Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][N:7]=[CH:6]2)#[CH:2].[N:12]([CH2:15][CH2:16][C@@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=[N+:13]=[N-:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].C(Cl)Cl>CC(O)(C)C.O>[NH:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]3[N:14]=[N:13][N:12]([CH2:15][CH2:16][C@@H:17]([NH2:29])[CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=4)[CH:2]=3)=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: CC(C)(C)OC(=O)N[C@H](CCN=[N+]=[N-])Cc1ccc(C(F)(F)F)cc1
Reactant: C#Cc1ccc2[nH]ncc2c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: N[C@H](CCn1cc(-c2ccc3[nH]ncc3c2)nn1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 2.9 %

Procedure:
5-Ethynyl-1H-indazole (50 mg, 0.35 mmol) and (S)-tert-butyl 4-azido-1-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (143 mg, 0.35 mmol) were dissolved in 2 mL tBuOH/H2O (1/1) and CuSO4.5H2O (1.8 mg, 0.007 mmol) and sodium ascorbate (14 mg, 0.07 mmol) were added. The reaction was stirred for 3 days at room temperature and 10 mL DCM was added and the phases were separated. The aqueous phase was extracted with 50 mL DCM (3×50 mL) and the combined organic phases were dried over MgSO4 and evaporated. The BOC protected intermediate was purified on preparative TLC (6% MeOH in DCM) and treated with 4 mL 30% TFA in DCM for 2 hours. Toluene (30 mL) was added and the mixture was evaporated. The residue was redissolved in 2 mL MeOH, 3 drops of NaOH (5 M, aqueous) was added, and the solution was applied onto a preparative TLC plate for purification (10% MeOH in DCM). 4 mg of the title compound was obtained (0.01 mmol) as a colorless film. LCMS (API-ES) m/z (%): 401.0 (100%, M++H); 1H NMR (300 MHz, CD3OD) δ ppm 8.25-8.30 (m, 1H), 8.17-8.22 (m, 1H), 8.06-8.11 (m, 1H), 7.85 (dd, J=8.76, 1.60 Hz, 1H), 7.54-7.64 (m, 3H), 7.39 (d, J=8.10 Hz, 2H), 4.61 (t, J=7.35 Hz, 2H), 2.98-3.11 (m, 1H), 2.85-2.97 (m, 1H), 2.72-2.83 (m, 1H), 2.06-2.22 (m, 1H), 1.87-2.05 (m, 1H).
Reaction SMILES: CC([CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=1)[C:6]([O-:8])=[O:7])(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[F:17][C:15]([F:16])([F:18])[C:11]1[N:10]=[C:9]([CH2:5][C:6]([OH:8])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)C(C(=O)[O-])c1cccc(C(F)(F)F)n1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of 1,1-dimethylethyl[6-(trifluoromethyl)-2-pyridinyl]acetate (698 mg, 2.67 mmol), triethylsilane (1.067 mL, 6.68 mmol) in Dichloromethane (DCM) (10 mL) was added TFA (2.68 mL, 34.7 mmol) dropwise via syringe. The reaction was stirred overnight at room temperature. LCMS analysis indicated good conversion, so the reaction was concentrated to a yellow oil. 5 mL of diethyl ether was added but no precipitation occurred, so the solution was concentrated to afford [6-(trifluoromethyl)-2-pyridinyl]acetic acid (535 mg, 2.61 mmol, 98% yield) as a yellow oil which solidified to a yellow solid. LC-MS (ES) m/z=206 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.89 (s, 2H), 7.70 (d, J=7.83 Hz, 1H), 7.81 (d, J=7.58 Hz, 1H), 7.97-8.16 (m, 1H), 12.26-12.88 (br. s., 1H).
Reaction SMILES: [CH2:1](Br)[CH3:2].[F:4][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=1)[CH2:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:11]1[CH2:12][CH2:13][C@@H:9]([CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[C:5]([F:4])[CH:6]=2)[CH2:10]1)[CH3:2]
Reactant: CCBr
Reactant: Fc1cccc(C[C@@H]2CCNC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCN1CC[C@@H](Cc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 57.6 %

