Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:19][C:20](=[O:45])[CH2:21][CH2:22][CH:23]([CH:25]1[C:41]2([CH3:42])[CH:28]([CH:29]3[CH:38]([CH2:39][CH2:40]2)[C:37]2([CH3:43])[CH:32]([CH2:33][CH:34]([OH:44])[CH2:35][CH2:36]2)[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:46](=O)([O:55]N1C(=O)CCC1=O)[O:47][N:48]1[C:52](=[O:53])[CH2:51][CH2:50][C:49]1=[O:54].C(N(CC)CC)C.C(#N)C>ClCCl>[O:54]=[C:49]1[CH2:50][CH2:51][C:52](=[O:53])[N:48]1[O:47][C:46](=[O:55])[O:44][CH:34]1[CH2:33][CH:32]2[C:37]([CH3:43])([CH:38]3[CH:29]([CH2:30][CH2:31]2)[CH:28]2[C:41]([CH3:42])([CH:25]([CH:23]([CH3:24])[CH2:22][CH2:21][C:20](=[O:45])[NH:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:26][CH2:27]2)[CH2:40][CH2:39]3)[CH2:36][CH2:35]1
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(OC(=O)ON5C(=O)CCC5=O)CCC4(C)C3CCC12C
Temperature: 25 °C
Reaction time: 6 h
Yield: 80.8 %

Procedure:
Referring to scheme 22, amide 88 (14.5 g, 23 mmol) was dissolved in anhydrous dichloromethane (150 mL). To the solution were added disuccinimidyl carbonate (8.87 g, 34 mmol), triethylamine (15 mL) and acetonitrile (50 mL). The reaction mixture was stirred at room temperature under argon for 6 h and then evaporated dryness. The residue was dissolved in dichloromethane (300 mL). It was washed with saturated NaHCO3 aqueous solution (3×100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Compound 89 (14.3 g, 81%) was obtained as colorless powder after drying in high vacuum, which was directly used for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:28]1(=O)[CH2:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[CH2:18][CH2:17]1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=C1CCC1
Reactant: CCOC(=O)c1cc2cc(OC3CCNCC3)ccc2n1-c1cncnc1
Product: CCOC(=O)c1cc2cc(OC3CCN(C4CCC4)CC3)ccc2n1-c1cncnc1

Procedure:
In analogy to the procedure described for the synthesis of example 43, step 7, the title compound was synthesized from 5-(piperidin-4-yloxy)-1-pyrimidin-5-yl-1H-indole-2-carboxylic acid ethyl ester (example 44, step 2) and cyclobutanone. The title compound was obtained in 58% yield as light yellow solid. MS (m/e): 421.1 (MH+, 100%).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2=[O:21])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[OH:21][CH2:11][CH:10]([C:14]1[C:13]([OH:12])=[C:18]([CH3:19])[C:17]([CH3:20])=[CH:16][CH:15]=1)[C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=1
Reactant: Cc1ccc2c(c1C)OC(=O)C2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(C(CO)c2ccc(C(C)C)cc2)c(O)c1C
Yield: 36 %

Procedure:
Using 3-(4-isopropylphenyl)-6,7-dimethyl-1-benzofuran-2 (3H)-one synthesized in Reference Example 3, the title compound was synthesized in the same manner as in Reference Example 8. Yield 36%. Melting point: 83-84° C. (ethyl acetate-hexane).
Reaction SMILES: Cl.CN(C)S([N:7]1[CH:11]=[C:10]([CH:12]([OH:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=[C:8]1[Si](C(C)(C)C)(C)C)(=O)=O>CO>[OH:19][CH:12]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:10]1[NH:9][CH:8]=[N:7][CH:11]=1
Reactant: CN(C)S(=O)(=O)n1cc(C(O)c2ccccc2)nc1[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CO
Product: OC(c1ccccc1)c1cnc[nH]1
Yield: 28.1 %

