Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]=[C:7]=[S:8])=O)C.C(O[C:12]([C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH3:29])[N:22]=1)=[O:13])C.CC[O-].[Na+].C(O)C>C(Cl)Cl>[CH2:28]([O:27][C:23]1[N:22]=[C:21]([CH2:20][N:19]2[C:18]3[CH:17]=[CH:16][NH:15][C:14]=3[C:12](=[O:13])[NH:6][C:7]2=[S:8])[CH:26]=[CH:25][CH:24]=1)[CH3:29]
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1[nH]ccc1NCc1cccc(OCC)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOc1cccc(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)n1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 15.3 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.12 g, 0.90 mmol) was added to 3-[(6-ethoxy-pyridin-2-ylmethyl)-amino]-1H-pyrrole-2-carboxylic acid ethyl ester (0.24 g, 0.82 mmol) in CH2Cl2 (5 mL) and the solution was stirred at ambient temperature for 35 minutes. The solvent was evaporated and 0.4M NaOEt in ethanol (3 mL, 1.2 mmol) was added to the residue and the mixture was refluxed for 1 h. More NaOEt (0.4M in ethanol, 1.5 mL, 0.6 mmol) was added and the solution was refluxed for another 1.5 h. The solvent was evaporated, the residue was dissolved in water and the pH adjusted to neutral pH with 1M HCl. The resulting solid was collected, washed, and dried to give crude product. This material was purified by preparative HPLC to yield the title compound (38 mg, 15%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16]C)=[O:15])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:18].[OH-].[Na+].Cl>C(O)C>[C:14]([C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH2:4][C:3]3[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:2]=3[Cl:1])=[C:6]([CH3:18])[NH:7]2)=[CH:12][CH:11]=1)([OH:16])=[O:15]
Reactant: COC(=O)c1ccc2c(Cc3ccc(Cl)cc3Cl)c(C)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1[nH]c2cc(C(=O)O)ccc2c1Cc1ccc(Cl)cc1Cl
Yield: 96.3 %

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-6-(methoxycarbonyl)-2-methylindole (0.330 g), ethanol (15 ml) and 10% aqueous sodium hydroxide (10 ml) is heated under reflux for 1.5 hours. This is processed with hydrochloric acid to have a pH of 3, and the crystal formed is taken out through filtration. This is dried to obtain 6-carboxy-3-(2,4-dichlorobenzyl)-2-methylindole (73) (0.305 g).
Reaction SMILES: Cl.Cl.[CH:3]1([NH2+:9][C:10]2[C:14]3([CH2:19][CH2:18][NH2+:17][CH2:16][CH2:15]3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[N:34][CH:35]=1.N1C(C)=CC=CC=1C.[Li+].[Br-].C1COCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:3]1([NH:9][C:10]2[C:14]3([CH2:15][CH2:16][N:17]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])=[N:34][CH:35]=4)[CH2:18][CH2:19]3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[C:12](=[O:27])[N:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C1N=C([NH2+]C2CCCCC2)C2(CC[NH2+]CC2)N1c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCC3(CC2)C(NC2CCCCC2)=NC(=O)N3c2cccc(F)c2)cn1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of 188 mg (0.45 mmol) 4-(cyclohexylammonio)-1-(3-fluorophenyl)-2-oxo-1,3-diaza-8-azoniaspiro[4.5]dec-3-ene dihydrochloride (5-2) and 136 mg (0.473 mmol) tert-butyl 5-(bromomethyl)pyridin-2-ylcarbamate (prepared in a manner similar to that described in PCT application WO 00/0665570, substituting Methanesulfonicanhydredl/lutidine/LiBr/THF 0-55° C. in the bromination step) in 2.5 mL DMF was added 399 mg (2.89 mmol) granular potassium carbonate and the mixture stirred vigorously at 55° C. overnight. The reaction mixture was treated with 30 mL H2O and extracted with EtOAc (3×25 mL). The combined extracts were washed with H2O (1×20 mL), brine (1×20 mL), dried over Na2SO4, filtered, and concentrated to dryness in vacuo to give a crude oily solid (390 mg). Purification by automated flash chromatography (0-6% MeOH in CH2Cl2 over 20 m) afforded tert-butyl 5-{[4-(cyclohexylamino)-1-(3-fluorophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-en-8-yl]methyl}pyridin-2-ylcarbamate as a white solid. 1H NMR (DMSO, 400 MHz): δ 9.67 (s, 1H), 8.09 (d, J=7.78 Hz, 1H), 7.97 (s, 1H), 7.69 (d, J=8.42 Hz 1H), 7.46 (dd, J=8.52, 2.10 Hz 1H), 7.36 (m, 1H), 7.14 (m, 2H), 7.07 (d, J=8.15 Hz 1H), 3.68 (m, 1H), 3.22 (s, 2H), 2.53 (m, 2H), 2.09 (m, 2H), 1.82 (m, 4H), 1.73 (m, 1H), 1.61 (m, 1H), 1.47 (s, 9H), 1.29 (m, 5H), 1.12 (m, 1H). High resolution mass spec (FT/ICR): calc M+H=551.3141. found 551.3157
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[C:15]2=[O:31])=[CH:9][C:8]=1[CH3:32])(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51]Br)=[CH:49][CH:48]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C=O)C>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]([C:10]2[CH:9]=[C:8]([CH3:32])[C:7]([OH:6])=[C:12]([CH3:13])[CH:11]=2)([CH2:51][C:50]2[CH:53]=[CH:54][C:47]([O:46][CH3:45])=[CH:48][CH:49]=2)[C:15]1=[O:31]
Reactant: Cc1cc(C2C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1ccc(CC2(c3cc(C)c(O)c(C)c3)C(=O)N(Cc3ccccc3Cl)c3ccccc32)cc1
Yield: 63.5 %

