Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6]([CH3:16])([CH3:15])[N:5]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH:2]=C.I([O-])(=O)(=O)=[O:28].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:16][C:6]1([CH3:15])[N:5]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[C@H:4]([CH2:1][CH:2]=[O:28])[C@@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7]1
Reactant: C=CC[C@@H]1[C@@H](c2ccccc2)OC(C)(C)N1C(=O)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)O[C@H](c2ccccc2)[C@@H](CC=O)N1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To the crude (4R,5R)-benzyl 4-allyl-2,2-dimethyl-5-phenyloxazolidine-3-carboxylate (1.29 g, 3.66 mmol) in THF (50 mL) and water (20 mL) was added osmium tetroxide (0.45 ml, 0.0180 mmol, 4%) solution. The reaction was stirred for 10 min, after which sodium periodate (3.91 g, 18.3 mmol) was added portion wise over 1 hr. Stirring was continued for 2 h. Saturated aqueous Na2S2O3 was added and the reaction was stirred for 15 min. The volatiles were removed in vacuo and the aqueous residue extracted with Et2O (3×50 mL). The combined ether layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated. The crude residue was evaporated onto silica gel and purified via flash chromatography (0% to 20%; EtOAc in hexanes) to afford (4R,5R)-benzyl 2,2-dimethyl-4-(2-oxoethyl)-5-phenyloxazolidine-3-carboxylate. MS m/z=354 [M+1]+. Calc'd for C21H23NO4: 353.
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][N:14]([C:16]2([CH2:20][C:21]#[N:22])[CH2:19][NH2+:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([N:46]=[C:47]=[O:48])[CH:41]=1>CC#N.CS(C)=O>[C:21]([CH2:20][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13]2)[CH2:17][N:18]([C:47](=[O:48])[NH:46][C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=2)[CH2:19]1)#[N:22]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)C[NH2+]C1
Reactant: O=C=Nc1cccc(F)c1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CC#N
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CN(C(=O)Nc2cccc(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[4-Carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (25 mg, 0.060 mmol) was dissolved in MeCN (0.50 mL) and treated with DIPEA (0.020 mL, 0.12 mmol) and 1-fluoro-3-isocyanatobenzene (0.010 mL, 0.090 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then diluted with DMSO (1.0 mL) and purified directly by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH4OH modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #38-1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[N:26][CH:27]=3)[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:39])[C:13]=2[CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[N:26][CH:27]=3)[CH:18]([CH3:19])[CH3:20])=[C:14]([CH3:39])[C:13]=2[CH:40]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)nc2)C(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-[{[5-({1-[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)pyridin-2-yl]carbonyl}(methyl)amino]propanoate (0.15 g) synthesized in the above-mentioned (2) was dissolved in ethanol (3 mL), 1N aqueous sodium hydroxide solution (1.0 mL) was added to the solution at room temperature, and the mixture was stirred at room temperature for 0.5 hr. Ethanol was evaporated under reduced pressure, and 1N hydrochloric acid (1.0 mL) was added to the residue. The precipitate was washed with water to give the title object compound (0.14 g, quantitative) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(C(C)C)CC)(C)C>CN(C1C=CN=CC=1)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:47][C:46]2[CH:48]=[CH:49][CH:50]=[C:44]([O:43][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH2:39][CH2:40][O:41][CH3:42])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:45]=2)=[O:19])[N:7]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccccc4)c3)c2cc1OC

Procedure:
The procedure for Example 138B was used to react phenyl 3-tert-butyl-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 154A (151 mg, 0.45 mmol) with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (103 mg, 0.30 mmol). To this solution was added diisopropylethyl amine (80 μL, 0.45 mmol) and DMAP (4 mg, 0.03 mmol). After heating for 2 hours the reaction was concentrated to dryness. The resulting solid was chromatographed using silica gel (eluting with an ethyl acetate/hexane gradient 0-85%). The main peak was concentrated to give 59 mg. 1H (DMSO-d6) 9.23 (s, 1H), 8.54 (s, 1H), 8.47 (s, 1H), 7.55 (m, 6H), 7.40 (m, 3H), 7.18 (s, 1H), 6.95 (m, 1H), 6.35 (s, 1H), 4.34 (m, 2H), 3.98 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.25 (s, 9H). LCMS (ESI) m/z 583 (M+H)
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][NH:27][CH3:28])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[CH3:39][CH2:40][O:41][C:42](Cl)=[O:43]>CN(C=O)C>[NH2:31][C:29]([C:16]1[CH:17]=[C:18]([C:21]2[CH:25]=[C:24]([CH2:26][N:27]([CH3:28])[C:42](=[O:43])[O:41][CH2:40][CH3:39])[S:23][CH:22]=2)[CH:19]=[C:20]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:9]1[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]1)=[O:30]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CNC)c4)cc23)CC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)N(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 53.6 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMF (1.0 mL) at 0° C. was added triethylamine (0.06 mL, 0.44 mmol), and ethyl chloridocarbonate (0.021 mL, 0.22 mmol). The resultant mixture was reacted for 30 min followed by purification on Gilson Preparatory HLPC to afford 31.4 mg of the title compound (53.5%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:9][C:10]1[CH:15]=[C:14]([C:16]([NH:18][C:19]2[S:20][C:21]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:17])[CH:13]=[CH:12][N:11]=1>>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[C:22]1[N:23]=[C:19]([NH:18][C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([CH2:9][N:5]3[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]3)[CH:15]=2)=[O:17])[S:20][C:21]=1[C:29]1[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=1
Reactant: OC1CCNCC1
Reactant: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(CCl)c1
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1ccnc(CN2CCC(O)CC2)c1
Yield: 53 %

