Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture comprising ethyl 3-hydroxybenzoate (5.00 g), benzyl bromide (4.29 ml), potassium carbonate (6.24 g) and acetone (50 ml) was stirred at room temperature for 16 hours. After the reaction mixture was evaporated under reduced pressure to remove the solvent, water (200 ml) was added to the residue, and the resulting mixture was extracted with ethyl acetate. After the organic layer was concentrated, a 1 N aqueous solution of sodium hydroxide (50 ml) was added to the residue dissolved in methanol (50 ml), and the resulting mixture was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was acidified by the addition of concentrated hydrochloric acid and was then extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride, was dried with anhydrous sodium sulfate and was then evaporated under reduced pressure to remove the solvent. The resulting residue was recrystallized from ethyl acetate/hexane to obtain 3-benzyloxybenzoic acid (5.10 g) as colorless crystals.
Reaction SMILES: CC(OCC1CS[C@@H]2[C@H](N)C(=O)N2C=1C(O)=O)=O.[OH-].[Na+].[S:21]([CH:25]([C:29]1[CH:33]=[CH:32][S:31][CH:30]=1)[C:26](O)=[O:27])([OH:24])(=[O:23])=[O:22].S(Cl)([Cl:36])=O>CN(C)C=O.CCOCC.O>[S:21]([CH:25]([C:29]1[CH:33]=[CH:32][S:31][CH:30]=1)[C:26]([Cl:36])=[O:27])([OH:24])(=[O:23])=[O:22]
Reactant: O=C(O)C(c1ccsc1)S(=O)(=O)O
Reactant: O=S(Cl)Cl
Agent: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=C(Cl)C(c1ccsc1)S(=O)(=O)O

Procedure:
With cooling and stirring, 1.84 g. (0.0068 mole) of 7-ACA was suspended in 25 ml. of water and to the suspension was added dropwise 6.8 ml. of a 1N-aqueous solution of sodium hydroxide to dissolve 7-ACA. On the other hand, to a suspension of 1.5 g. (0.0068 mole) of α-sulfo-3-thienylacetic acid in 10 ml. of ether were added 5.5 ml. of thionyl chloride dropwise and 3 drops of dimethylformamide, then the resulting solution was stirred for 5 hours at room temperature. The reaction solution was subjected to the evaporation to dryness under reduced pressure to give α-sulfo-3-thienylacetyl chloride as a residue. The residue was dissolved in 10 ml. of ethyl acetate and the solution was added dropwise to the 7-ACA solution mentioned above, followed by stirring for 30 minutes. The aqueous layer was separated from the reaction solution and adjusted it pH to 6.5 by adding a saturated aqueous solution of NaHCO3. The resulting solution was freeze-dried to obtain 3.6 g. of a crude product. The product was purified according to column chromatography using Amberlite XAD-2 to obtain 1.6 g. (42%) of 7-(α-sulfo-3'-thienylacetamido)cephalosporanic acid.
Reaction SMILES: Br[CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:9][C:10]1[N:15]=[C:14]([NH:16][C:17](=[S:19])[S-:18])[CH:13]=[CH:12][CH:11]=1.C([NH+](CC)CC)C.C(OC(C)C)(C)C>C(#N)C>[CH3:9][C:10]1[N:15]=[C:14]([NH:16][C:17](=[S:18])[S:19][CH2:2][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(NC(=S)[S-])n1
Reactant: CC(C)(C)C(=O)CBr
Agent: CC[NH+](CC)CC
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: Cc1cccc(NC(=S)SCC(=O)C(C)(C)C)n1
Temperature: 2 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
1-Bromo-3,3-dimethylbutan-2-one (40.0 g) is added to a suspension of triethylammonium (6-methylpyrid-2-yl)dithiocarbamate (64.0 g) in anhydrous acetonitrile (600 cc) at a maximum temperature of 20° C. The reaction is continued for 2 hours at 20° C. The insoluble hydrobromide of triethylamine is removed by filtration and washed with acetonitrile (50 cc). The organic phases are combined and evaporated under reduced pressure (20 mm.Hg) at 45° C. The residual oil is treated with diethyl ether (1200 cc). After 1 hour at 20° C., the ethereal solution is filtered, washed twice with distilled water (total 400 cc), dried over sodium sulphate and evaporated. The product obtained (60.0 g) is dissolved in boiling diisopropyl ether (870 cc) and the boiling solution is filtered. After 1 hour's cooling at 2° C., the resulting crystals are filtered off, washed twice with ice-cold diisopropyl ether (total 100 cc) and dried under reduced pressure (0.1 mm.Hg) at 40° C. to give 3,3-dimethyl-2-oxobutyl (6-methylpyrid-2-yl)dithiocarbamate (44.1 g) melting at 80° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>CN(C)C=O>[F:17][C:4]1[CH:3]=[C:2]([CH3:18])[C:10]2[N:9]3[C@H:11]([CH3:16])[CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: C[C@@H]1CNC(=O)c2cc3cc(F)cc(Br)c3n21
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(F)cc2cc3n(c12)[C@H](C)CNC3=O
Temperature: 110 °C

