Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1C2(CC[N:8]([C:11](=[O:31])[CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:30][CH2:29][C:24]5([O:28][CH2:27][CH2:26][O:25]5)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=O)CC2)OCC1.[NH2:32]N>C(O)C.O1CCCC1>[O:28]1[C:24]2([CH2:29][CH2:30][N:21]([C:18]3[CH:17]=[CH:16][C:15]([C:13]4[NH:32][NH:8][C:11](=[O:31])[CH:12]=4)=[CH:20][CH:19]=3)[CH2:22][CH2:23]2)[O:25][CH2:26][CH2:27]1
Reactant: NN
Reactant: O=C(CC(=O)N1CCC2(CC1)OCCO2)c1ccc(N2CCC3(CC2)OCCO3)cc1
Solvent: C1CCOC1
Solvent: CCO
Product: O=c1cc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)[nH][nH]1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
1-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-propane-1,3-dione (which was obtained in Example 143) (0.43 g, 1 mmol) was dissolved in a mixture of ethanol (10 mL) and tetrahydrofuran (4 mL). The solution was treated with 0.08 mL (2.4 mmol) of hydrazine and heated at reflux for 4 days. After cooling to room temperature, the resulting suspension was filtered, and the precipitate was washed with ethanol and dried in vacuo to give 0.24 g of light yellow solid; 1H NMR (DMSO-d6) δ 1.67-1.71 (t, 4H), 3.29-3.32 (t, 4H), 3.91 (s, 4H), 5.72 (s, 1H), 6.97 (d, 2H), 7.48 (d, 2H), 9.50 (brs, 1H), 11.80 (brs, 1H); MS (ES) m/z: 302 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.O=S(Cl)Cl.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[CH3:11]
Reactant: CO
Reactant: Cc1cc(F)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.7 %

Procedure:
To a stirred solution of 4-fluoro-2-methyl-benzoic acid (13 g, 84 mmol) in MeOH (500 mL) was added SOCl2 (20 g, 168 mmol) dropwise at 0° C. After the addition, the reaction mixture was stirred at room temperature for 16 hours. When TLC indicated that no starting material was left, the mixture was concentrated under reduced pressure to give a crude product (12.7 g, yield 90.7%), which was used in the next step reaction without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH:15]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]1[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=1)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]2)([CH3:16])[CH3:17]
Reactant: BrCc1cccc2ccccc12
Reactant: CCOC(=O)c1cc2cc(C(C)C)ccc2[nH]1
Product: CC(C)c1ccc2c(c1)cc(C(=O)O)n2Cc1cccc2ccccc12

Procedure:
Using general procedure B, 5-isopropyl-1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a pale brown solid. MS: 342.0 ([M−H]−).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[C:10]([OH:13])(=[O:12])[CH3:11]>>[C:10]([O:13][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)O
Reactant: Cc1ccccc1
Agent: O=O
Product: CC(=O)OCc1ccccc1

Procedure:
A process for producing benzyl acetate by oxyacetoxylation of toluene with acetic acid and oxygen in a liquid phase in the presence of oxyacetoxylation-active catalyst, comprising steps of feeding toluene, acetic acid, and oxygen to an oxyacetoxylation reactor to cause reaction and to obtain an effluent from the reactor; introducing the effluent from the reactor to a gas-liquid separator to separate a gas phase mainly composed of oxygen and nitrogen and a liquid phase mainly composed of toluene, acetic acid, and benzyl acetate; introducing the liquid phase discharged from the gas-liquid separator to a starting material recovery column to separate the liquid phase by distillation into a column top distillate mainly composed of toluene and acetic acid and a column bottom liquid mainly composed of benzyl acetate; recycling the column top distillate from the starting material recovery column to the oxyacetoxylation reactor; introducing the column bottom liquid of the starting material recovery column to a low-boiler removal column to separate the column bottom liquid by distillation into a column top fraction mainly composed of benzaldehyde and a column bottom fraction mainly composed of benzyl acetate; introducing the column bottom fraction of the low-boiler removal column to a high-boiler removal column for distillation to obtain benzyl acetate from the column top thereof.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([CH3:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH3:2].[BrH:22]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([CH3:19])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([Br:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)C(C)(C)CCCCC=Cc1ccccc1Cl
Reactant: Br
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)CCCCCC(Br)c1ccccc1Cl
Temperature: 15 °C
Yield: 81.8 %