Procedure:
Ethyl bromide (0.22 g) was added to a suspension of 3-(R)-(3-fluorobenzyl)pyrrolidine (Intermediate 98, 0.36 g) and potassium carbonate (0.55 g) in acetonitrile and the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with ethyl acetate, filtered and the filtrate was evaporated to dryness. The residue was triturated with DCM, the solvent was decanted off and evaporated to dryness to give (R)-1-ethyl-3-(3-fluorobenzyl)pyrrolidine (0.24 g) as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][S:7][CH2:8][CH2:9][NH2:10].[C:11]([CH:13]=[C:14](OCC)[NH:15][C:16]#[C:17][CH3:18])#[N:12].C(N)C#C.C(C=C(OCC)OCC)#N>>[C:11]([CH:13]=[C:14]([NH:15][CH2:16][C:17]#[CH:18])[NH:10][CH2:9][CH2:8][S:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)#[N:12]
Reactant: NCCSCc1nccs1
Reactant: CC#CNC(=CC#N)OCC
Agent: C#CCN
Agent: CCOC(=CC#N)OCC
Product: C#CCNC(=CC#N)NCCSCc1nccs1

Procedure:
When 2-[(thiazol-2-yl)methylthio]ethylamine is reacted in an inert solvent with about an equimolar amount of 1-cyano-2-ethoxy-2-propynylaminoethylene [prepared from propargylamine and 1-cyano-2,2-bis(ethoxy)ethylene, which is itself prepared according to the procedure described in J. Am. Chem. Soc., 71, 47 (1949)], the title product is produced.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O.CO.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:13]([O:12][C:11]([NH:10][C@H:8]([C:5]1[CH:6]=[CH:7][C:2]([C:11]([O:12][CH3:13])=[O:17])=[CH:3][CH:4]=1)[CH3:9])=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 176.2 %

Procedure:
A mixture of (S)-tert-butyl (1-(4-bromophenyl)ethyl)carbamate (D1) (9.20 g, 27.3 mmol), 1,3-bis(diphenylphosphino)-propane (2.25 g, 5.46 mmol), palladium (II) acetate (1.22 g, 5.46 mmol), and triethylamine (11.5 ml, 81.9 mmol) in N,N-dimethylformamide/methanol (60 ml/60 ml) was stirred at 80° C. overnight under carbon monoxide atmosphere. After cooling to room temperature, the mixture was diluted with ether (300 ml) and washed with water (3×100 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a mixture petroleum ether/ethyl acetate 5:1 to afford the title compound (D2) (6.72 g) as white solid.
Reaction SMILES: C([O:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([NH2:22])[C:12]=2[N:11]=[C:10]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1>[Pd].C(O)C>[NH2:22][C:13]1[C:12]2[N:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:9]([OH:8])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2O
Reaction time: 18 h
Yield: 28.3 %

Procedure:
A mixture of 1-(benzyloxy)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.32 g, 0.87 mmol) and 10% palladium on carbon (0.015 g) in ethanol (10 mL) was placed in a pressure vessel, which was purged with hydrogen three times and then placed under hydrogen pressure (45 psi, 3.1×105 Pa) and shaken on a Parr apparatus for 18 hours. An analysis by LC/MS indicated the presence of starting material. Additional 10% palladium on carbon (0.05 g) was added, and the hydrogenation was continued for an additional five hours. The reaction mixture was filtered, and the filter cake was washed with ethanol. After several days, crystals formed in the filtrate. The filtrate was concentrated under reduced pressure until it became cloudy, and the mixture was allowed to stand for 18 hours. More crystals formed, and the crystals were collected by filtration, washed with diethyl ether, and dried to provide 0.068 g of 4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-ol as an off-white powder, decomp. 201-209° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[C@:9]12([CH3:19])[C:16]([CH3:18])([CH3:17])[CH:13]([CH2:14][CH2:15]1)[CH2:12][C:10]2=O>N1C=CC=CC=1>[CH3:19][C@:9]12[C:16]([CH3:18])([CH3:17])[CH:13]([CH2:14][CH2:15]1)[CH:12]=[C:10]2[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: C#Cc1ccccn1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)C2
Solvent: c1ccncc1
Product: CC1(C)C2C=C(C#Cc3ccccn3)[C@]1(C)CC2

