Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])(=O)C.[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15]Br.[OH-].[K+]>C(O)C>[Br:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: CC(=O)Nc1ccccc1O
Reactant: BrCc1ccccc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccccc1OCc1ccccc1Br

Procedure:
To a 500 mL, 3-neck round-bottomed flask equipped with a mechanical stiffer, a condenser and a thermometer was charged 23.6 grains (0.156 mol) of 2-Acetamidophenol in 300 mL of ethanol (200 proof). 41.02 grams (0.164 mol) of 2-Bromobenzyl bromide was added, followed by the addition of 21.24 grains (1.09 molar equivalents) of potassium hydroxide (“KOH”) in a 45% aqueous solution which formed a clear reaction solution. The reaction solution was heated to reflux for several hours until the starting materials were consumed. Additional KOH (6.0 molar equivalents) was then added and the reaction mixture was further heated for several hours to form 2-(o-Bromobenzyloxy) aniline. The reaction mixture was cooled and about 3/4 of the ethanol was removed under vacuum at 30-40° C. Methyl-tert-butyl ether (“MTBE”) (200 mL) and water (300 mL) was added, the resulting layers were mixed and the lower aqueous layer was separated from the product-rich MTBE layer. The water layer was washed with MTBE (100 mL) and the MTBE layers were combined. The combined MTBE layers were washed with water (150 mL). Then, to the MTBE layers was added slowly 17.4 grams of HCl (1.0 molar equivalent) in a 37% aqueous solution to crystallize the product. The resulting crystal slurry was cooled to 0° C. and stirred for 1 hour. The crystals were filtered and washed with 30 mL of ice-cold ethanol and twice with 30 mL portions of ice-cold MTBE. The crystals were dried under nitrogen and vacuum to yield 41.5 grams (84% yield by weight) of 2-(o-Bromobenzyloxy) aniline HCl salt in 99.02% purity.
Reaction SMILES: C[O:2][C:3](=[O:41])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][C:34]([C:37](=[O:39])[CH3:38])=[C:33]([OH:40])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[C:37]([C:34]1[CH:35]=[CH:36][C:29]2[O:28][C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:14]=[CH:13][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:41])=[O:2])(=[O:10])=[O:11])=[CH:17][CH:16]=4)=[CH:23][CH:22]=3)=[O:26])=[C:31]([CH3:32])[C:30]=2[C:33]=1[OH:40])(=[O:39])[CH3:38]
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4ccc(C(C)=O)c(O)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1ccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c2c1O
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.8 %

Procedure:
To (S)-2-{4′-[(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester (15 mg) was added 0.5 mL of THF and 2 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and 2 mL of water was added. The aqueous solution was acidified and the resulting solid was collected through filtration to give 7 mg of (S)-2-{4′-[(5-acetyl-4-hydroxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.4, 6.8 Hz, 6 H) 1.9 (m, 1 H) 2.7 (s, 3 H) 2.8 (s, 3 H) 3.6 (dd, J=9.3, 6.1 Hz, 1 H) 7.3 (d, J=9.1 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (dd, J=9.1, 3.8 Hz, 2 H) 10.5 (s, 1 H) 13.7 (s, 1 H).
Reaction SMILES: C([NH+](CC)CC)C.[N:8]([C@@H:11]1[C@@H:15]([CH2:16][P:17]([OH:20])(=[O:19])[OH:18])[O:14][C@@H:13]([N:21]2[CH:29]=[C:27]([CH3:28])[C:25](=[O:26])[NH:24][C:22]2=[O:23])[CH2:12]1)=[N+:9]=[N-:10].C(N1C=CN=C1)(N1C=CN=C1)=O.C([NH+](CCCC)CCCC)CCC.[O-:55][P:56]([NH:59][P:60]([O-])([O-:62])=[O:61])(=[O:58])[O-:57]>CN(P(N(C)C)(N(C)C)=O)C.O.CO>[CH3:28][C:27]1[C:25](=[O:26])[NH:24][C:22](=[O:23])[N:21]([C@@H:13]2[O:14][C@H:15]([CH2:16][P:17]([O:18][P:60]([OH:62])([NH:59][P:56]([OH:58])([OH:57])=[O:55])=[O:61])([OH:20])=[O:19])[C@@H:11]([N:8]=[N+:9]=[N-:10])[CH2:12]2)[CH:29]=1
Reactant: O=P([O-])([O-])NP(=O)([O-])[O-]
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CP(=O)(O)O)O2)c(=O)[nH]c1=O
Agent: CCCC[NH+](CCCC)CCCC
Agent: CC[NH+](CC)CC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CP(=O)(O)OP(=O)(O)NP(=O)(O)O)O2)c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 69.4 %

