Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC.O>C(Cl)Cl.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>[NH2:13][C:12]1[CH:14]=[CH:15][C:9]([O:8][C:3]2[C:2]([C:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Oc2nccnc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nccnc2Oc2ccc(N)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Into a sealed 150-mL flask were placed 4-(3-chloropyrazin-2-yloxy)aniline (2 g, 9 mmol) (see Step 1, Example 215), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.19 g, 13.5 mmol), trans-dichlorobis-(triphenylphosphine)palladium (II) (0.5 g, 0.72 mmol), sodium carbonate (4.78 g, 45.1 mmol) and 30 mL of 4:1 DME-water. After the mixture was degassed for 5 min, the reaction was stirred at 80° C. for 18 h. The cooled reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (2×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo. Flash column chromatography (20% to 60% EtOAc/Hexanes) afforded tert-butyl 4-(3-(4-aminophenoxy)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate) as a cream solid. MS (ESI, pos. ion) m/z: 369.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:13]2[C:12](=[O:14])[NH:11][C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7]=2[CH:6]=[C:5]1[CH3:19].N#N.[CH3:22]I>CS(C)=O.O1CCCC1>[CH3:3][N:4]1[C:13]2[C:12](=[O:14])[N:11]([CH3:22])[C:10]3[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7]=2[CH:6]=[C:5]1[CH3:19]
Reactant: CI
Reactant: Cc1cc2c(n1C)C(=O)Nc1ccccc1N2
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cc2c(n1C)C(=O)N(C)c1ccccc1N2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
0.33 g (0.011 mole) of 80% sodium hydride (in paraffin) are added to a cold solution (5° C.) of 2.3 g (0.01 mole) of 1,2-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one in 20 ml of dry dimethylsulfoxide and 20 ml of tetrahydrofuran under an inert gas atmosphere (N2). The mixture is stirred for 30 minutes and is allowed to come to room temperature (30 minutes). Thereafter, it is again cooled to 5° C. and 1.4 g (0.01 mole) of methyl iodide, dissolved in 5 ml of dry tetrahydrofuran, are added dropwise. After the mixture has been stirred at 35° C. for 2 hours, 50 ml of ice-water are added, and the mixture is extracted several times with ethyl acetate. The combined extracts are concentrated in vacuo, and the residue is chromatographed on neutral silica gel (methylene chloride/methanol), yield: 1.7 g.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[S:8]([C:11]1[CH:12]=[CH:13][C:14]([OH:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:10])=[O:9]>ClCCl>[OH:21][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: C1COCCN1
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)N2CCOCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Morpholine (174 mg, 2.00 mmol) was added dropwise to methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (may be prepared as described in Description 63; 500 mg, 2.00 mmol) in dichloromethane (20 ml) at 25° C., and the mixture was allowed to stir at 25° C. for 2 h. The mixture was then concentrated in vacuo to yield the crude title compound. 350 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[CH:41][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17]([CH2:18][OH:19])[O:16][CH:15]3[CH:11]([N:12]=[C:13]([N:20]([CH2:28][CH2:29][CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]3)[C@H:10]2[O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:5][CH:4]=1.C1C(=O)N(Br)C(=O)C1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].ClCCl.O.CC1(C)N([O])C(C)(C)CCC1>[CH:18]([C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH2:28][CH2:29][CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[S:14]2)[C@@H:10]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[C@@H:9]1[O:8][CH2:7][C:6]1[CH:41]=[CH:42][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:19]
