Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH:8]([NH:13][C:14](=[O:39])[C@@H:15]([N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:24]1=[O:38])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:9](=[O:12])[CH2:10][F:11])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:30]([NH:29][C:25]1[C:24](=[O:38])[N:23]([C@@H:15]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([NH:13][CH:8]([C:9](=[O:12])[CH2:10][F:11])[CH2:7][C:6]([OH:40])=[O:5])=[O:39])[CH:28]=[CH:27][CH:26]=1)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(=O)CF
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC(NC(=O)[C@H](Cc1ccccc1)n1cccc(NC(=O)c2ccccc2)c1=O)C(=O)CF
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 3(R,S)-[2(S)-(3-benzoylamino-2-oxo-2H-pyridin-1-yl)-3-phenyl-propionylamino]-5-fluoro-4-oxo-pentanoic acid tert-butyl ester (776 mg, 1.41 mmol) in dichloromethane (6 mL) was cooled to 0° C. Trifluoroacetic acid (2 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 3 hours. The mixture was then concentrated under reduced pressure and the residue redissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The solid was then dried to constant weight under vacuum. This gave the title product as a pink solid (627 mg, 90%); 1H NMR (400 MHz, d6-DMSO) δ 2.59-2.95 (2H, m), 3.34-3.47 (2H, m), 4.30-4.81 (2H, m), 5.15-5.33 (2H, m), 5.87-6.09 (1H, m), 6.38 (1H, t), 7.15-7.32 (5H, m), 7.60-7.78 (4H, m), 7.92 (2H, d), 8.17-8.21 (1H, m), 9.01-9.11 (1H, m), 9.28 (1H, m), 12.51 (1H, br s); 19F NMR (376 MHz, d6-DMSO, proton-decoupled) δ−226.8, 232.6; M+H 494.4, M−H 492.4.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.CN.[N+:18]([C:21]1[CH:30]=[CH:29][C:24]([CH2:25][N:26]=[C:27]=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C:27]([N:2]([CH:3]2[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]2)[CH3:1])=[O:28])=[CH:29][CH:30]=1)([O-:20])=[O:19]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C=NCc1ccc([N+](=O)[O-])cc1
Agent: CN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)NCc1ccc([N+](=O)[O-])cc1)C1CCNCC1

Procedure:
The title compound was prepared by the reaction of 4-(N-methylamino)-1-tert-butoxycarbonylpiperidine (prepared by the method described in Example 1, Step A, using methylamine in place of ethylamine) with (4-nitrobenzyl)isocyanate (prepared from phosgene and (4-nitrobenzyl)amine), followed by treatment of the product with 50% TFA in CH2Cl2 to remove the tert-butoxycarbonyl group, affording the title compound. ESI-MS: 293.1 (M+H).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:27])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:17]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(CBr)cc1O[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of methyl 2-{[tert-butyl(dimethyl)silyl]oxy}-4-methylbenzoate (3.4 g) in carbon tetrachloride (68 mL) were added, and NBS (2.16 g) and AIBN (398 mg) were added thereto at room temperature, followed by stirring at 80° C. for 1 hour. Completion of the reaction was confirmed by means of TLC, and to the reaction liquid was added water to stop the reaction, followed by extraction with EtOAc. The organic layer was washed with brine, dried using MgSO4, and then concentrated under reduced pressure, followed by purification by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 95:5) to obtain methyl 4-(bromomethyl)-2-{[tert-butyl(dimethyl)silyl]oxy}benzoate (3.79 g) as a colorless liquid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClCCl.Cl.Cl.[N:16]1([C:22]([O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(Cl)(Cl)Cl>[C:1]1([S:7]([N:19]2[CH2:20][CH2:21][N:16]([C:22]([O:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[O:23])[CH2:17][CH2:18]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(Oc1cccnc1)N1CCNCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Oc1cccnc1)N1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (0.23 ml) and benzenesulfonyl chloride (0.075 ml) were added to a dichloromethane (5 ml) solution containing 3-pyridyl 1-piperazinecarboxylate dihydrochloride (150 mg), followed by stirring overnight at room temperature. The reaction solution was diluted with chloroform, the organic layer was washed with aqueous saturated sodium hydrogencarbonate solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: chloroform), and the resulting solid was recrystallized from 2-propanol to obtain 3-pyridyl 4-(phenylsulfonyl)-1-piperazinecarboxylate (130 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CCO>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(c2nc(Cl)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
To a solution of 2,4-dichloro-thieno[3,2-d]pyrimidine (0.20 g, 1.0 mmol) in EtOH (3.2 mL) was added K2CO3 (0.31 g, 2.2 mmol) followed by N-methylpiperazine (0.13 mL, 1.2 mmol). After stirring at rt for 12 h, the mixture was filtered to afford 0.23 g of the desired product. MS: 269.0. 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (d, J=5.6 Hz, 1H), 7.27 (d, J=5.6 Hz, 1H), 4.05-4.00 (m, 4H), 2.62-2.56 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)=[O:8].Br[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][C:35]=1[Cl:36])[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]3[CH2:30][CH2:29][CH:28]([NH:31][CH2:32][CH2:38][C:39]4[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CNC1CCN(C(=O)c2ccc(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(C(=O)N3CCC(NCCc4ccc(F)c(F)c4)CC3)cc2)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,4-dichloro-N-{6-[4-(4-methylamino-piperidine-1-carbonyl)phenoxy]pyridin-3-yl}benzamide dihydrochloride (114 mg, 0.2 mmol) was dissolved in DMF (3 mL). To the resulting solution were added 4-bromomethyl-1,2-difluorobenzene (31 μl, 0.24 mmol) and potassium carbonate (111 mg, 0.8 mmol), and this solution was stirred for 4 hours at room temperature. The resulting reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. This residue was purified by silica gel column chromatography (chloroform:methanol=50:1), to thereby yield 60 mg of the title compound.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]([NH:31][NH2:32])=[O:30])[CH:19]=[C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]=1[OH:22])([CH3:15])[CH3:14].Cl>C(OCC)(OCC)OCC.C(OCC)(=O)C>[CH3:15][C:13]([C:16]1[CH:17]=[C:18]([CH2:27][CH2:28][C:29]2[O:30][CH:1]=[N:32][N:31]=2)[CH:19]=[C:20]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:21]=1[OH:22])([CH3:12])[CH3:14]
Reactant: CC(C)(C)c1cc(CCC(=O)NN)cc(C(C)(C)C)c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOC(OCC)OCC
Product: CC(C)(C)c1cc(CCc2nnco2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 774.4 %

