62% of theory), m.p. 145°-146°C.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:14][CH2:13]1
Reactant: CC(C)CBr
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)-phenyl]-piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1-bromo-2-methylpropane (0.009 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 313 (M+, 1), 271 (15), 270 (bp), 147 (8) 133 (8).
Reaction SMILES: [F:1][C:2]1([F:15])[O:7][C:6]2[CH:8]=[CH:9][C:10]([NH2:12])=[CH:11][C:5]=2[O:4][C:3]1([F:14])[F:13].[CH2:16](Br)[C:17]#[CH:18].C1(C)C=CC=CC=1>FC1C=CC=CC=1>[CH2:18]([NH:12][C:10]1[CH:9]=[CH:8][C:6]2[O:7][C:2]([F:1])([F:15])[C:3]([F:13])([F:14])[O:4][C:5]=2[CH:11]=1)[C:17]#[CH:16]
Reactant: C#CCBr
Reactant: Nc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Solvent: Fc1ccccc1
Solvent: Cc1ccccc1
Product: C#CCNc1ccc2c(c1)OC(F)(F)C(F)(F)O2
Temperature: 50 °C

Procedure:
2,2,3,3-Tetrafluoro-6-aminobenzodioxane (6.694 g, 30.0 mmol) and Aldrich basic alumina (activated, Brockmann 1, 150 mesh, CAS #1344-28-1) (51 g) were mixed in fluorobenzene (100 mL) and then treated with 80% propargyl bromide in toluene (2.56 mL, 23.0 mmol). The resulting mixture was thoroughly stirred and heated at 50° C. for 17 hours. The mixture was cooled to ambient temperature and filtered. The alumina was rinsed thoroughly with dichloromethane (150 mL), the filtrate was reduced in volume under reduced pressure, washed with concentrated aqueous NH4OH (5 mL), dried (Na2SO4), concentrated and chromatographed on silica eluting with 0-10% EtOAc/hexanes to provide the titled compound. 1H NMR (CDCl3) δ ppm 2.24 (t, 1H), 3.92 (m, 2H), 3.96 (m, 1H), 6.43 (d, 1H), 6.45 (dd, 1H), 6.96 (d, 1H); MS (DCI) 262 (M+H).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:25][C:26]1[N:27]=[C:28]([CH3:31])[S:29][CH:30]=1.O>CN(C)C=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:25][C:26]2[N:27]=[C:28]([CH3:31])[S:29][CH:30]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(CCl)cs1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1Cc1csc(C)n1
Reaction time: 0.25 h

Procedure:
To a solution of Example 74B (0.79 g, 2.43 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (Aldrich, 98 mg, 2.43 mmol) and the reaction mixture was stirred for 15 min and 4-(chloromethyl)-2-methylthiazole (0.36 g, 2.43 mmol) was added. The reaction mixture was stirred at room temperature for 18 hr, poured into water (75 mL) and then extracted with EtOAc (75 mL). The organic layer was washed with water (2×75 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to provide the title compound. MS, DCI, m/z 436 (M+H)+.