Procedure:
Using a method similar to Example 37, with 3-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1-(2-chloro-benzyl)-1,3-dihydro-indol-2-one (333 mg, 0.68 mmol), a 0.5M solution of potassium bis(trimethylsilyl)amide (1.38 mL, 0.69 mmol), and (4-methoxybenzyl bromide (0.094 mL, 0.69 mmol) in DMF (8 mL) followed by treatment with TBAF (0.75 mL, 0.75 mmol) gives a crude brown oil. Purify by flash chromatography (gradient of 50% hexanes/CH2Cl2 to CH2Cl2) to give material which still contains a second entity. Chromatograph again (step gradient of 5% EtOAc/hexanes, 20% EtOAc/hexanes, 33% EtOAc/hexanes) to give 215 mg (63%) of the title compound. MS (ES): m/z=498 (M+1), 496 (M−1); 1H NMR(DMSO-d6): δ8.26 (s, 1H), 7.55 (m, 1H), 7.54 (dd, J=0.9 Hz, J=8.0 Hz, 1H), 7.24 (m, 1H), 7.14 (m, 2H), 7.00 (m, 3H), 6.90 (m, 1H), 6.75 (dd, J=2.2 Hz, J=8.0 Hz, 1H), 6.52 (m, 2H), 6.40 (m, 1H), 5.76 (d, J=6.3 Hz, 1H), 4.79 (abq, J=17.2, 2H), 3.59 (q, J=12.9, 2H), 3.46 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>>[C:25]([O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:22]([CH3:24])[CH3:23])(=[O:27])[CH3:26]
Reactant: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Reactant: CC(=O)Cl
Product: CC(=O)Oc1ccc(C)cc1[C@H](CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
A solution of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol (0.9 g) in acetylchloride (20 ml) is stirred at room temperature for 18 h. The acetyl chloride is evaporated, ether is added, and the precipitate of 2-(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl acetate hydrochloride is filtered off; mp 126-130° C. Anal Calcd for C24H33NO2.HCl: C, 71.35; H, 8.48; Cl, 8.78; N, 3.47. Found: C, 71.02; H, 8.30; Cl, 8.64; N, 3.43. [α]D (c=1, MeOH) +11°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:13]=[C:12]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:11]=1>CN(C)C=O.O>[Br:1][C:2]1[NH:3][CH2:4][N:5]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]=[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:11]=2)[CH:6]=1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: Brc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: BrC1=CN(c2nc(N3CCOCC3)nc(N3CCOCC3)n2)CN1
Temperature: 120 °C