Procedure:
The triethylammonium salt of compound 53 (50.0 mg, 0.09 mmol) was dissolved in HMPA (2 mL) and 1,1′-carbonyldiimidazole (106 mg, 0.66 mmol) was added at room temperature and stirred for 2 h. Methanol (35 μL) was added and stirring was continued for 45 min. The tri-n-butylammonium salt of imidodiphosphate (427 mg, 0.46 mmol) dissolved in HMPA (2 mL) was added with syringe to the solution of activated AZT monophosphate, and the combined solution was stirred at room temperature for 4 h. The reaction mixture was cooled in ice-bath and water (5 mL) was added. Purification by HPLC gave 30.6 mg of the titled compound 57.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[C:15]#[N:16])[C:4](=[O:17])[C:3]=1[C:18]#[N:19].[Br:20]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:20][C:7]1[C:2]([Cl:1])=[C:3]([C:18]#[N:19])[C:4](=[O:17])[N:5]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[C:15]#[N:16])[CH:6]=1
Reactant: N#Cc1cccc(F)c1-n1ccc(Cl)c(C#N)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(F)c1-n1cc(Br)c(Cl)c(C#N)c1=O
Temperature: 50 °C
Yield: 21.3 %

Procedure:
To a solution of 4-chloro-1-(2-cyano-6-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step E (4.0 g) in N,N-dimethylformamide (40 mL) was added N-bromosuccinimide (3.90 g) at room temperature. The reaction mixture was heated at 50° C. for 16 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.10 g).
Reaction SMILES: CCN(CC)CC.C(OC([N:15]1[CH2:19][C:18]([F:21])([F:20])[C:17]([CH3:23])([CH3:22])[C@H:16]1[C:24]([OH:26])=O)=O)(C)(C)C.[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C>[F:27][C:28]([F:32])([F:31])[CH2:29][NH:30][C:24]([C@@H:16]1[C:17]([CH3:22])([CH3:23])[C:18]([F:20])([F:21])[CH2:19][NH:15]1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C(C)(C)[C@H]1C(=O)O
Reactant: NCC(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H](C(=O)NCC(F)(F)F)NCC1(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 107 %

Procedure:
NEt3 (75.2 g, 743 mmol) was slowly added to a 10° C. solution of (2S)-4,4-difluoro-3,3-dimethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (98.3 g, 352 mmol), chlorodiphenylphosphate (101 g, 376 mmol), and ethyl acetate (1.0 L). The mixture was warmed to ambient temperature for 45 min., and was then cooled to 10° C. 2,2,2-Trifluoroethylamine (39.5 g, 399 mmol) was slowly added and the resultant mixture was stirred at ambient temperature for 2.75 h. 20% Aqueous citric acid (1.0 L) was added and the resulting layers were separated. The aqueous fraction was extracted with ethyl acetate (2×300 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (2×500 mL), and then with saturated aqueous NaCl (300 mL). The resulting organic fraction was concentrated to a weight of 900 g using a rotary evaporator. A 3 N HCl/ethyl acetate solution (500 mL) was added to the concentrate, and the mixture was stirred at ambient temperature for 24 h. The resulting solid was filtered, washed with ethyl acetate (100 mL), and was then dried in a vacuum oven at 55° C. to provide 98.0 g (93.9%) of (2S)-4,4-difluoro-3,3-dimethyl-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide; hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.46 (br s, 2H), 9.50 (t, J=6.2Hz, 1H), 4.17–4.33 (m, 2H), 3.68–4.02 (m, 3H), 1.23 (app d, J=2.1 Hz, 3H), 0.97 (app d, J=2.0 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 165.6, 127.9 (dd, JCF=250.2, 257.2 Hz), 125.6 (q, JCF=279.0 Hz), 64.8, 48.2 (t, JCF=33.4 Hz), 45.7 (t, JCF=21.2 Hz), 18.2 (d, JCF=7.5Hz), 17.2 (app dd, JCF=2.3, 5.8 Hz); MS (CI) m/z 261.1015 (261.1026 calcd for C9H14N2OF5, M−HCl+H+).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:32])[CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@H:12]1[C:16](=[O:17])[CH2:15][CH2:14][C@@H:13]1[C:18]1[CH:23]=[CH:22][C:21]([CH:24]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[OH:25])=[CH:20][CH:19]=1.Cl>C1COCC1>[CH:26]1([CH:24]([OH:25])[C:21]2[CH:20]=[CH:19][C:18]([C@H:13]3[CH2:14][CH2:15][C:16](=[O:17])[C@@H:12]3[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:5]([OH:32])=[O:4])=[CH:23][CH:22]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)CCC/C=C\C[C@H]1C(=O)CC[C@@H]1c1ccc(C(O)C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC/C=C\C[C@H]1C(=O)CC[C@@H]1c1ccc(C(O)C2CCCCC2)cc1
Reaction time: 8 h
Yield: 102.9 %