Procedure:
8-(2-Chlorophenyl)-2,2-dimethyl-oct-7-enoic acid ethyl ester (7 g, 22.8 mmol) was dissolved in glacial acetic acid (60 mL). The solution was cooled in an ice-bath (ca. 15° C.), while dry hydrogen bromide was passed into the solution for 8 h. The reaction mixture was poured into ice-water (130 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with saturated NaHCO3 solution (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product (10 g) was purified by column chromatography (200 g silica gel, eluting with ethyl acetate/heptane=1/20 to 1/10) to furnish 8-bromo-8-(2-chlorophenyl)2,2-dimethyloctanoic acid ethyl ester (7.46 g, 81.8% yield) as a yellow oil. 1H NMR (Field: 300 MHz, Solvent: CDCl3/TMS) δ (ppm): 7.59 (d, 1H, J=7.8 Hz), 7.34 (t, 1H, J=7.5 Hz), 7.26 (d, 1H, J=6.9 Hz), 7.19 (t, 1H, J=7.2 Hz), 5.45 (t, 1H, J=7.5 Hz), 4.09 (q, 2H, J=7.2 Hz), 2.26-2.09 (m, 4H), 1.52-1.46 (m, 2H), 1.41-1.31 (m, 2H), 1.28-1.18 (m, 2H), 1.20 (t, 3H, J=7.2 Hz), 1.14 (s, 6H). 13C NMR (Field: 75 MHz, Solvent: CDCl3/TMS) δ (ppm): 177.80, 139.43, 132.65, 129.64, 129.24, 128.88, 127.45, 60.28, 50.30, 42.25, 39.21, 29.48, 27.98, 25.36, 24.88, 14.49. HRMS (GC-CI): Calculated for C18H26BrClO2 (M+H)+389.0883, found 389.0867.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH:10]=[N:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[CH3:13]C1C=C(C#CC=O)C=CC=1>>[OH:12][N:11]=[CH:10][C:9]#[C:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:13])[CH:3]=1
Reactant: Cc1cccc(C#CC=O)c1
Reactant: ON=CC#Cc1cccc(Cl)c1
Product: Cc1cccc(C#CC=NO)c1

Procedure:
The title compound was synthesized following the procedure reported for Compound 31e but starting from Compound 91b instead of Compound 31d. The crude title compound (brownish oil) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([NH:11][S:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[F:32][C:33]([F:44])([F:43])[O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:25])=[C:9]([N:11]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([O:34][C:33]([F:32])([F:43])[F:44])=[CH:36][CH:37]=3)[S:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2nc3ccc(F)cn3c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc3ccc(F)cn3c2C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of compound 6-E (0.300 g, 0.75 mmol) and K2CO3 (0.218 g, 1.58 mmol) in DMF (5 mL) was cooled in an ice bath and treated with a solution of 4-trifluoromethoxybenzyl bromide (0.132 mL, 0.83 mmol) in DMF (1 mL) and stirred at ambient temperature for 18 hours. The solution was partitioned between EtOAc and water, and the organic phase was separated, washed with water (3×) then brine and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was pre-absorbed on silica gel and purified by flash chromatography, using a gradient of EtOAc (10-50%) in heptanes as the eluant, to give the Compound 118, as a colorless solid (0.330 g, 82%). 1H-NMR (CDCl3): δ 8.17 (d, J=8.6 Hz, 2H), 7.85 (d, J=8.6 Hz, 8H), 7.69-7.74 (m, 1H), 7.41 (dd, J=9.9, 5.0 Hz, 1H), 7.29 (d, J=8.6 Hz, 2H), 7.03-7.14 (m, 3H), 4.74 (s, 2H), 3.97 (s, 3H), 2.26 (s, 3H); MS: m/z 538.0 (MH+).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([NH2:13])([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:13][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)([CH3:5])[CH2:3][OH:2]
Reactant: COC(=O)C(C)(N)c1cccc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)(CO)c1cccc(Br)c1
Temperature: -7 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
A solution of the (RS)-2-amino-2-(3-bromo-phenyl)-propionic acid methyl ester (9.39 g, mmol) in tetrahydrofuran (360 ml) was treated portionwise at −5° C. with lithiumaluminiumhydride (1.41 g, 36 mmol; 282 mg/2 min). After complete addition, stirring was continued at 0-5° C. for 30 minutes. For the workup, the reaction mixture was cooled to −7° C., and water (9 ml) was added dropwise. Thereafter, 2 N sodium hydroxy solution (9 ml) was added and stirring continued for 15 minutes at room temperature. They grey suspension was filtrated through Dicalite® which was washed with tetrahydrofuran (200 ml). The filtrate was evaporated at reduced pressure. 8.67 g of crude (RS)-2-amino-2-(3-bromo-phenyl)-propan-1-ol were obtained as a colorless oil. The purity of the product allowed using it in the next step without further purification. Mass (calculated) C9H12BrNO [230.106]; (found) [M+H]+=230, 232.
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[C:19]([NH2:24])([CH2:22][CH3:23])([CH3:21])[CH3:20]>>[CH3:20][C:19]([NH:24][C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:21])[CH2:22][CH3:23]
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CCC(C)(C)N
Product: CCC(C)(C)Nc1c(-c2ccc(OC)cc2)c(=O)c1=O
Yield: 84.1 %