Procedure:
To a cooled solution of 4-bromo-1H-imidazole (0.249 g, 2.0 mmol) in anhydrous dimethylformamide (4 ml) was slowly added sodium hydride (60% dispersion in mineral oil) (0.088 g, 2.2 mmol). When the evolution of gas has ceased (30 mins), 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (3b)(0.571 g, 2.00 mmol) was added in a single portion and the resulting mixture heated in a microwave reactor at 120° C. for exactly 14 minutes (fixed temperature holdtime, high absorbtion setting). The resulting brown/yellow slurry was diluted with water (10 ml) and filtered. The filter cake was washed with cold water (2×10 ml) and then dried in a vacuum dessicator to give the title compound in suitably pure form to be used without further purification. m/z (LC-MS, ESP): 396 [M+H]+, R/T=3.61 mins.
Reaction SMILES: [CH2:1]([P:8]([NH:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])(CC1C=CC=CC=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:45])[NH2:44].[H][H]>CO.O.[C].[Pd]>[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45].[NH2:37][C@H:38]([C:46]([OH:48])=[O:47])[CH2:39][CH2:40][CH2:41][NH:42][C:43](=[NH:44])[NH2:45].[CH2:1]([P:8](=[N:17][C@H:18]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@H:23]1[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([OH:30])=[O:29])=[O:25])=[O:21])[CH3:19])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: C[C@H](NP(=O)(Cc1ccccc1)Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: [Pd]
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Solvent: O
Solvent: CO
Product: C[C@H](N=[P+]([O-])Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Yield: 103.6 %

Procedure:
Dibenzylphosphoryl-L-alanyl-L-prolyl-L-proline (1 g, 1.84 mmole) and L-arginine (0.64 g, 3.67 mmol) were dissolved in a mixture (20 ml) of methanol and water (1:1, v/v) and 5% palladium carbon (0.1 g) was added thereto. Hydrogen gas (41.2 ml, 1.84 mmol) was adsorbed by the solution while stirring. The catalyst was removed by filtration, and the solvent was distilled off under reduced pressure. Water was added thereto and the water solution was freeze-dried to obtain monobenzylphosphoryl-L-alanyl-L-prolyl-L-proline di-L-arginine salt (1.46 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37][CH2:38]Br>CN(C)C=O>[Br:35][CH2:36][CH2:37][CH2:38][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=1
Reactant: BrCCCBr
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCCBr)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
N-{2-chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy)phenyl]-N′-propylurea 500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(3-bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[6-(3-Bromopropoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (50 mg), potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][CH2:16][CH2:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.BrBr.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]3[CH2:15][CH2:16][CH2:17][C:18]4[S:22][C:21]([CH3:23])=[CH:20][C:19]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc2c(s1)CCCC1CC(=O)N(c3ccc(Cl)cc3)N=C21
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(s1)CCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Yield: 35.5 %

Procedure:
To a solution of 3.6 g of 2-(4-chlorophenyl)-9-methyl-2,4,4a,5,6,7-hexahydro-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one in 30 ml of acetic acid is added 0.6 ml of bromine at 40° C. with stirring and the reaction mixture is stirred at 40-45° C. for 30 minutes. The mixture is poured into water and the resultant oil is collected by decantation. The crude product is subjected to column chromatography on silica gel and eluted with chloroform to give 1.27 g of 2-(4-chlorophenyl)-2,5,6,7-tetrahydro-9-methyl-3H-thieno[2',3':6,7]cyclohepta[1,2-c]pyridazin-3-one, melting at 149.5°-151° C.
Reaction SMILES: [N+:1]([C:4]1[CH:42]=[CH:41][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]3[C:17](=[O:35])[CH2:18][C:19]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[O:20][C:15]=3[C:14]=2[CH2:38][CH2:39][CH3:40])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC(OCCCOC2C=CC3C(=O)CC(CCC(OCC)=O)(CCC(OCC)=O)OC=3C=2CCC)=CC=1>C(OCC)(=O)C.CCCCCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:37]=[CH:36][C:16]3[C:17](=[O:35])[CH2:18][C:19]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:38][CH2:39][CH3:40])=[CH:41][CH:42]=1)([O-:3])=[O:2]
Reactant: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Agent: CCCc1c(OCCCOc2ccc(Cl)cc2)ccc2c1OC(CCC(=O)OCC)(CCC(=O)OCC)CC2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc([N+](=O)[O-])cc2)ccc2c1OC(CCC(=O)O)(CCC(=O)O)CC2=O
Yield: 46.2 %