Reactant: CCCN(C(=O)OC(C)(C)C)C1=NC2C(O[C@H](CO)[C@@H](OCc3ccc(OC)cc3)[C@@H]2OCc2ccc(OC)cc2)S1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClCCl
Product: CCCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](C=O)O[C@@H]2S1
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
To a mixture of tert-butyl (5R,6S,7R)-6,7-bis(4-methoxybenzyloxy)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(propyl)carbamate (2 g, 3.32 mmol), KHCO3 (1.49 bg, 15 mmol), TBAB (53 mg, 0.16 mmol) and TEMPO (26 mg, 0.17 mmol) in dichloromethane (60 mL) and H2O (12 mL) was added NBS (592 mg, 3.33 mmol) at 15° C. After stirred for 30 min, the reaction mixture was quenched by saturated Na2SO3 (10 mL). The organic layer was dried over anhydrous magnesium sulfate and condensed to provide a residue, which was purified by silica gel column, eluted with 20-30% AcOEt in dichloromethane to give compound 20 as a yellow syrup (1.2 g, purity 60%). (ES, m/z): [M+H]+ 601.1. 1H NMR (300 MHz, CDCl3) δ 9.61 (s, 1H), 7.23-7.28 (m, 4H), 6.82-6.86 (m, 4H), 6.19-6.21 (d, J=6.9 Hz, 1H), 4.60-4.67 (m, 2H), 4.41-4.55 (m, 3H), 4.02-4.03 (m, 1H), 3.88-3.93 (m, 1H), 3.68-3.81 (m, 9H), 1.46-1.53 (m, 11H), 0.83-0.86 (t, J=7.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:12]=[C:13]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:14]=[N:15][CH:16]=3)[N:10]=2)[CH:7]=1.[Cl:21]N1C(=O)CCC1=O>C(#N)C>[Cl:21][C:8]1[N:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]1[CH:12]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:14]=[N:15][CH:16]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(O)c1cncc(-c2cn3cc(F)ccc3n2)c1
Solvent: CC#N
Product: CC(C)(O)c1cncc(-c2nc3ccc(F)cn3c2Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Example 2 Step E (0.068 g, 0.251 mmol) in acetonitrile (1.25 ml) was added N-chlorosuccinimide (0.040 g, 0.301 mmol). The resulting mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure. The resulting residue was diluted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (100% ethyl acetate) provided the title compound: LCMS m/z 306.08 [M+H]+; 1H NMR (500 MHz, CDCl3) 9.23 (d, J=1.7 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.51 (t, J=2.0 Hz, 1H), 8.08 (t, J=2.5 Hz, 1H), 7.65 (dd, J=9.3, 4.9 Hz, 1H), 7.24-7.20 (m, 1H), 2.02 (br s, 1H), 1.69 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][C:32](Cl)=[O:33]>>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([NH:15][C:14]1[N:9]2[N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:22]=[C:10]2[CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH:13]=1)=[O:33]
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Reactant: O=C(Cl)Cc1ccc(Cl)cc1Cl
Product: O=C(Cc1ccc(Cl)cc1Cl)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12

Procedure:
The title compound, MS m/e (%): 474 (M+H+, 100), was prepared in accordance with the general method of example 31 from 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 2,4-dichlorophenylacetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[I:28][C:29]1[CH:30]=[CH:31][C:32]([S:35](Cl)(=[O:37])=[O:36])=[N:33][CH:34]=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:35]([C:32]1[CH:31]=[CH:30][C:29]([I:28])=[CH:34][N:33]=1)(=[O:37])=[O:36]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(I)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(I)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2,4-Dimethoxy-benzyl)-thiazol-2-yl-amine (0.453 g, 1.81 mmol) was dissolved in Tetrahydrofuran (5 mL, 70 mmol) and cooled in an ice bath. 1.0 M of Lithium hexamethyldisilazide in Tetrahydrofuran (2.0 mL) was added dropwise to the reaction. After addition was complete, the reaction mixture was warmed to ambient temperature. After 30 min, the reaction was cooled to at 0° C. and a solution of 5-Iodo-pyridine-2-sulfonyl chloride (0.50 g, 1.6 mmol) in Tetrahydrofuran (4 mL, 50 mmol) was added dropwise. The reaction mixture was stirred 4 h then quenched with saturated aqueous ammonium chloride. The reaction mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and additional saturated aqueous ammonium chloride was added. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered through celite, and concentrated in vacuo. The residue was purified on the ISCO twice (hexanes to ethyl acetate) to afford the product as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:40])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:23])=[O:22].[OH-].[Li+].O1CCCC1>O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:40])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])[S:21]([C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)(=[O:22])=[O:23]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)O)S(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCN(CC(C)(C)O)S(=O)(=O)c3cccc(CC(=O)O)c3)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
By the same manner to Example 2-12, the compound obtained in Example 2-22 (70 mg) and lithium hydroxide (20 mg) were added to tetrahydrofuran (4 ml) and water (2 ml) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and partitioned between 2M hydrochloric acid and ethyl acetate. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried and concentrated under reduced pressure to give the titled compound as a white solid. Yield: 23 mg (34%); MS APCI+ve 565 (M+H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:2]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1)=[O:1]
Reactant: Cc1cncc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cncc(C=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
3-Hydroxymethyl-5-methylpyridine (972 mg, 7.89 mmol) was dissolved in dichloromethane (30 mL). To this, manganese dioxide (7.5 g) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite and the solvent was evaporated off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=19/1) to give 3-formyl-5-methylpyridine (936 mg, yield: 98%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][CH:6]=1)=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]=1>C(#N)C>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][N:16]3[CH:2]=2)=[CH:6][CH:7]=1)[CH3:13]
Reactant: Nc1ccc(I)cn1
Reactant: CCOc1ccc(C(=O)CBr)cc1
Solvent: CC#N
Product: CCOc1ccc(-c2cn3cc(I)ccc3n2)cc1
Temperature: 110 °C
Yield: 91.1 %

Procedure:
1.20 g (corresponding to 4.94 mmol) of 2-bromo-4′-ethoxyacetophenone and 1.09 g (corresponding to 4.95 mmol) of 2-amino-5-iodopyridine were dissolved in 20 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 110° C. for 1.5 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. Then, the precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 10 mL of water and 5 mL of methanol. Then, about 20 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 1.64 g (corresponding to 4.50 mmol) of 2-(4′-ethoxyphenyl)-6-iodoimidazo[1,2-a]pyridine (FIG. 2-3, Step 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:13][C:14]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1)[CH2:9][C:10]#[CH:11]>>[CH3:21][C:20]1[C:14]2[O:13][C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:16][C:15]=2[CH:17]=[CH:18][CH:19]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1nc2cccc(C)c2o1
Product: Cc1cccc2nc(CCC#Cc3ccccn3)oc12
Yield: 54.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (26 mg, 0.16 mmol) and 2-(but-3-ynyl)-7-methyl benzo[d]oxazole (30 mg, 0.16 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 23 mg (87 μmol, 54%) of 7-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as a brown oil.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[CH:15]2>>[C:1]1([S:7]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([F:11])=[CH:20][CH:19]=3)[CH:15]=[CH:16]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Yield: 73 %