Procedure:
A gentle stream of HCl gas was bubbled through a refluxing solution of 2-(tert-butyl-dimethyl-silanyl)-4-(hydroxy-phenyl-methyl)-imidazole-1-sulfonic acid dimethylamide (0.2 g, 0.51 mmol) in methanol (5 ml) for 1 hour. The solvent was evaporated and sodium hydroxide solution was added. The mixture was extracted with dichloromethane (2 times). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol/aqueous conc. ammonia=90:10:1) to yield 25 mg (26%) of rac-5-(hydroxy-phenyl-methyl)-1H-imidazole, MS (EI): 174.1 ((M+.) and 5 mg (5%) of rac-5-(methoxy-phenyl-methyl)-1H-imidazole as colourless oil: MS (ISP): 189.1 ((M+H)+.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1.Cl>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: Clc1cnccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnccn3)cc(C)c21
Temperature: 90 °C
Yield: 38.1 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)acetic acid ethyl ester (0.5 g, 2.0 mmol) in anhydrous DMF (5 mL) were added Cs2CO3 (1.629 g, 5.0 mmol) and 2-chloro-pyrazine (0.275 g, 2.4 mmol) at room temperature. The reaction mixture was heated to 90° C. for 3 hours then poured into ice-water (10 mL). The mixture was acidified to pH 2 using dilute hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (EtOAc/hexane/AcOH=3:2:trace) to give the product as an oil (0.250 g, 38.1%). 1HNMR (400 MHz, DMSO-d6) δ9.22 (s, 1H), 8.53 (d, J=1.17 Hz, 1H), 8.35 (d, J=2.64 Hz, 1H), 8.18 (dd, J=2.78, 1.32 Hz, 1H), 7.25 (d, J=2.05 Hz, 1H), 7.10 (d, J=1.46 Hz, 1H), 5.53 (dd, J=9.08, 2.34 Hz, 1H), 3.94-4.11 (m, 2H), 3.13 (dd, J=15.52, 2.63 Hz, 1H), 2.20-2.40 (m, 4H), 1.06-1.26 (m, 3H). MS (ESI) m/z=329 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].[F:15][CH:16]([F:20])[C:17](O)=[O:18]>>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:17](=[O:18])[CH:16]([F:20])[F:15]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: O=C(O)C(F)F
Product: O=C(NC1C(=O)Nc2ccccc2NC1=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using the method of Example 62, using 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione and difluoroacetic acid, stirring overnight at ambient temperature after the addition of the acid, and washing reaction solid with dichloromethane instead of isopropanol: chloroform (3:1) gives the title compound: mass spectrum (APCI, m/e): 270 (M+1); NMR (1H, 300 MHz, DMSO-d6): δ 10.88 (s, 2H), 9.13 (d, 1H, J=6.9 Hz), 7.29-7.13 (m, 4H), 6.49 (t, 1H, 2J(H,F)=53.7 Hz), 4.79 (d, 1H, J=6.9 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O.C(OC)(C)(C)C>[OH:16][N:15]=[CH:1][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1
Reactant: CC(=O)NCc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: COC(C)(C)C
Solvent: O
Product: CC(=O)NCc1ccc(C=NO)cc1
Yield: 97.6 %