Procedure:
The title compound was prepared by the method of Example 22 substituting the title product of Example 38 (110 mg) for the title product of Example 21. Trituration with ethyl acetate/hexane produced 46 mg of the titled compound as a solid, m.p. 171°-172° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([CH:11]=[O:12])[CH:3]=1.C(Cl)Cl.[CH3:16][CH2:17][O:18]C(C)=O>>[O:12]1[CH2:16][CH2:17][O:18][CH:11]1[C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(C)=O
Reactant: Cc1cc(C=O)ncc1[N+](=O)[O-]
Solvent: ClCCl
Product: Cc1cc(C2OCCO2)ncc1[N+](=O)[O-]

Procedure:
2-(1,3-Dioxolanyl)-4-methyl-5-nitropyridine was synthesized by the method of Example XLIX except that the starting material was 4-methyl-5-nitropyridine-2-carboxaldehyde. Yield: 2.3 g (91%); mp 77°-79° C.; (lit mp 77° C.); TLC, Rf 0.74 (CH2Cl2 /EtOAc, 3:2, v/v); 1H NMR (90 MHz, CDCl3) δ 2.65 (s, 3H, 4-CH3), 4.10 (s, 4H, CH2CH2), 5.85 (s, 1H, 2-CH), 7.50 (s, 1H, 3-H), 9.12 (s, 1H, 6-H). Anal. (C9H10N2O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[N+:7]([O-])[CH:8]=[CH:9][C:10]=1[N+]([O-])=O.P(Cl)(Cl)[Cl:20]>C(Cl)(Cl)Cl>[Cl:20][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[O:4][C:3]1[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccccc1Cl
Reactant: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Clc1ccccc1Oc1cnccc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4.9 g of 3-(o-chlorophenoxy)-4-nitropyridine N-oxide in 200 ml of chloroform is cooled to -5° C. and a large excess of phosphorous trichloride is added. The mixture is stirred 1 hour at 0° C. and slowly warmed to 25° C. The solution is refluxed 1 hour, cooled, concentrated at reduced pressure and dissolved in 100 ml of dichloromethane. The solution is washed with 50 ml of ice-cold concentrated ammonium hydroxide. The solution is dried over anhydrous MgSO4, filtered, concentrated at reduced pressure and distilled to yield 4-chloro-3-(o-chlorophenoxy)pyridine; bp 103°-105° C. at 0.1 mm.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(N(CC)CC)C>C(Cl)Cl>[CH:19]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:18]
Reactant: CCOC(=O)COCCCCCO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)COCCCCC=O
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a solution of dimethylsulphoxide (18.6 ml, 263 mmol) in 75 ml of CH2Cl2 at -60° C. under nitrogen, is added dropwise a solution of trifluoroacetic anhydride (27.8 ml, 197 mmol) in 75 ml of CH2Cl2, over about 15 minutes. The reaction mixture is stirred for a further 15 minutes at -60° C. and the hydroxy/ester (1) (25 g, 132 mmol) in 150 ml CH2Cl2 is then added at such a rate as to keep the reaction temperature below -60° C. (over about 30 minutes). After a further 15 minutes at this temperature, triethylamine (55 ml, 395 mmol) is added slowly over about 15 minutes, the reaction mixture is allowed to warm to ambient temperature (about 1.5 hours) and is then quenched with water. The product is isolated by extraction with dichloromethane and purified by chromatography on Florisil to provide the title compound as an oil (20.7 g, 84%), νmax (film) 1750, 1725, 1195, 1130 cm-1.
Reaction SMILES: [C:1]([C:5]1[C:13]2[O:12][CH2:11][C:10]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:20]([O:22][C:23](=[O:31])[C:24]1[CH:29]=[CH:28][C:27]([N:16]([CH:17]([CH3:19])[CH3:18])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]3[O:12][CH2:11][C:10]([CH3:14])([CH3:15])[C:9]=3[CH:8]=2)=[CH:26][CH:25]=1)[CH3:21]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC(C)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N(c2cc(C(C)(C)C)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Yield: 15.3 %