Procedure:
LiOH (1 mL, 1 mmol, 1 M) was added to a solution of 4 (43 mg, 0.10 mmol) in THF (5.5 mL). The mixture was stirred overnight and then 1 M HCl was added. The resulting mixture was extracted with dichloromethane (3×25 mL) and the combined organic solution was dried (Na2SO4), filtered and evaporated. Flash chromatography on silica gel (3% methanol/dichloromethane) gave 5 (41 mg, 100%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][N:27]([CH2:29][CH2:30][CH2:31][NH2:32])[CH3:28]>O1CCOCC1>[CH3:26][N:27]([CH3:28])[CH2:29][CH2:30][CH2:31][NH:32][C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CN(C)CCCN
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)nc3ccccc23)CC1
Solvent: C1COCCO1
Product: CN(C)CCCNc1nc(NC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2n1

Procedure:
tert-Butyl 4-(2-chloroquinazolin-4-ylamino)piperidine-1-carboxylate (3.34 g. 9.21 mmol) and 3-(N,N-dimethyl amino)propylamine (2.9 ml, 23.03 mmol) in dioxane (15 ml) in a sealed-tube were heated to 120° C. overnight. The solvent was removed and the crude product was purified by silica gel column chromatography using 10% NH3 ca. 7 N MeOH in CH2Cl2 and 90% CH2Cl2 solution as eluent to produce the title compound as a pure white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([SH:18])[NH:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:5])C.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:27][CH2:28][N:29]([CH3:31])[CH3:30].[OH-].[Na+]>CCO>[CH3:30][N:29]([CH3:31])[CH2:28][CH2:27][S:18][C:8]1[NH:9][C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[C:6]([C:4]([OH:3])=[O:5])[N:7]=1
Reactant: CCOC(=O)c1nc(S)[nH]c1-c1ccc(F)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN(C)CCSc1nc(C(=O)O)c(-c2ccc(F)cc2)[nH]1
Temperature: 50 °C
Reaction time: 48 h
Yield: 33.2 %

Procedure:
5-(4-Fluoro-phenyl)-2-mercapto-1H-imidazole-4-carboxylic acid ethyl ester (3 g, 11.28 mmol) was dissolved in EtOH (30 mL) at RT. K2CO3 (6.23 g, 45 mmol) and (2-chloro-ethyl)-dimethyl-amine HCl salt (1.54 g, 10.72 mmol) were added. The mixture was stirred at 50° C. for 48 h. It was then concentrated and the residue was dissolved in THF/water (20 mL each) at RT. NaOH (2 g, 50 mmol) was added. The mixture was stirred at RT for 12 h. It was then concentrated to remove most THF and the pH of the solution was adjusted to ˜5 using 3 N HCl. The mixture was concentrated and residue was purified by prep HPLC. Lyophilization of pure fractions afforded 1.1 g pure 2-(2-dimethylamino-ethylthio)-5-(4-fluorophenyl)-1H-imidazole-4-carboxylic acid, S-81. LC-MS [M+H] 310.2.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]([C:30]2[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=2)[CH:27]=[CH:28][CH:29]=1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][O:23][C:24]3[CH:25]=[C:26]([C:30]4[CH2:31][CH2:32][C:33](=[O:36])[NH:34][N:35]=4)[CH:27]=[CH:28][CH:29]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCOc1cccc(C2=NNC(=O)CC2)c1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=C1CCC(c2cccc(OCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][O:9][CH2:10][CH2:11][OH:12])[CH:2]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[N:8][O:9][CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[NH:21][C:20]3=[O:44])=[CH:16][CH:15]=2)[CH:2]=1
Reactant: OCCON=Cc1cccnc1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: O=C1NC(=O)C(Cc2ccc(OCCON=Cc3cccnc3)cc2)S1
Yield: 85.9 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 0.90 g of 2-(3-pyridylmethyleneaminooxy) ethanol (prepared as described in Preparation 5), 2.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 1.32 ml of tributylphosphine and 1.23 g of 1,1'-(azodicarbonyl)dipiperazine, 1.37 g of the title compound were obtained as a crystalline powder, melting at 155°-157° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:29])[NH:25][C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[CH2:31]=[O:32]>C(#N)C.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:30])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:29])[N:25]([CH2:31][OH:32])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1
Reactant: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)N1
Reactant: C=O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (500 mg, 1.17 mmol) in acetonitrile (15 mL) and pyridine (1.5 mL) was added formaldehyde (37% aq) (5.0 mL). The reaction mixture was stirred at 65° C. for 5 minutes. Cooled to room temperature and filtered off the resulting solid. Washed with water and dried under vacuum to provide 450 mg (84%) of (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione as a yellow solid. LCMS (ES): >95% pure, m/z 458 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:15][CH:16]([CH3:18])[CH3:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[O:25][C:26]=1[CH3:27]>>[CH:16]([O:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])[O:25][C:26]=1[CH3:27])[CH:10]=[CH:9]2)[C:3]([OH:2])=[O:19])([CH3:18])[CH3:17]
Reactant: COC(=O)C(Cc1ccc2[nH]ccc2c1)OC(C)C
Reactant: COc1ccccc1-c1nc(CCl)c(C)o1
Product: COc1ccccc1-c1nc(Cn2ccc3cc(CC(OC(C)C)C(=O)O)ccc32)c(C)o1