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), (1R)-(+)-camphor (6.0 mmol, 912 mg); yields 2-{[(1R)-1,7,7-timethylbicyclo[2.2.1]hept-2-en-2-yl]ethynyl}pyridine as a transparent yellow oil (125 mg, 9% overall yield). 1H NMR (CDCl3, 300 MHz) δ 8.57 (m, 1H), 7.64 (m, 1H), 7.43 (m, 1H), 7.17 (m, 1H), 6.49 (d, J=3 Hz, 1H), 2.41 (t, J=3 Hz, 1H), 1.92 (br m, 1H), 1.65 (m, 1H), 1.18 (m, 1H), 1.17 (s, 3H), 1.09 (br m, 1H), 0.84 (s, 3H), 0.82 (s, 3H). MS (EI ionization) 237 (M+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:35]=[CH:34][CH:33]=[CH:32][C:6]=1[C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[C:23]4=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]4[N:21]=[C:20]3[CH2:30][CH3:31])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8])(=[O:3])[CH3:2]>O1CCOCC1>[C:1]([O:4][C:5]1[CH:35]=[CH:34][CH:33]=[CH:32][C:6]=1[C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[C:23]4=[N:24][C:25]([CH3:29])=[CH:26][C:27]([CH3:28])=[C:22]4[N:21]=[C:20]3[CH2:30][CH3:31])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCN2C(=O)c1ccccc1OC(C)=O
Solvent: C1COCCO1
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(ccn2C(=O)c2ccccc2OC(C)=O)c1
Yield: 22.8 %

Procedure:
To a refluxing solution of 220 mg (0.47 mmol) of the product of Example 19 in 5 mL of 1,4-dioxane was added 320 mg (1.41 mmol, 3.0 eq) of 2,3-dichloro-5,6-dicyano-1,4-quinone. The mixture was refluxed for 6 hours then cooled and concentrated in vacuo. The resultant oil was flash chromatographed with ethyl acetate to yield 50 mg (23%) of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15](=[O:25])[N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([N:16]1[CH:17]=[C:12]([C:4]2[S:3][C:2]([NH:1][C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[O:33])=[N:6][C:5]=2[C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:13]=[CH:14][C:15]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)n(Cc3ccccc3)c2)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccc(=O)n(Cc3ccccc3)c2)s1)c1ccncc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
2-Amino-5-(1-benzyl-2-oxo-1,2-dihydropyridin-5-yl)-4-(2-furyl)thiazole (349 mg, 1.00 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and isonicotinic acid (246 mg, 2.00 mmol), PyBOP (1.14 g, 2.20 mmol) and triethylamine (0.613 mL, 4.40 mmol) were added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:1), followed by reslurrying with a mixed solvent of methanol and diethyl ether to afford the entitled Compound 128 (128 mg, 28%) as a pale brown solid.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8](I)[CH:7]=1.[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[OH:14][C:9]1[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:7][C:6]([CH:2]=[O:3])=[CH:11][C:10]=1[O:12][CH3:13]
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(C2OCCO2)cc(I)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C=O)cc(-c2ccccc2)c1O
Yield: 77.6 %

Procedure:
Under N2, tetrakis-triphenylphosphinepalladium(0) was added to a mixture of the above dioxolane (10 g, 31 mmoles), benzeneboronic acid (4.5 g, 37 mmoles), toluene (67 mL), 2 M aqueous sodium carbonate (33 mL) and methanol (20 mL). The resulting mixture was heated at reflux under N2 for 16 hours. After cooling the mixture was diluted with water (150 mL) and washed with heptane (400 mL). The aqueous phase was made acidic with 3N hydrochloric acid and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography over silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:2) to afford 5.49 g (77%) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde. M.p. 107-108° C. 1,2-Dibromoethane (41 mL, 0.48 moles) was added to a mixture of the above 4-hydroxy-3-methoxy-5-phenylbenzaldehyde (5.49 g, 24 mmoles) and potassium carbonate (17 g, 123 mmoles) in DMF (80 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 8.1 g (100%) of 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde as an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[C:23]1([NH:29][C:30]([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:29][C:30](=[O:31])[C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[O:10][C:3]=34)=[CH:34][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Reactant: O=C(Nc1ccccc1)c1ccc(B(O)O)cc1
Product: COc1cc(-c2cc3nccc(-c4ccc(C(=O)Nc5ccccc5)cc4)c3o2)cc(OC)c1OC