Procedure:
A solution of N-(4-formylbenzyl)acetamide (1.7 g), hydroxylamine hydrochloride (1.0 g) and sodium acetate (1.0 g) in ethanol (10 mL) and water (6 mL) was stirred for one hour at room temperature. After the reaction solution was diluted with t-butylmethylether, the solution was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to yield crude N-{4-[(hydroxyimino)methyl]-benzyl}acetamide (1.8 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[CH2:22][N:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH2:20][CH2:19]4)=[CH:13][C:12]=2[CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCN1CCc2cc(-c3cc4cc(Cc5ccccc5)ccc4o3)ccc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCN1CCc2cc(-c3cc4cc(Cc5ccccc5)ccc4o3)ccc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
To a solution of tert-butyl 3-(6-(5-benzylbenzofuran-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)propanoate (40 mg, 0.086 mmole) in CH2Cl2 (1 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 3 hours. All the solvents were evaporated. The mixture was purified by reverse phase preparative HPLC to give the title compound (14 mg, 40%) [hS1P1 EC50=160 nM, 261 nM]. 1H NMR (400 MHz, CD3OD) δ 7.77 (m, 2H), 7.42 (dd, 1H), 7.40 (s, 1H), 7.20-7.30 (m, 5H), 7.10 (m, 3H), 4.50 (s, 2H), 4.04 (s, 2H), 3.64 (dd, 2H), 3.55 (dd, 2H), 3.26 (dd, 2H), 2.90 (dd, 2H). MS (ESI) m/z: Calculated: 411.18; Observed: 412.10 (M++1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:24][S:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:28][CH:27]=1>CN(C)C=O>[CH3:1][NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:37]2[CH2:36][CH2:35][N:34]([CH2:33][CH2:32][C:29]3[CH:30]=[CH:31][C:26]([S:25][CH3:24])=[CH:27][CH:28]=3)[CH2:39][CH2:38]2)=[O:9])=[CH:10][CH:11]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: CSc1ccc(CCN2CCNCC2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CNc1ccc(C(=O)N2CCN(CCc3ccc(SC)cc3)CC2)cc1

Procedure:
The 1-(4-methylaminobenzoyl)-4-[2-(4-methylmercaptophenyl)ethyl]piperazine is prepared from 1.66 g of 4-methylaminobenzoic acid, 1.95 g of N,N-carbonyldiimidazole and 2.35 g of 1-[2-(4-methylmercaptophenyl)ethyl]piperazine in dimethylformamide at 85°. The base is purified via the hydrochloride (m.p. 185°, decomp.) and melts at 120°-121°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C(N(CCCC)CCCC)CCC.[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH2:35])=[CH:32][CH:31]=1.Cl>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:35][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:32][CH:31]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)c(C(=O)OC)c1
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)c1ccc(C=Cc2ccc(F)cc2)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 90.1 %

Procedure:
A mixture of dimethyl 4-bromoisophthalate (54.75 g., 200.5 mmol), water (330 ml), tributylamine (55.63 g., 300.7 mmol), 4-fluorostyrene (55.63 g., 300.7 mmol) and bis(triphenylphoshine)palladium(II)chloride (2.81 g., 4.01 mmol) was heated at reflux with stirring under an inert atmosphere for 6 hours. The reaction was cooled to ambient temperature and acidified to pH 2 with 2M HCl (700 ml). The aqueous layer was removed and the residual solid washed with water (2 L), dissolved in dichloromethane (1 L) and passed through a pad of silica, eluting with more dichloromethane (2 L). Evaporation of the dichloromethane gave a solid, which was further washed with iso-hexane (1 L), and dried to give methyl 4-[2-(4-fluorophenyl)ethenyl]-3-methoxycarbonylbenzoate (56.75 g) as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:43])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:43])=[O:3])=[CH:10][C:11]=3[CH2:36][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)c(CC2CCCCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1CC1CCCCC1
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-cyclohexylmethylphenoxy}-2-methylpropionic acid ethyl ester (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-cyclohexylmethylphenoxy}-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J=8.3 Hz, 2H), 7.65 (dd. J=8.8, 2.2 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=6.6 Hz, 1H), 6.74 (s, 2H). 6.70 (s, 1H), 4.21 (t, J=6.4 Hz, 2H), 3.00 (t, J=5.9 Hz, 2H), 2.46-2.36 (m, 5H), 1.67-1.51 (m, 11H), 1.47-1.42 (m, 1H), 1.18-1.09 (m, 3H), 0.85-0.83 (m, 2H), MS (ES) m/e 554 (M+1).
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=1
Reactant: CC(C)CCCCCCCCCCCCCBr
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCCC(C)C)cc1