Procedure:
In a manner similar to that in Example 108, by using 4-hydroxypiperidine in place of imidazole, the entitled Compound 111 (92.0 mg, 53%) was obtained from Compound 107.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CS(=O)(=O)CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)NC(=O)OCCS(C)(=O)=O)cc1)n2C)c1ccccn1
Yield: 65 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl) aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and 2-(methylsulfonyl)ethyl chloroformate. Yield: 65% of theory, C31H35N7O7S (649.7); Rf value: 0.54 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=650; (M+H+Na)++=336.6; (M+Na)+=672; (M+2Na)++=347.6.
Reaction SMILES: [C:1]([C:5]1[CH:46]=[CH:45][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:44])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:37]([CH:39]([CH3:41])[CH3:40])[CH3:38])[C:32]([O:34]CC)=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:42])[N:20]([CH3:43])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:44])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH:31]([N:37]([CH:39]([CH3:40])[CH3:41])[CH3:38])[C:32]([OH:34])=[O:33])=[CH:27][CH:26]=4)[C:21](=[O:42])[N:20]([CH3:43])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:45][CH:46]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn(C)c2=O)cc1)N(C)C(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(C(=O)O)N(C)C(C)C)cc2)n1
Temperature: 60 °C
Yield: 55 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 28 (400 mg, 0.642 mmol), THF (5 mL) and ethanol (5 mL). A solution of lithium hydroxide (124 mg, 10.2 mmol) in water (5 mL) was added, and the mixture was heated at 60° C. for 48 h. After this time, the reaction was cooled to room temperature, and the mixture was slowly acidified to pH 4.0 with 10% aqueous citric acid. The resulting precipitate was filtered, and the filter cake was washed with water (20 mL), then triturated with a 1:10 mixture of methylene chloride/ethyl acetate (20 mL). The resulting residue was dried to a constant weight under vacuum at 45° C. to afford 29 in 55% yield (210 mg) as an off-white solid: mp 197-198° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.29 (s, 1H), 7.99 (d, 2H, J=8.5 Hz), 7.95 (d, 2H, J=8.5 Hz), 7.55 (d, 2H, J=8.5 Hz), 7.39 (d, 2H, J=8.5 Hz), 7.35 (dd, 1H, J=7.0, 1.5 Hz), 7.32-7.28 (m, 2H), 7.24 (s, 1H), 4.23 (s, 1H), 3.56 (s, 3H), 3.30 (m, 1H), 2.30 (s, 3H), 2.23 (s, 3H), 1.33 (s, 9H), 1.13 (d, 3H, J=6.5 Hz), 1.10 (d, 3H, J=6.5 Hz); MS (ESI+) m/z 596 (M+H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[C:6]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C(OCC)C>[CH2:3]([C:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH:2]=[CH2:1]
Reactant: O=C1CCCCC1
Reactant: C=CC[Mg]Br
Solvent: CCOCC
Product: C=CCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of allyl magnesium bromide in diethyl ether (1 M, 53 mL, 53 mmol) was added dropwise to a solution of cyclohexanone (5.00 mL, 48.2 mmol) in diethyl ether at 0° C. The cloudy white reaction mixture was allowed to stir at rt overnight. The reaction was quenched with saturated aqueous NH4Cl (100 mL) and diluted with water (20 mL) and diethyl ether (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to afford a 1-allylcyclohexanol as a colorless oil (6.97, 103%) that contained a small amount of diethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[C:10]1([CH2:16][C:17]([N:19]2[CH2:26][CH2:25][CH2:24][C@H:20]2[C:21](O)=[O:22])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:21](=[O:22])[C@@H:20]2[CH2:24][CH2:25][CH2:26][N:19]2[C:17](=[O:18])[CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([F:9])[CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)Cc1ccccc1
Reactant: Nc1ccc(Br)cc1F
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Product: O=C(Nc1ccc(Br)cc1F)[C@@H]1CCCN1C(=O)Cc1ccccc1
Yield: 97.8 %