Procedure:
In analogy to the procedure described in example 44, rac-3-(1H-indol-5-yl)-2-isopropoxy-propionic acid methyl ester (preparation 8) was reacted with 4-chloromethyl-2-(2-methoxy-phenyl)-5-methyl-oxazole to give rac-2-isopropoxy-3-{1-[2-(2-methoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-5-yl}-propionic acid as colorless solid.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:14])[CH:6]=1)(=O)C.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1O>>[O:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:9]1[C:8]1[CH:12]=[CH:13][C:5]([NH2:4])=[CH:6][C:7]=1[CH3:14]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Reactant: Nc1ccccc1O
Product: Cc1cc(N)ccc1-c1nc2ccccc2o1
Temperature: 200 °C

Procedure:
To a suspension of 4-acetylamino-2-methyl-benzoic acid (2.0 g, 10.3 mmol) in PPA (˜85 g) was added aminophenol (1.2 g, 10.8 mmol). The reaction was heated to 200° C. for 2 h, then carefully quenched in aqueous sodium carbonate (˜50% saturated) at room temperature. Ethyl acetate was added, and the organic layer was washed with water and brine, and dried over sodium sulfate. The crude product was obtained as an orange oil and was subsequently purified by flash column chromatography on silica gel eluting with ethyl acetate in hexanes to afford the desired product, 4-benzooxazol-2-yl-3-methyl-phenylamine as a colorless solid, 290 mg (13%). 1H NMR (300 MHz, DMSO-d6): δ 7.84-7.81 (m, 1H), 7.64-7.62 (m, 2H), 7.32-7.27 (m, 2H), 6.51 (d, J=9.0 Hz, 2H), 5.83 (s, 2H), 2.61 (s, 3H). LC-MS m/z=225 [C14H12N2O+H]+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:44][CH:45]1[C@H:49]2[C@H:50](OC3CCCCO3)[N:51](C(OC(C)(C)C)=O)[C:52]3[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:53]=3[C:54](=[O:55])[N:48]2[CH2:47][CH2:46]1)[CH2:9][CH2:10][CH2:11][O:12][CH:13]1[C@H:17]2[C@H:18](OC3CCCCO3)[N:19](C(OC(C)(C)C)=O)[C:20]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=3[C:22](=[O:23])[N:16]2[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:44][CH:45]1[C@@H:49]2[CH:50]=[N:51][C:52]3[CH:59]=[C:58]([O:60][CH3:61])[CH:57]=[CH:56][C:53]=3[C:54](=[O:55])[N:48]2[CH2:47][CH2:46]1)[CH2:9][CH2:10][CH2:11][O:12][CH:13]1[C@@H:17]2[CH:18]=[N:19][C:20]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=3[C:22](=[O:23])[N:16]2[CH2:15][CH2:14]1
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)[C@@H](OC1CCCCO1)[C@@H]1C(OCCCCOC3CCN4C(=O)c5ccc(OC)cc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)CCN1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2c(c1)N=C[C@H]1C(OCCCCOC3CCN4C(=O)c5ccc(OC)cc5N=C[C@@H]34)CCN1C2=O
Reaction time: 1 h
Yield: 78.6 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 8b (134 mg, 0.14 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 9b (60 mg, 0.11 mmol, 78%) as a solid: [α]20D=+477° (c=0.09, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.88-2.06 (m, 8H, 2-H, 2′-H, 13-H, 13′-H), 2.16-2.36 (m, 4H, 1-H, 1′-H), 3.46-3.57 (m, 2H, 3-H, 3′-H), 3.63-3.69 (m, 2H, 11a-H, 11a′-H), 3.60-3.69 (m, 2H, 3-H, 3′-H), 3.82 (s, 6H, 7-OMe, 7′-OMe), 3.98-4.19 (m, 4H, 12-H, 12′-H), 6.72 (s, 2H, 9-H, 9′-H), 7.44 (s, 2H, 6-H, 6′-H), 7.59 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 29.65, 46.6, 53.7, 56.0, 68.6, 109.6, 112.6, 120.2, 140.6, 147.0, 151.7, 162.8, 164.6; IR (neat): 3354, 2950, 1622, 1600, 1506, 1447, 1387, 1262, 1216, 1092, 1026 cm−1;MS (FAB) m/z (relative intensity) 611 ([M+2×MeOH]+., 9), 579 ([M+MeOH]+., 19), 547 (M+., 100).
Reaction SMILES: [CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:22][CH:21]=2)[CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>CO>[CH:1]1([C:5]2[O:9][N:8]=[C:7]([C:10]3[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])[C:6]=2[CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[C:28]4[C:33](=[CH:34][CH:35]=3)[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29]4)=[CH:24][CH:25]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C4CCC4)cc3)ccc12
Temperature: 120 °C
Yield: 88.7 %