Procedure:
A solution of 10 g. of 14-methylpentadecyl bromide and 10.8 g. of ethyl 4-aminobenzoate in 75 ml. hexamethylphosphoramide is heated at 120° C. for 17 hours. The cooled solution is diluted with 100 ml. water, filtered, and the residue is washed with 100 ml. 50% ethanol-water. The product is dried, then crystallized from ethanol to yield ethyl 4-(14-methylpentadecyl)aminobenzoate as colorless crystals.
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])/[CH:2]=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].C([O-])(=O)/C=C/C([O-])=O.Br[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[N:25]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:11]([O:10][C:1](=[O:9])[C:2]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[N:25]2)=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:12]
Reactant: CCOC(=O)/C=C\C(=O)OCC
Reactant: Brc1ccc2nccnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: CCOC(=O)C=C(C(=O)OCC)c1ccc2nccnc2c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
The title compound can be prepared through a palladium mediated coupling reaction, using diethyl maleate or fumarate as a common reagent (e.g. Tetrahedron, 2002, 58, 6545). For example, a mixture of 6-bromoquinoxaline (1 eq.), diethyl maleate (2.3 eq.), palladium acetate (0.05 eq.), tri(o-tolyl)phosphine (0.1 eq.) and potassium carbonate (2 eq.) in DMF may be warmed to 100° C. and stirred for 16 hours. Quenching with water, extraction with diethyl ether and purification of the crude product by flash chromatography should provide the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27]C(=O)C)[CH:16]=[C:17]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[OH-].[Na+]>C(O)C>[N:1]1([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH2:27])[CH:16]=[C:17]([C:19]5[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(=O)Nc1cc(-c2c(F)cccc2F)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-c2c(F)cccc2F)cc(-n2cnc3cc(-n4cccn4)ccc32)c1
Temperature: 100 °C
Yield: 89 %

Procedure:
To a solution of the compound of Example 152 (2.1 g, 4.895 mmol) in ethanol (50 ml) was added 10% aqueous solution of NaOH (10 ml) and the mixture was heated at 100° C. for 2 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 89% yield (1.6 g).
Reaction SMILES: C[Al](C)C.C(N(C(C)C)CC)(C)C.[C:14](Br)(=[O:16])[CH3:15].[CH3:18][O:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][CH:22]=[O:23].Cl>C(Cl)Cl>[CH3:18][O:19][CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][C@H:22]1[O:23][C:14](=[O:16])[CH2:15]1
Reactant: CC(=O)Br
Reactant: CCCCCCCCCC(CC=O)OC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCC(C[C@@H]1CC(=O)O1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A solution of N,N′-(1R,1′R)-1,1′-(benzylazanediyl)bis(2-methylpropane-1,1-diyl)bis(1,1,1-trifluoromethanesulfonamide) (81.2 mg, 0.15 mmol, 30 mol %) in CH2Cl2 (1 mL) was treated at rt under N2 slowly with a solution of AlMe3 (10.8 mg, 0.15 mmol) in CH2Cl2 (0.5 mL). The mixture was stirred at room temperature (rt) for 2 h, cooled to −45° C. and treated sequentially with diisopropylethylamine (11 mg, 1.7 equiv), acetyl bromide (117 mg, 1.9 equiv) and 5 (107 mg, 0.500 mmol, 1.0 equiv). The resulting pale yellow solution was stirred for 14 h at −45° C., warmed to rt, and poured into a separatory funnel containing 0.1 N HCl (10) mL). The organic layer was washed with saturated NaHCO3, brine, and dried (Na2SO4). The solvent was removed in vacuo and the yellow oily product was purified by chromatography on SiO2 (4% EtOAc/hexanes to 6% EtOAc/hexanes) to give 6 (99.1 mg, 77%) as a colorless oil: 1H NMR (CDCl3) 4.8-4.65 (m, 1H), 3.60-3.50 (m, 1H), 3.3-3.2 (m, 1H), 3.35, 3.32 (2s, 3H), 3.22-3.08 (m, 1H), 2.18-1.82 (m, 2H) 1.65-1.35 (m, 2H), 1.35-1.20 (m, 14H), 0.90-0.80 (m, 3H).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:17]12CC(C=C1)C=[CH:18]2>O1CCOCC1>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2[CH2:6][CH:5]([CH2:4][N:1]3[CH:18]=[CH:17][N:3]=[N:2]3)[O:9][N:8]=2)=[CH:11][CH:12]=1
Reactant: [N-]=[N+]=NCC1CC(c2ccc(Br)cc2)=NO1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: Brc1ccc(C2=NOC(Cn3ccnn3)C2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 65.7 %