Procedure:
In a manner similar to Example 1, Step 2; 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) and tert-amyl amine (0.48 mL, 4.11 mmol) were converted to the title compound (0.14 g, 84%) m.p.: 133-135° C.; 1H NMR (DMSO-d6) δ 8.28(br s,1H), 8.04(m,2H), 7.11(m,2H), 3.83(s,3H), 1.80(q,2H), 1.42(s,6H), 0.85(t,3H); IR (KBr) 2980, 1765, 1725, 1600, 1423, 1310, 1260, 1175, 1030, 850 cm−1; MS (m/z) 273 [M+].
Reaction SMILES: [C:1]([N:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][CH:8]1[NH2:14])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([N:7]1[CH:12]=[C:11]([CH2:13][Br:22])[CH:10]=[CH:9][CH:8]1[NH2:14])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC1=CN(C(=O)C(C)(C)C)C(N)C=C1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)N1C=C(CBr)C=CC1N

Procedure:
N-Pivaloyl-2-amino-5-methylpyridine (5.12 g, 26.6 mmol) was dissolved in CCl4 (75 mL) at 23° C., and treated with NBS (9.69 g, 54.4 mmol), followed by AIBN (937 mg, 5.71 mmol) with stirring. The resulting orange, biphasic suspension was then warmed to reflux for 4 h. After 4 h at reflux, the rust-colored mixture was cooled to RT, filtered through a Celite® pad, and concentrated in vacuo to a red residue. Purification over silica gel (gradient, 0 to 25% EtOAc/hexanes) provided the title compound as a light yellow solid. MS m/z: 272 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=1[NH2:7])[CH2:2][CH3:3].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:19][CH:20]1[O:24][CH:23]([CH3:25])[CH:22]([CH3:26])[O:21]1>>[CH3:26][CH:22]1[CH:23]([CH3:25])[O:24][CH:20]([CH2:19][NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[O:21]1
Reactant: CCCOc1ccccc1N
Reactant: CC1OC(CBr)OC1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCOc1ccccc1NCC1OC(C)C(C)O1