Procedure:
To a solution of methyl 6-[4-({[5-cyclobutyl-3-(2,6-dichlorophenyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (65 mg, 0.116 mmol) in a 2:1 mixture of tetrahydrofuran and methanol (1.5 mL) was added 1N sodium hydroxide (0.175 mL, 0.175 mmol). The solution was heated in a microwave reactor at 120° C. for 500 seconds. The solution was concentrated and water was added followed by 0.175 mL of 1N HCl. The solution was extracted twice with ethyl acetate. The combined organic phases were washed one time with brine and concentrated. Ether was added and the solution was again concentrated to dryness to afford the title compound as a white solid (56 mg, 89%). 1H-NMR (DMSO-d . 13.14 (s, 1H), 8.88 (d, J=9 Hz, 1H), 8.20-8.16 (m, 2H), 8.09 (d, J=9 Hz, 1H), 7.90 (d, J=9 Hz, 1H), 7.69-7.49 (m, 6H), 6.90 (d, J=9 Hz, 2H), 4.83 (s, 2H), 4.00 (quintet, J=9 Hz, 1H), 2.43-2.34 (m, 4H), 2.10-1.92 (m, 2H). HRMS C31H23Cl2NO4 m/z 544.10769 (M+H)+Cal; 544.10747 (M+H)+Obs.
Reaction SMILES: ClC1C=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)C=1.[CH2:12]([N:16]1[C:25](=[O:26])[C:24]2[N:23](CCC=C)[CH:22]=[N:21][C:20]=2[N:19]([CH2:31][CH2:32][CH2:33][CH3:34])[C:17]1=[O:18])[CH2:13][CH2:14][CH3:15]>C(Cl)(Cl)Cl>[CH2:12]([N:16]1[C:25](=[O:26])[C:24]2[N:23]([CH2:6][CH2:5][CH:4]3[O:10][CH2:8]3)[CH:22]=[N:21][C:20]=2[N:19]([CH2:31][CH2:32][CH2:33][CH3:34])[C:17]1=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: C=CCCn1cnc2c1c(=O)n(CCCC)c(=O)n2CCCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCCCn1c(=O)c2c(ncn2CCC2CO2)n(CCCC)c1=O

Procedure:
39.4 g of m-chloroperbenzoic acid (70% pure) were added to a solution of 42.7 g of 1,3-dibutyl-7-(3-butenyl)xanthine in 900 ml of chloroform within 15 minutes, with stirring. After stirring at room temperature for 27 hours, the mixture was washed with 10% strength sodium dithionite solution, saturated sodium bicarbonate solution and water, dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column with a mixture of methylene chloride/acetone (7:3, v:v) and recrystallized from petroleum ether.