Procedure:
Following general procedure E and using 7-t-butyl-3,3-dimethyl-5-(isopropyl)amino-2,3-dihydro-benzofuran (Compound 36, 0.63 g, 2.4 mmol), ethyl-4-iodo-benzoate (0.62 3 g, 2.9 mmol), cesium carbonate (1.12 g, 3.4 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.025 g, 0.025 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.050 g, 0.079 mmol) in 10 mL of anhydrous toluene, the title compound (0.15 g) contaminated with 67% of 7-t-butyl-3,3-dimethyl-5-(isopropyl)amino-2,3-dihydro-benzofuran (Compound 36) was obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:18])=[N:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)=[N:7]2.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:19]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[C:4]([OH:18])=[N:5][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[N:7]3)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1nc(-c2cncnc2)nc2cccc(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Oc1nc(-c2cncnc2)nc2cccc(-c3ccccc3)c12
Temperature: 90 °C
Reaction time: 24 h
Yield: 40.4 %

Procedure:
A stirred suspension of 5-bromo-2-(pyrimidin-5-yl)quinazolin-4-ol (2.0 g, 6.6 mmol), phenylboronic acid (1.2 g, 9.9 mmol) and a solution of potassium carbonate (2.6 g, 19.8 mmol) in dimethoxyethane and water (3:1, 15 mL) was degassed and charged with 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (0.24 g, 0.33 mmol). The reaction mixture was heated to 90° C. where it stirred for 24 h under nitrogen atmosphere. At the conclusion of this period, the reaction mixture was concentrated to yield the crude product. The crude product was purified by flash column chromatography on silica gel using 2% methanol in dichloromethane as eluent to yield 5-phenyl-2-(pyrimidin-5-yl)quinazolin-4-ol (800 mg, 27% yield). 1H NMR (400 MHz, DMSO-d6, δ): 7.29-7.40 (m, 6H); 7.79-7.87 (m, 4H); 9.37 (s, 1H); 9.45 (s, 2H); 12.59 (br s, 1H). LCMS Method O: retention time 1.68 min, [M+1]=301.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:9])[C@@H:4]([CH3:8])[C:5]([OH:7])=[O:6].[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=3)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(N(CCCC)CCCC)CCC.[I-].ClC1C=CC=C[N+]=1C>O1CCCC1>[CH2:10]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][C:34]3[CH:39]=[CH:38][C:37]([O:6][C:5](=[O:7])[C@H:4]([CH3:8])[C@@H:3]([O:2][CH3:1])[CH3:9])=[CH:36][CH:35]=3)=[O:32])=[CH:29][CH:30]=2)=[CH:21][CH:20]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(O)cc3)cc2)cc1
Reactant: CO[C@@H](C)[C@@H](C)C(=O)O
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCCCN(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(OC(=O)[C@H](C)[C@H](C)OC)cc3)cc2)cc1

Procedure:
(2R, 3S)-3-methoxy-2-methylbutyric acid prepared in the above i) (0.79 g), 4-hydroxyphenyl 4'-octyloxy-4-biphenylcarboxylate (2.5 g) and tributylamine (2.66 g) were dissolved in dehydrated tetrahydrofuran (40 ml) and 2-chloro-1-methylpyridinium iodide (1.84 g) was added thereto. The mixture was heated under reflux for 7 hours. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography [eluent:chloroform:n-hexane (4:1)] and recrystallized from ethanol to obtain the title compound (0.36 g).