Procedure:
2-Propoxyaniline (0.5 mole) and sodium carbonate (30 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2-Bromomethyl-4,5-dimethyl-1,3-dioxolane (0.55 mole) is slowly added and the reaction mixture is heated at reflux for a period of about 1 hour. After this time the reaction mixture is filtered and additional sodium carbonate (5 grams) is added to the filtrate. The mixture is then distilled under reduced pressure to yield the desired product N-(4,5-dimethyl-1,3-dioxolan-2-ylmethyl)-2-propoxyaniline.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[H-].[Na+].Cl[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[N:25]=1.O>CS(C)=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:24]1[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([N:31]2[CH:35]=[CH:34][N:33]=[CH:32]2)[N:25]=1)[CH3:2]
Reactant: Cc1cc(Cl)nc(-n2ccnc2)n1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1cc(C)nc(-n2ccnc2)n1
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a solution of (benzhydrylidene-amino)-acetic acid ethyl ester (2.67 g, 10.0 mmol) in DMSO (50 mL) was added NaH (600 mg of a 60% dispersion on mineral oil, 15.0 mmol) slowly at r.t. under nitrogen and the mixture was stirred for 5 min. Then a solution of 4-chloro-2-imidazol-1-yl-6-methyl-pyrimidine (1.95 g, 10.0 mmol) in DMSO (15 mL) was added and the reaction mixture stirred at r.t overnight. Water was added and the solution was extracted with ethyl acetate, washed with brine and dried over Na2SO4. Evaporation of the solvent gave residue which was purified by column chromatography to give 1.30 g (31%) of (benzhydrylidene-amino)-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-acetic acid ethyl ester. [M+H]+ 426.18.
Reaction SMILES: [S:1]1[C:5]([C:6]2(C#N)[CH2:9][CH2:8][CH2:7]2)=[CH:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2.C[Mg]I.CC[O:21][CH2:22][CH3:23]>>[S:1]1[C:5]([C:6]2([C:22](=[O:21])[CH3:23])[CH2:7][CH2:8][CH2:9]2)=[CH:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2
Reactant: N#CC1(c2cc3ccccc3s2)CCC1
Reactant: CCOCC
Agent: C[Mg]I
Product: CC(=O)C1(c2cc3ccccc3s2)CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-(benzo[b]thiophen-2-yl)cyclobutanecarbonitrile (7.7 g) in ether (50 ml) was added dropwise at ambient temperature under nitrogen to stirred ethereal methylmagnesium iodide solution (3M; 18 ml). When the addition was complete, the mixture was stirred at reflux temperature for 3.5 hours, then it was cooled to ambient temperature. The resulting solid was collected by filtration, washed well with ether, and added in portions to 5M hydrochloric acid (143 ml). The resulting mixture was heated at 95° C. with occasional stirring for 1.5 hours, then allowed to stand at ambient temperature for 18 h. The product was extracted into dichloromethane (3×200 ml), then the combined extracts were washed with water (2×400 ml) and saturated aqueous sodium hydrogen carbonate solution (400 ml), dried (Na2SO4), and the solvent removed in vacuo to give 1-[1-(benzo[b]thiophen-2 yl)cyclobutyl]ethanone as a brown oil (5 g) which was used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[Br:13]Br>CO>[Br:13][CH2:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: CC(=O)CCc1ccc(Br)cc1
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)CCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
To a solution of 4-(4-bromophenyl)-2-butanone (1 mmol) in methanol (8 mL) stirred at room temperature, a solution of bromine (160 mg, 51.6 μL, 1 mmol) in methanol (1 mL) was added in one portion. The orange reaction mixture was then stirred at room temperature for 2 h, and, after the starting material had been consumed (TLC monitoring, hexanes-ethyl acetate 4:1 v/v), the reaction was quenched by adding a 0.3 M sodium thiosulfate solution (618 μL), and diluted with ethyl acetate (15 mL). The resulting mixture was washed with water (15 mL), the organic layer was separated, and the aqueous layer was extracted further with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a residue that was chromatographed on a silica gel column using hexanes-ethyl acetate (15:1 v/v) as mobile phase to give 1-bromo-4-(4-bromophenyl)-2-butanone as a white solid (193 mg, 63%): mp 63-64° C., Rf=0.42 (hexanes-ethyl acetate 4:1 v/v); 1H NMR (400 MHz, CDCl3): δ 2.89 (t, J=6.8 Hz, 2H). 2.96 (t, J=6.8 Hz, 2H), 3.84 (s, 2H), 7.07 (d, J=8 Hz, 2H), 7.41 (d, J=8 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 29.3, 34.3, 41.2, 120.2, 130.2, 131.7, 139.4, 201.0; HRMS (EI) Calcd. for C10H10Br2O: 303.9098 (M+). Found: 303.9090.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:16]=[CH:17][N:18]=2)[CH:15]=1.S([O-])([O-])(=O)=S.[Na+].[Na+].O>CN(C)C=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([C:16]([I:1])=[CH:17][N:18]=2)[CH:15]=1
Reactant: Brc1ccc2nccn2c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2ncc(I)n2c1
Reaction time: 2 h
Yield: 91.5 %