Procedure:
1.2 g (R)-6-bromo-8-fluoro-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one was dissolved in 12 ml N,N-dimethylformamide under argon. 0.45 gTetrakis-(triphenylphosphine)palladium, 1.56 g potassium carbonate and 0.55 ml trimethylboroxine were added. The mixture was heated overnight at 110° C., allowed to cool to room temperature, filtered over dicalite and washed through with tetrahydrofuran. The solvents were evaporated under reduced pressure and the residue purified by column chromatography on silica gel (1:1 to 1:3 toluene/ethyl acetate) to afford the title product as an off-white solid. Yield: 300 mg ISP-MS: m/e 233.1 ([M+H]+).
Reaction SMILES: Cl.O1CCOCC1.[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH:17]([NH:33]C(OC(C)(C)C)=O)[C:16]1=[O:41])=[O:13])([CH3:11])([CH3:10])[CH3:9]>C(O)C>[C:8]([C:12]([CH2:14][N:15]1[C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH:17]([NH2:33])[C:16]1=[O:41])=[O:13])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc2c(c1)N(CC(=O)C(C)(C)C)C(=O)C(N)CN2C1CCCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
4N HCl-dioxane (7 ml) was added to a solution of 1-tert-butylcarbonylmethyl-2-oxo-3-tert-butoxycarbonylamino-5-cyclohexyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (517 mg) in ethanol (20 ml), the mixture was stirred at 50° C. for one hour. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography(chloroform:methanol=20:1), to thereby obtain 400 mg of the title compound (Yield: 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:69]=[CH:68][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:69]=[CH:68][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:65])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 27.1 %

Procedure:
To a solution of 185 mg (0.87 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 278 mg of TBTU (0.87 mmol) in 13 ml DMF, were added 0.74 ml (4.33 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 290 mg (0.87 mmol) (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 140 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by two successive column chromatographies (90 g silica gel; diethylether/heptane 1:1; then 8 g silica gel; DCM/heptane 70:30 to 90:10) to give 125 mg white foam (27%). M (EI) 530.2 (M)+.
Reaction SMILES: [SH3+].S1CCCC1.[C:7]([C:10]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[CH:11]=1)(=[O:9])[CH3:8].[Br:24]Br>C(Cl)Cl.C(OCC)C>[Br:24][CH2:8][C:7]([C:10]1[CH:23]=[CH:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[CH:11]=1)=[O:9]
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Reactant: BrBr
Agent: [SH3+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: C1CCSC1
Product: O=C(CBr)c1ccc2c(ccc3ccccc32)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Preparation of a sulfonium salt according to Formula 3 wherein X- is CF3SO3- and R1, R2, and S combined are tetrahydrothiophene is as follows. To a stirred solution of 5 grams (22.6 mM) of 2-acetylphenanthrene in a mixture of 30 ml of methylene chloride and 30 ml of diethyl ether cooled in an ice/acetone bath was added 3.5 grains (22 mM) of bromine dropwise over 15 minutes. The red bromine color was immediately discharged upon addition to the stirred solution. The cooling bath was removed and the stirred mixture warmed to room temperature over 30 minutes, then the mixture was stirred at room temperature for 2 hours. The reaction mixture was stripped of solvent on a rotary evaporator, then was suspended in 50 ml diethyl ether and evaporated to dryness. This process was repeated twice more to remove the byproduct hydrogen bromide from the solid product. The residual solid was triturated with 15 ml cold diethyl ether, filtered, and dried in a vacuum oven to yield 4.35 grams of 2-(bromoacetyl)-phenanthrene.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[S:18][C:19]([Cl:27])=[CH:20][C:21]=1[CH:22]=[CH:23][C:24](=[O:26])[CH3:25]>C(O)C>[Cl:16][C:17]1[S:18][C:19]([Cl:27])=[CH:20][C:21]=1[CH:22]1[CH2:3][C:2](=[O:1])[CH2:25][C:24](=[O:26])[CH2:23]1
Reactant: CC(=O)C=Cc1cc(Cl)sc1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2cc(Cl)sc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,5-dichlorothiophene (100.0 g) and dichloromethylmethylether (165.3 g) in dichloromethane (800 ml) was added dropwise a solution of titanium tetrachloride (272.7 g) in dichloromethane (160 ml) at −10 to −15° C. taking 50 minutes, and at the same temperature, the mixture was stirred for 30 minutes. The reaction solution was poured into ice, and the organic layer was washed with water, sodium hydrogen carbonate solution, water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 2,5-dichloro-3-formylthiophene (115.0 g) as oil. To a mixture of acetone (1000 ml), sodium hydroxide (28.6 g) and water (1200 ml) was added at 0° C. a solution of 2,5-dichloro-3-formylthiophene (58.6 g) in acetone (200 ml) for 1.5 hours, and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the crystals were filtered, washed with water and dried to give 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g). To a solution of 20% sodium ethoxide in ethanol (211 g) was added diethyl malonate (99.3 g) at room temperature, and then 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g) little by little. The mixture was stirred at room temperature for 30 minutes, heated for 2 hours while stirring, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated, to which was added 2M sodium hydroxide (340 ml). The mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (340 ml) for 15 minutes, and the mixture was stirred at 100° C. for 1.5 hours. The mixture was cooled, and precipitated crystals were filtered and washed with ethyl acetate-isopropylether (1:4) and isopropylether to give 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (78.9 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]=12.[H-].[Na+].Cl[CH2:19][C:20]1[N:21]=[CH:22][N:23]([C:26]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]=1[CH3:25]>CN(C)C=O.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:15])[N:12]([CH2:19][C:20]3[N:21]=[CH:22][N:23]([C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:24]=3[CH3:25])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c(CCl)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1c2n(c3ccccc13)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2n(c3ccccc13)C(=O)N(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Temperature: 5 °C
Reaction time: 0.67 h
Yield: 64.6 %