Procedure:
The title compound was prepared from benzene sulfonyl chloride and 5-fluoro-1H-indole, according to Method A, described above. Yield 73%; 1H NMR (CDCl3) δ 7.77-7.82 (dd, J=9 Hz, 1H), 7.71-7.74 (m, 2H), 7.47 (d, J=4 Hz, 1H), 7.30-7.45 (m, 3H), 7.03-7.07 (dd, J=9 Hz, 1H), 6.87-6.95 (dt, J=9 Hz, 1H), 6.51 (d, J=4 Hz, 1H); MS (AP+) m/z 276.0 (M++1), 214.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].C(N(CC)CC)C.[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N+:21]([O-:23])=[O:22])=[C:16]([CH:20]=1)[C:17](Cl)=[O:18].O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:17](=[O:18])[C:16]1[CH:20]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=1[N+:21]([O-:23])=[O:22])[CH3:2]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethanol (1.23 mL), triethylamine (3.05 mL) and tetrahydrofuran (35 mL) was dropwise added a solution of 5-chloro-2-nitrobenzoic acid chloride (4.44 g) obtained in Example 9-4a) in tetrahydrofuran (10 mL) under ice-cooling. The mixture was stirred at room temperature overnight, and water was then added. The solution was diluted with ethyl acetate, and the organic layer was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate and concentrated to give the title compound (4.43 g) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([CH:8]([CH:14]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)C(OCC)=O)=[O:7])=[CH:4][CH:3]=1.CS(C)=O>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH2:8][CH:14]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][C:22]3[C:27]2=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(Br)cc1)C1c2ccccc2Oc2ccccc21
Solvent: O
Solvent: CS(C)=O
Product: O=C(CC1c2ccccc2Oc2ccccc21)c1ccc(Br)cc1

Procedure:
Ethyl 2-(4-bromobenzoyl)-2-(9H-xanthen-9-yl)acetate (10.0 g, 0.02 mol) was heated in a solution of dimethylsulphoxide (100 ml) and water (0.72 ml) following the procedure described in Example (iv) to give 1-(4-bromophenyl)-2-(9H-xanthen-9-yl)ethanone as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O:18][C:19]1[C:20](=[O:24])[C:21](=O)[CH:22]=1)CCC>C(O)C>[N:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH:1][C:21]2[C:20](=[O:24])[C:19](=[O:18])[CH:22]=2)=[CH:9][CH:10]=1
Reactant: CCCCOc1cc(=O)c1=O
Reactant: Nc1cccc(-c2ccncc2)c1
Solvent: CCO
Product: O=c1cc(Nc2cccc(-c3ccncc3)c2)c1=O
Yield: 76.8 %

Procedure:
A solution of 4-(3-aminophenyl)pyridine (0.81 g) and 3-n-butoxy-3-cyclobutene-1,2-dione (0.73 g) in ethanol (20 ml) is stirred at ambient temperature for 15 hours. The resultant precipitated solid is washed with methanol and ether and recrystallized from dimethyl formamide to give 0.91 g of the title compound, mp 252-255.5° C.
Reaction SMILES: [C:1]([O-:5])([CH3:4])([CH3:3])[CH3:2].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)[CH:12]=1.[Cl:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>C1(C)C=CC=CC=1>[C:1]([O-:5])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:32][C:33]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]2)[CH:12]=1)=[O:34]
Reactant: COc1ccc(N)cc1N1CCN(C(=O)O)CC1
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(C)c(Cl)c2)cc1N1CCN(C(=O)O)CC1

Procedure:
A solution of 34.4 mmol (10 g) of 4-(5-amino-2-methoxyphenyl)piperazine-1-carboxylic acid tert-butanolate (described in J. Med. Chem., 1999, p.202) and 37.8 mmol (5.9 g) of 3-chloro-4-methylphenyl isocyanate in 150 ml of toluene is heated at reflux for 2 hours. The reaction mixture is concentrated, and the residue is taken up in 200 ml of 4N hydrochloric acid and then heated at reflux for 4 hours. After cooling, the precipitate formed is filtered off and treated with a 2N sodium hydroxide solution in order to regenerate the corresponding base.