Procedure:
4-Bromo-2-fluoroaniline (1.0 g, 5.3 mmol) was treated with N-phenylacetylproline (1.3 g, 5.52 mmol) and EEDQ as described in Example 1 to provide 2.1 g of N-(4-bromo-2-fluorophenyl)-1-(phenylacetyl)-L-prolinamide. A portion of this intermediate (0.51 g, 1.26 mmol) was suspended in 5 mL toluene and treated with 0.38 mL of trans-1,2-bis(tri-n-butylstannyl)ethylene (0.69 mmol, 0.55 equiv) followed by 0.029 g of Pd(PPh3)4. The reaction was sealed under nitrogen and heated to 100° C. for 2 hours. The mixture was then cooled to room temperature and stirred vigorously with an equal volume of aqueous saturated KF for 2 hours. Filtration through diatomaceous earth (Celite®) followed by extractive workup and HPLC purification provided the desired product. 1H NMR (DMSO-d6, 500 MHz, mixture of rotamers) δ 10.10 and 9.86 (s, 1H), 7.94 and 7.81 (m, 1H), 7.52 (m, 1H), 7.20-7.35 (m, 16H), 4.82 and 4.64 (m, 2H), 3.65 (m, 4H), 1.94-2.11 (m, 8H); LCMS (Rt=1.76 min, m/z 677.34).
Reaction SMILES: Br[C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH2:14]1[O:16][CH2:15]1>>[CH3:13][O:12][C:11]1[C:2]([CH2:14][CH2:15][OH:16])=[CH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1cc2ccccc2cc1Br
Reactant: C1CO1
Product: COc1cc2ccccc2cc1CCO

Procedure:
The title compound was synthesized as described above from 2-bromo-3-methoxynaphthalene and ethylene oxide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17](O)[CH3:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:34]=[N+:35]=[N-:36])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:34]([CH:17]([C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[CH3:18])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(C)O)cc1OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)N=[N+]=[N-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. mixture of crude 1-(3-benzyloxy-4-methoxy-phenyl)-ethanol (10 mmol maximum) and diphenylphosphoryl azide (2.6 mL, 12 mmol) in toluene (18 mL) is added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.6 mL, 11 mmol). The mixture is stirred at 0° C. for two hours and then at room temperature overnight. The reaction mixture is washed with water and concentrated to give 4-(1-azido-ethyl)-2-benzyloxy-1-methoxybenzene, which is used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16](Cl)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[N:18]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CCN(CC)CC.O>CC(O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([NH:26][CH2:25][CH2:24][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: Clc1nccn2c(-c3cccc(Br)n3)cnc12
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: O
Product: Brc1cccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Temperature: 25 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-chloro-imidazo[1,2-a]pyrazine (from Example 38 supra) (3.09 g, 10.0 mmol), 2-morpholin-4-yl-ethylamine (2.6 g, 20.0 mmol), NEt3 (2.02 g, 20.0 mmol) in 2-propanol (300 mL) was stirred and heated at reflux for 16 hours. The solution was then cooled to room temperature and poured into water. The resulted solid was filtered and washed with water. The crude product was purified by chromatography (CH2Cl2:CH3OH, 20:1) to give [3-(6-bromo-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 2.5 g, 62%). LC-MS: [M+H]+ 403.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:17]=2)[C:3]1([CH3:31])[CH3:30].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:27][O:26][C:24](=[O:25])[C:23]([CH3:29])([O:22][C:18]1[CH:17]=[C:16]([CH:4]2[C:3]([CH3:31])([CH3:30])[CH2:2][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=3)[NH:5]2)[CH:21]=[CH:20][CH:19]=1)[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)C(O)C(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)N2
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(OC(C)(C)C(=O)OC)c1)N2
Yield: 47 %

Procedure:
A mixture of methyl 4-hydroxy-2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dim ethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (510 mg, 1.19 mmol) and triethylsilane (400 mg, 3.44 mmol) in dichloromethane (6 mL) was stirred and cooled with a ice bath. A solution of trifluoroacetic acid (554 mg, 4.86 mmol) in dichloromethane (6 mL) was added slowly to the mixture. The reaction mixture was treated with sodium carbonate, and stirred for 30 min. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (silica gel, petroleum ether:ethyl acetate=15:1) to afford 230 mg of methyl 2-(3-(1-methoxy-2-methyl-1-oxopropan-2-yloxy)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate. (Yield: 47%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8]>[OH-].[Na+].C(O)C>[CH3:1][C:2]1[O:3][C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCCCCc1cc(C(=O)OCC)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1cc(C(=O)O)c(C)o1