Procedure:
5-Azidomethyl-3-(4-bromo-phenyl)-4,5-dihydro-isoxazol (12.3 g, 43.6 mmol) and bicyclo[2.2.1]hepta-2,5-diene (23.6 ml, 218.1 mmol) were added to dioxane (200 ml), heated to 100° C. and stirred for six hours. The reaction mixture was concentrated in vacuo followed by addition of ethyl ether (200 ml). The precipitate was collected and washed with ethyl ether (3×20 ml) and dried under nitrogen to give the desired product (8.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])=[CH:4][CH:3]=1.[N+:17]([C:20]1[CH:25]=[CH:24][C:23](ON)=[CH:22][CH:21]=1)([O-:19])=[O:18].O>C(O)(=O)C>[CH2:11]([C:10]1[O:15][C:23]2[CH:24]=[CH:25][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][C:22]=2[C:9]=1[C:8](=[O:16])[C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:12][CH2:13][CH3:14]
Reactant: NOc1ccc([N+](=O)[O-])cc1
Reactant: CCCCC(=O)CC(=O)c1ccc(O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
1-(4-hydroxyphenyl)-1,3-heptandione, 697 g, is dissolved in 2532 g acetic acid. O-(4-Nitrophenyl)hydroxylamine, 488 g, is added in portions at ca 20° C. The formed slurry is diluted with 739 g acetic acid and the mixture heated to 115° C. and stirred for 3 h. The dark solution is cooled and 1635 g water is added keeping the temperature at 70-80° C. The temperature is adjusted to 60° C. and seeding crystals are added. When crystallisation has started, the slurry is cooled to 4° C., filtered and washed with 870 g of 67% aqueous acetic acid followed by 580 g water. Drying at reduced pressure at 70° C. gives 736 g 2-butyl-3-(4-hydroxybenzoyl)-5-nitrobenzofuran. Yield 69%.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])=[N+:2]=[N-:3].[H-].[Na+].[CH2:30](Br)[C:31]#[CH:32].CO.C(Cl)Cl>CN(C=O)C.C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:32][C:31]#[CH:30])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: C#CCOCCOCCOCCOCCOCCOCCOCCOCCN=[N+]=[N-]
Reaction time: 4 h
Yield: 69.9 %

Procedure:
23-Azido-3,6,9,12,15,18,21-heptaoxatricosan-1-ol (azido-PEG8-ol) (1.1 g, 3.17 mmol, 1.0 equiv.) was dissolved in N,N′-dimethylformamide (6 mL), and sodium hydride (152 mg, 6.34 mmol, 2.0 equiv.) was added, followed by propargyl bromide (80% in PhMe, 683 μL 6.34 mmol, 2.0 equiv.). The reaction ran for 4 h at rt, at which time it was found complete by NMR aliquot. The reaction was taken up in CH2Cl2 (25 mL) and washed with a saturated aqueous ammonium chloride solution (25 mL). The aqueous solution was back-extracted with dichloromethane (2×10 mL), and combined organics were dried over MgSO4 and concentrated to a brown oil. Chromatography (3 cm×20 cm Silica gel, 3% MeOH/CH2Cl2) yielded azido-PEG8-yne (960 mg, 78% yield). IR (thin film/NaCl) 2874 (m), 2110 (m), 1160 (s), 1105 (s) cm−1; 1HNMR (400 MHz, CDCl3) δ 4.20 (d, J=2.4 Hz, 2H), 3.58 (m, 30H), 3.39 (t, J=5.1 Hz, 2H), 2.43 (t, J=2.4 Hz, 1H), 1.82 (s, 1H); 13CNMR (125 MHz, CDCl3) δ 79.82, 74.72, 70.75, 7022, 68.27, 58.62, 50.84; HRMS (ES+) calc'd for C19H35N3O8 (M+Na) m/z 456.231637. Found 456.23182.