Reaction SMILES: COC(=O)CCCCCCCCCCC=O.[Br-].C(OC(C1SC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1.[C:61]([O:65][C:66]([C:68]1[S:69][C:70]([CH:73]=[CH:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][C:85]([O:87][CH3:88])=[O:86])=[CH:71][CH:72]=1)=[O:67])([CH3:64])([CH3:63])[CH3:62]>CN(C=O)C.CO.[Pd]>[C:61]([O:65][C:66]([C:68]1[S:69][C:70]([CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][C:85]([O:87][CH3:88])=[O:86])=[CH:71][CH:72]=1)=[O:67])([CH3:64])([CH3:63])[CH3:62]
Reactant: COC(=O)CCCCCCCCCCC=Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: [Pd]
Agent: CC(C)(C)OC(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: COC(=O)CCCCCCCCCCC=O
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCCCCCCCCCCCc1ccc(C(=O)OC(C)(C)C)s1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
12-Oxo-dodecanoic acid methyl ester (14.5 g, 63.4 mmol) and (5-tert-butoxycarbonyl-thiophen-2-ylmethyl)-triphenylphosphonium bromide (29.1 g, 63.4 mmol) were dissolved in DMF (350 mL). DBU was added and the mixture was heated to 80° C. for 35 minutes. The reaction mixture was allowed to cool to room temperature and separated between diethyl ether (3×500 mL) and water (2000 mL). The organic phases were collected and washed with water (1×500 mL). The organic phase was dried (MgSO4) and the solvent was removed in vacuo. The remaining crude material was added heptane (300 mL) and stirred for 30 minutes, filtered and the solvent was removed in vacuo to yield 13.6 g of crude material of an E/Z mixture of 5-(12-methoxycarbonyl-dodec-1-enyl)thiophene-2-carboxylic acid tert-butyl ester. This mixture was dissolved in methanol (200 mL). 2 g of 10% Palladium on carbon (50% wet with water) was added and the mixture was stirred under a hydrogen atmosphere with 10 bar pressure for 90 minutes, filtered and the solvent was removed in vacuo to yield 11.6 g of 5-(12-methoxycarbonyl-dodecyl)-thiophene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[Br:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([Br:21])[C:13]=1[CH2:22]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[C:14]([Br:21])[C:13]=1[CH2:22][NH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1cc(Br)c(CBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNCc2c(Br)cc([N+](=O)[O-])cc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-methoxybenzylamine (2.15 g, 15.7 mmol) was added to a solution of 1,3-dibromo-2-(bromomethyl)-5-nitrobenzene (4.91 g, 13.1 mmol) in DMF (100 mL) under nitrogen at rt. K2CO3 (1.99 g, 14.4 mmol) was then added and the reaction mixture was stirred at rt overnight. The reaction mixture was quenched with 500 mL of water, and extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was purified by flash chromatography on Biotage 40M columns, eluting with 90:10 hexanes-ethyl acetate to provide N-(2,6-dibromo-4-nitrobenzyl)-N-(4-methoxybenzyl)amine as a red viscous liquid. 1H NMR (500 MHz, CDCl3): δ 3.81 (d, J=3.6 Hz, 4H); 4.20 (s, 3H); 6.88 (d, J=8.4 Hz, 2H); 7.27 (d, J=5.9 Hz, 2H); 8.40 (s, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:20])[NH:9][CH:10]([C:12]1[CH:13]=[N:14][C:15]([F:19])=[CH:16][C:17]=1[I:18])[CH3:11])([CH3:6])([CH3:5])[CH3:4].I[CH2:22][CH3:23]>CN(C)C=O>[C:3]([O:7][C:8](=[O:20])[N:9]([CH2:22][CH3:23])[CH:10]([C:12]1[CH:13]=[N:14][C:15]([F:19])=[CH:16][C:17]=1[I:18])[CH3:11])([CH3:4])([CH3:5])[CH3:6]
Reactant: CCI
Reactant: CC(NC(=O)OC(C)(C)C)c1cnc(F)cc1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C(C)c1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
Add sodium hydride (84.0 mg, 2.1 mmol, 60% dispersion in mineral oil) to a solution of [1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (0.37 g, 1.0 mmol) in dimethylformamide (10 mL). Stir at room temperature for 30 min. Add iodoethane (0.2 mL, 2.1 mmol). Stir for 1 hour. Quench the reaction with water. Extract with CH2Cl2. Wash the organic layer with water and saturated aqueous sodium chloride. Dry over MgSO4. After filtration, afford crude product ethyl-[1-(6-fluoro-4-iodo-pyridin-3-yl)-ethyl]-carbamic acid tert-butyl ester (0.4 g, 97%) with 90% HPLC purity, MS (ES) m/z 395 [M+1]+.