Procedure:
Saponification of the ester was accomplished by refluxing 12 hours in 10 ml of 25% aqueous sodium hydroxide and 5 ml of ethanol. Acidification precipitated the crude acid, which was purified by sublimation to give 2-methyl-5-pentyl-3-furoic acid, mp 47°-48° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[O:6][C:5]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([O:24]CC4C=CC=CC=4)=[CH:19][C:18]=3[Cl:32])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1.[H][H]>[Pd]>[CH3:1][C:2]1([CH3:33])[O:6][C:5]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([OH:24])=[CH:19][C:18]=3[Cl:32])=[CH:8][CH:9]=[CH:10][C:4]=2[CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(OCc4ccccc4)cc3Cl)c2O1
Agent: [Pd]
Product: CC1(C)Cc2cccc(OCCCCOc3c(Cl)cc(O)cc3Cl)c2O1

Procedure:
In a first step as depicted in Scheme 1, an appropriately substituted phenol, for example, the known compound 2,6-dichloro-4-phenylmethoxyphenol, was reacted under basic conditions with a haloalkane derivative of a desired carbon chain length, for example 1-bromo-4-chlorobutane, to attach the bridging group B, thereby affording the corresponding 1,3-dichloro-2-(4-chlorobutoxy)-5-(phenylmethoxy)benzene (A). Intermediate (A) was then reacted under basic conditions with, for example, the known compound 2,2-dimethyl-2,3-dihydrobenzo[b]furan-7-ol, to attach moiety D, as well as the benzo-fused ring, affording the corresponding 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene (B). Intermediate (B), for example 2-[4-(2,2-dimethyl-(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-1,3-dichloro-5-(phenylmethoxy)benzene, as set forth above, was then reduced with hydrogen gas in the presence of a catalyst, for example 10% palladium on carbon, providing the corresponding 4-[4-(2,2-dimethyl(2,3-dihydrobenzo[2,3-b]furan-7-yloxy))butoxy]-3,5-dichlorophenol (C). Intermediate (C) was then reacted under basic conditions with, for example, 1,1,1,3-tetrachloropropane, which simultaneously dehydrohalogenates, thereby introducing the moiety -E-G-C(R4)═C(R5)(R5) into the molecule to provide Compound 12, a novel compound of formula I. Example 1 set forth below, provides a detailed method to how Compound 12 shown in Scheme 1 was prepared.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[NH:18][C:17](=[O:19])[O:16][N:15]=2)=[CH:4][CH:3]=1.Cl[CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][N:18]1[C:17](=[O:19])[O:16][N:15]=[C:14]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCn1c(-c2ccccc2-c2ccc(C)cc2)noc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
To a mixture of 3-(4′-methylbiphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one (44.1 g), 1-(chloromethoxy)-2-methoxyethane (24 g) and methylene chloride (500 mL) was added a solution (30 mL) of diisopropylethylamine (36.2 mL) in methylene chloride was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (46.6 g, 78%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](CC(O)=O)=[CH:2]1.CN1C=CC=[C:12]1[C:16]([OH:18])=[O:17].O1C=CC=C1CC(O)=O>>[S:1]1[CH:2]=[CH:3][CH:4]=[C:5]1[CH2:12][C:16]([OH:18])=[O:17]
Reactant: O=C(O)Cc1ccsc1
Reactant: Cn1cccc1C(=O)O
Agent: O=C(O)Cc1ccco1
Product: O=C(O)Cc1cccs1

Procedure:
3-thienylacetic acid; N-methylpyrrole-2-carboxylic acid; furylacetic acid; 2-, 3- or 4-pyridylacetic acid;
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:15][C:16]([Si](C)(C)C)([F:18])[F:17]>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]([OH:8])[C:16]([F:18])([F:17])[F:15]
Reactant: Cn1ccnc1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ccnc1C(O)C(F)(F)F
Yield: 86.8 %

Procedure:
According to Reference Example 8-2, by use of 1-methyl-2-imidazolecarboxaldehyde (100 mg, 0.908 mmol), potassium carbonate (25.1 mg, 0.182 mmol), (trifluoromethyl)trimethylsilane (201 μL, 1.36 mmol) and N,N-dimethylformamide (2.0 mL), the mixture was stirred and reacted at room temperature for 2 hours. Then, slurry purification was performed using diisopropyl ether, to give 1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)imidazole (Compound DI) (142 mg, yield: 87%).