Procedure:
10.7 g N-iodosuccinimide was added in divided portions to 100 mL solution of 9 g 6-bromoimidazo[1,2-a]pyridine in N,N-dimethylformamide, and the mixture was stirred for 2 hours. An aqueous sodium thiosulfate solution was added thereto and stirred for 1 hour, water was added thereto, and the formed crystals were collected by filtration. The product was recrystallized from tetrahydrofuran/ethanol to give 13.5 g of the title compound (colorless crystals).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:25]1([CH2:24][CH2:23][CH2:22][N:9]2[CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Reactant: BrCCCn1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1CCCn1ccnc1
Yield: 37.5 %

Procedure:
Using General Procedure A: 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (91.3 mg, 0.341 mmol), 1-(3-Bromo-propyl)-1H-imidazole (129 mg, 0.680 mmol), KI (5.6 mg, 0.034 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.4 mL) were stirred at 60° C. overnight. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 90:5:5) followed by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (48 mg, 38%) as a colorless oil.
Reaction SMILES: [O:1]([C@@H:9]([CH2:14][CH2:15][OH:16])[C:10]([O:12][CH3:13])=[O:11])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.Cl[CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>ClCCl>[CH2:29]([O:28][CH2:27][O:16][CH2:15][CH2:14][C@H:9]([O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3])[C:10]([O:12][CH3:13])=[O:11])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)[C@H](CCO)O[Si](C)(C)C(C)(C)C
Reactant: ClCOCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CCOCOCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.5 %

Procedure:
(Step 2) To methyl (S)-2-(tert-butyldimethylsiloxy)-4-hydroxybutanoate (220 mg, 0.886 mmol) obtained in Step 1, dichloromethane (0.89 mL), diisopropylethylamine (0.464 mL, 2.66 mmol), and {(chloromethoxy)methyl}benzene (0.30 mL, 2.21 mmol) were added, and the resulting mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, a saturated aqueous ammonium chloride solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=20/80), whereby methyl (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoate (191 mg, 59%) was obtained,
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.[NH4+].[Cl-]>C1COCC1.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[CH:3][CH:4]=1
Reactant: O=C1COC1
Reactant: Brc1ccc(Br)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccc(Br)cc2)COC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1,4-Dibromobenzene (2 g, 8.48 mmol) was taken up in THF (35 mL) and cooled to −78° C. before adding n-BuLi (3.39 mL, 8.48 mmol) dropwise. After stirring at −78° C. for 30 minutes, oxetan-3-one (0.611 g, 8.48 mmol) was added and the reaction was warmed to room temperature for 1 hour at which time water and saturated NH4Cl were added and the products were extracted into EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography (6-50% EtOAc-hexanes) gave the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:16]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.[Cu]I>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([CH2:10][N:11]5[CH2:15][CH2:14][CH2:13][CH2:12]5)=[N:7][C:6]=4[CH:16]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: Ic1ccc2oc(CN3CCCC3)nc2c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4oc(CN5CCCC5)nc4c3)nc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A reaction mixture of 260 mg (0.792 mmol) 5-iodo-2-pyrrolidin-1-ylmethyl-benzoxazole, 171 mg (0.8 mmol) 5-(4-chloro-phenyl)-2-ethynyl-pyridine, 23 mg (0.02 mmol) tetrakis-triphenylphosphane-palladium, 3.8 mg (0.02 mmol) CuI and 350 mg (1.075 mmol) Cs2CO3 in 10 mL THF is stirred for 14 h in an argon atmosphere at RT. Then the reaction mixture is evaporated down and the residue is purified by column chromatography on silica gel (DCM/MeOH 80:1).