Procedure:
The title compound was prepared by procedure C using 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine (45.00 mg; 0.14 mmol; 1.00 eq.) instead of 7-chloro-2-iodo-furo[3,2-b]pyridine, and 4-phenylaminocarbonylphenylboronic acid (37.32 mg; 0.15 mmol; 1.10 eq.) instead of 4-fluorophenylboronic acid and was obtained as a yellow solid (68 mg, 100%). (HPLC (method F): 77%, RT: 4.21 min); 1H NMR (500 MHz, DMSO-d6) δ[ppm] 10.41 (s, 1H), 8.65-8.56 (m, 1H), 8.30 (d, J=7.9, 2H), 8.21 (d, J=8.5, 2H), 7.85-7.76 (m, 3H), 7.70 (dd, J=3.9, 1.2, 1H), 7.38 (t, J=7.6, 2H), 7.34 (s, 2H), 7.13 (t, J=7.4, 1H), 3.92 (s, 6H), 3.79-3.70 (m, 3H); MS (m/z) 481 [M+H]+, RT: 4.2 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:20])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:27][C:28]([Br:32])=[CH:29][CH2:30]Br>CN(C)C=O>[CH2:1]([C:3]1[CH:4]=[C:5]([O:20][CH2:30][CH:29]=[C:28]([Br:32])[Br:27])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH3:19])[CH3:18])=[CH:12][CH:11]=1)[CH3:2]
Reactant: CCc1cc(O)ccc1Oc1ccc(OC(C)C)cc1
Reactant: BrCC=C(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(OCC=C(Br)Br)ccc1Oc1ccc(OC(C)C)cc1
Temperature: 0 °C
Yield: 71.3 %

Procedure:
To a mixture of 0.65 g of 3-ethyl-4-(4-isopropoxyphenoxy)phenol, 0.35 g of potassium carbonate and 10 ml of N,N-dimethylformamide, a solution prepared by dissolving 0.73 g of 1,1,3-tribromo-1-propene in 5 ml of N,N-dimethylformamide was added dropwise at room temperature with stirring. After stirring at room temperature for 12 hours, the reaction solution was poured into ice-water, and extracted twice with 50 ml, of diethyl ether. Then, the ether layers were combined, washed with water, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 0.80 g of 3-ethyl-4-(4-isopropoxyphenoxy)-1-(3,3-dibromo-2-propenyloxy)benzene, yield 71%; nD23.0 1.5761.
Reaction SMILES: [Na].[F:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:4]=1[CH2:5][N:6]=[N+:7]=[N-:8].[C:14]([O:20]CC)(=[O:19])[CH2:15][C:16]([CH3:18])=O.[OH-].[Na+].Cl>O>[F:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:4]=1[CH2:5][N:6]1[C:16]([CH3:18])=[C:15]([C:14]([OH:20])=[O:19])[N:8]=[N:7]1
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: Cc1c(C(=O)O)nnn1Cc1c(F)cccc1F

Procedure:
The starting material is prepared as follows: 2.53 g (0.11 mole) of sodium are dissolved in 60 ml of alcohol, then a mixture of 16.9 g (0.1 mole) of 2,6-difluorobenzyl azide and 14,3 g (0.11 mole) of ethyl acetoacetat in 60 ml of alcohol is added and the batch is heated for 16 hours to reflux. After addition of 120 ml of normal sodium hydroxide solution, the reaction mixture is refluxed for another 2 hours, then diluted with 200 ml of water and acidified to pH 1 with hydrochloric acid while cooling. The precipitated product is filtered with suction, washed first with water and then with ether and dried, affording 1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid with a melting point of 166°-167° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C[Si]([P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)C>C1(C)C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[Si](C)(C)P(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1I
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: Cc1ccccc1
Product: Brc1ccccc1P(c1ccccc1)c1ccccc1