Procedure:
To a solution of 3,4-dihydro-5-methylpyrimido[1,6-a]-indol-1(2H)-one (0.67 g) in N,N-dimethylformamide (8 ml) at 5° C. was added sodium hydride (60% in mineral oil, 0.16 g). The mixture was stirred at 5° C. for 40 minutes and then at room temperature for 15 minutes and again cooled to 5° C. 4-Chloromethyl-5-methyl-1-trityl-1H-imidazole (1.50 g) was added to the solution in small portions over two minutes. After being stirred at 5° C. for 2 hours, the reaction mixture was diluted with chilled water to give precipitates. The precipitates collected were dissolved in dichloromethane. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Column chromatography (silica gel, 0.5% methanol in chloroform as an eluent) of the residue, followed by recrystallization from toluene-hexane, gave 3,4-dihydro-5-methyl-2-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrimido[1,6-a]indol-1 (2H)-one (1.16 g).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:33][CH:34]1[CH2:37][N:36]([CH:38]2[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[CH2:40][CH2:39]2)[CH2:35]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:33][CH:34]5[CH2:35][N:36]([CH:38]6[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]6)[CH2:37]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(N)C2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CN(C3CCNCC3)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (100 mg, 0.22 mmol) in DMF (1 mL) was added tert-butyl 4-(3-aminoazetidin-1-yl)piperidine-1-carboxylate (72 mg, 0.25 mmol), HATU (125 mg, 0.33 mmol), and DIEA (80 μL, 0.44 mmol). The reaction mixture was stirred for 1 h. It was then poured into 100 mL of rapidly stirring water. A white solid forms and was filtered, washed with water and dried. This solid was treated with TFA in DCM (3 mL 1:1) for 2 days. The solvent was then removed, and the product purified by reverse phase HPLC, free based and lyophilized to yield a white solid (17.8 mg, 14% yield 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (br. s., 2 H) 1.50-1.79 (m, 9 H) 1.93 (br. s., 2 H) 2.07 (br. s., 1 H) 2.35-2.44 (m, 2 H) 2.85-3.00 (m, 4 H) 3.52 (t, J=7.20 Hz, 2 H) 3.94 (s, 3 H) 4.05 (t, J=14.02 Hz, 2 H) 4.37-4.50 (m, 1 H) 4.68-4.84 (m, 1 H) 7.47-7.52 (m, 2 H) 7.98 (s, 1 H) 8.26 (s, 1 H) 8.29 (d, 1 H) 8.61 (d, J=6.57 Hz, 1 H). [M+H] calc'd for C29H38F2N8O3, 585; found 585.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:9])[C:7]=1Br.Br[C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.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>[Cl:9][C:6]1[CH:5]=[C:4]([C:20]([C:22]([F:25])([F:24])[F:23])=[CH2:21])[CH:3]=[C:2]([Cl:1])[C:7]=1[C:22]([F:25])([F:24])[F:23]
Reactant: CC1(C)OB(c2cc(Cl)c(Br)c(Cl)c2)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(C(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 70 °C
Yield: 113.2 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(bromo)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 2.86 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (0.60 g, 3.43 mmol), Cs2CO3 (2.86 mL, 2M, 5.72 mmol) and Pd(PPh3)2Cl2 (60 mg) in THF (30 mL) was heated at 70° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between ether and H2O. The aqueous layer was extracted with EA and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography over silica gel eluted with hexanes to give 1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene (0.6 g; yield 66.7%) as colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 7.72 (s, 2 H), 6.38 (s, 1 H), 6.28 (s, 1 H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([N+:16]([O-:18])=[O:17])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cccc2c1sc1ccccc12
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc([N+](=O)[O-])c2c1sc1ccccc12
Reaction time: 0.75 h