Procedure:
According to the method described in a literature (S. E. Tunney and J. K. Stille, J. Org. Chem., 1987, 52, 748), (2-bromophenyl)diphenylphosphine was obtained by reacting 2-bromoiodobenzene and (trimethylsilyl)diphenylphosphine in toluene in the presence of dichlorobis(acetonitrile)palladium. Into a four-necked flask was weighed 10.00 g (29.3 mmol) of (2-bromophenyl)diphenylphosphine obtained in the above. The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen, and 100 mL of anhydrous tetrahydrofuran (hereinafter referred to as THF) was added thereto. Thereto was added dropwise 18.3 mL of n-butyllithium-hexane (1.6 M) solution at −78° C. over a period of 30 minutes, followed by 1 hour of stirring at the same temperature. The resulting mixed solution was added dropwise to a 25 mL THF solution of 4.83 g (29.3 mmol) of diethyl chlorophosphite (manufactured by Aldrich) at −78° C. over a period of 30 minutes. After the dropwise addition, a cooling bath was removed and the whole was further stirred at room temperature for 1 hour. After the reaction, THF was removed by evaporation, the residue was dissolved in 50 mL of diethyl ether, and insoluble matter was removed by filtration. The solvent was removed by evaporation and the residue was purified by active alumina column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (10.30 g, a pale yellow oily substance). Yield 92%.
Reaction SMILES: [F:1][CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[CH:10]=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH2:6][CH2:5][N:4]1[CH3:18].Br[C:20]1[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=[C:24]([Br:26])[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:26][C:24]1[CH:25]=[C:20]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([N:7]3[CH2:6][CH2:5][N:4]([CH3:18])[CH:3]([CH2:2][F:1])[CH2:8]3)=[CH:10][N:11]=2)[C:21](=[O:28])[N:22]([CH3:27])[CH:23]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1CF
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1CF
Temperature: 25 °C
Yield: 53.6 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (60 mL), 111e (crude, 14.1 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (4.5 g, 16.9 mmol) and cesium carbonate (11.5 g, 35.2 mmol). After bubbling nitrogen through the resulting solution for 30 min, Xantphos (820 mg, 1.41 mmol) and tris(dibenzylideneacetone)dipalladium(0) (645 mg, 0.7 mmol) were added, and the reaction mixture was heated at reflux for 15 h. After this time the reaction was cooled to room temperature, filtered and concentrated to afford a black solid as the crude product. Then it was purified on silica gel (DCM:MeOH=100:1 to 50:1) to afford 111g as a yellow solid (3.1 g, yield 50%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][S:12](Cl)(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[CH:16]([NH2:19])([CH3:18])[CH3:17]>C1COCC1>[CH:16]([NH:19][S:12]([CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)(=[O:14])=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(CCS(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC(C)NS(=O)(=O)CCc1ccc(N)cc1

Procedure:
2-(4-Nitro-phenyl)-ethanesulfonyl chloride (300 mg) was suspended in 5 mL of THF. To the stirring solution was added isopropylamine (600 μL) dropwise at r.t. After 5 hours the solvent was evaporated. The nitro product was purified by flash chromatography (CH2Cl2/CH3OH 10:1 v/v) and was converted to the title compound under normal hydrogenation conditions. The title compound was obtained as a yellow solid (182 mg, 54%). 1H NMR (300 MHz, CD3OD) δ (ppm): 6.96 (d, J=8.3 Hz, 2H), 6.69 (d, J=8.3 Hz, 2H), 3.53 (m, 1H), 3.19 (m, 2H), 2.91 (m, 2H), 1.20 (s, 3H), 1.18 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:6][CH2:7][C:8]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccccc2)CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC1(c2ccccc2)CCCC1
Reaction time: 1 h
Yield: 103.4 %

Procedure:
A solution of methanesulphonyl chloride (1.62 g) in dry dichloromethane (10 ml) was added over 20 minutes to a stirred mixture of 1-hydroxymethyl-1-phenylcyclopentane (1.91 g) and triethylamine (1.64 g) in dry dichloromethane (50 ml) at 0° C. (white precipitate). After 1 hour, all at about 0° C., water was added to the reaction mixture and the organic and aqueous layers were separated. The organic layer was washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water, then dried over magnesium sulphate and concentrated to give almost pure 1-methanesulphonyloxymethyl-1-phenylcyclopentane (2.85 g) as an almost colourless oil which crystallised completely on standing in the fridge, melting point 55°-60° C., 1H n.m.r. (CDCl3): δ 2.51 (3H, s, CH3SO2), 4.16 (2H, s, CH2OSO2CH3).