Procedure:
4-Methoxy-dibenzothiophene (ii)(4.3 g, 20.0 mmol) was dissolved in glacial acetic acid (60 ml) and to this solution was added fuming nitric acid (3.37 ml) in a dropwise fashion ensuring that the temperature of the mixture did not rise above 25° C. The yellow suspension was stirred for a further 45 minutes before being poured carefully into water (200 ml) and stirred for 15 minutes. The yellow solid was removed by filtration and washed thoroughly with copious amounts of water and then hexanes. The residue thus obtained was then dried in a vacuum oven to give the title compound as a yellow solid which was used without any further purification. (5.19 g, 97%) m/z (LC-MS, ESP), RT=4.15 min, (M+H)=260.1
Reaction SMILES: CN(C)CCN.[CH:7]1([O:12][N:13]2C(=O)C3=CC=CC=C3C2=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.C(O)(=O)C.[C:28]([C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1[NH:38][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])(=O)[CH3:29]>CCO>[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([NH:38][S:39]([C:42]([F:45])([F:44])[F:43])(=[O:41])=[O:40])=[C:31]([C:28](=[N:13][O:12][CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH3:29])[CH:36]=1
Reactant: CC(=O)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Agent: CN(C)CCN
Solvent: CC(=O)O
Solvent: CCO
Product: CC(=NOC1CCCC1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 48.1 %

Procedure:
N,N-Dimethylethylenediamine (254 μL, 2.20 mmol) was added to a solution of N-(cyclopentyloxy)phthalimide (345 mg, 1.50 mmol) in EtOH (5 mL), and the reaction allowed to stir at RT for 15 h. Glacial acetic acid (2 mL) was then added to adjust the mixture to ca. pH 4 followed by a solution of N-(2-acetyl-4-chlorophenyl)trifluoromethanesulfonamide 19 (302 mg, 1.0 mmol) in EtOH (2 mL), and the reaction stirred for 2.25 h at RT. The reaction mixture was concentrated under vacuum, and the residue purified by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:19) to afford N-[4-chloro-2-(1-cyclopentyloxyiminoethyl)phenyl]trifluoromethanesulfonamide 163 (185 mg, 48%), as a pale yellow solid. 1H n.m.r. (400 MHz, CDCl3) δ 12.18, br s, 1H; 7.67, d, J=8.8 Hz, 1H; 7.49, d, J=2.4 Hz, 1H; 7.31, dd, J=2.4 and 8.8 Hz, 1H; 4.80, m, 1H; 2.30, s, 3H; 1.89, m, 4H; 1.74, m, 2H; 1.64, m, 2H. HRMS (M+) 384.0518.
Reaction SMILES: BrC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41]>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41].[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([NH:42][C:43]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:27][CH:28]=1)=[S:44])=[O:41]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1Br
Agent: O=C(N=C=S)c1ccccc1Br
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Br)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml). A solution of 2-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (85 mg, yield 93%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:11]([C:18]1[S:22][C:21]([CH2:23][NH2:24])=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][CH2:23][C:21]1[S:22][C:18]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:19][CH:20]=1)=[O:6]
Reactant: NCc1ccc(Oc2ccccc2)s1
Reactant: Nc1ncccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ncccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.4 %

Procedure:
To a solution of 2-aminonicotinic acid (3245 mg, 23.49 mmol) in N,N-dimethylformamide (200 mL) were added C-(5-phenoxy-thiophen-2-yl)methylamine (5305 mg, 25.84 mmol) described in Preparation Example 24, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (12.49 g, 28.19 mmol) and triethylamine (7.86 mL, 56.38 mmol), and the solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate, the organic layer was sequentially washed with an aqueous solution of saturated sodium bicarbonate, water, then brine, the solvent was evaporated in vacuo, and 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (4999 mg, 15.36 mmol, 65%) was obtained as crude product.