Procedure:
A catalytic amount of p-toluenesulfonic acid (25 mg) is added to a stirring solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenepropanoic acid hydrazide (0.50 g, 1.71 mmol) in triethyl orthoformate (10 mL). After 30 minutes, 10 mL of 1N hydrochloric acid is added, and stirring is continued for 30 minutes. The reaction mixture is diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate, twice with water, and once with brine. Drying the organic phase over magnesium sulfate and evaporation gives a crude product which is chromatographed on a column of silica with ethyl acetate/hexane (1/9 then 1/4) to afford 0.34 g (67%) of 2,6-bis(1,1-dimethylethyl)-4-[2-(1,3,4-oxadiazol-2-yl)ethyl]phenol, mp 100.0°-101.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:32])[C:5]([NH:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14]2)=[CH:6][C:7]=1[Cl:8].N[C:34](N)=[O:35].O>ClC(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([CH:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:17][CH2:18]3)[C:34](=[O:35])[NH:32][C:4]=2[CH:3]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)c(Cl)cc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 190 °C
Reaction time: 3 h

Procedure:
A mixture of 4 parts of 4,5-dichloro-N1 -{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,2-benzenediamine and 1.5 parts of urea is stirred for 3 hours in an oil-bath at 190° C. After cooling, water and trichloromethane are added. The layers are separated and the organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane, yielding 5,6-dichloro-1-{3-[4-(diphenylmethyl)-1-piperazinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one; mp. 214.7° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C(Cl)Cl.CO>[CH2:6]([O:5][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH2:17][Br:19])=[CH:14][CH:15]=1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: [Br-]
Reactant: CCOP(=O)(Cc1ccc(C(C)=O)cc1)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOP(=O)(Cc1ccc(C(=O)CBr)cc1)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a stirred solution of (4-acetylbenzyl)-phosphonic acid diethyl ester (2.56 g, 9.48 mmol) in DCM (100 ml) and MeOH (40 ml) at room temperature was added tetra-n-butylammonium tribromide (5.03 g, 10.43 mmol) followed by a drop of concentrated hydrochloric acid. The reaction mixture was stirred at room temperature for 18 h. The solvents were then removed under reduced pressure and the residue was partitioned between Et2O (100 ml) and sat. NaHCO3 (60 ml). The aqueous phase was separated and the organic phase was washed with brine (60 ml) and dried (Na2SO4). The solvent was removed under reduced pressure to give a pale yellow oil which was purified by flash chromatography (3:1 EtOAc/DCM) to give the title compound (2.01 g, 61%) as a colourless oil.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1C=C[C:7]([C:8](O)=O)=[CH:6][CH:5]=1.CCCC([O:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1Br)=[O:23])CC.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:3]([O:2][C:27]1[CH:26]=[CH:25][C:24]([C:22](=[O:23])[CH2:21][OH:20])=[CH:29][CH:28]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCCC(CC)OCC(=O)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(C(=O)CO)cc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 45 %

Procedure:
To a solution of terephthalic acid monomethyl ester (1.0 g, 5.6 mmol) and 4-hexyloxy-2′-bromoacetophenone (synthesized by following (2.0 g, 6.7 mmol) in DMF (10 mL) was added K2CO3 (0.77 g, 5.6 mmol) and heated at 60° C. After 10 h, the reaction mixture was cooled to room temperature and poured into water. The product was extracted using EtOAc, washed with brine, dried and concentrated. The crude residue was purified by combiflash to afford 1.0 g (45%) product. 1H NMR (500 MHz, CDCl3): δ 0.94 (t, 3H, J=7.0 Hz), 1.36-1.39 (m, 4H), 1.48-1.58 (m, 2H), 1.81-1.85 (m, 2H), 3.99 (s, 3H), 4.07 (t, 2H, J=6.5 Hz), 5.58 (s, 2H), 6.99 (d, 2H, J=9.0 Hz), 7.92 (d, 2H, J=9.0 Hz), 8.16 (d, 2H, J=9.0), 8.122 (d, 2H, J=9.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[NH:10][N:9]=2)=[C:4]([F:17])[CH:3]=1.S(OC)(O[CH3:22])(=O)=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([O:13][CH:14]([F:16])[F:15])[N:10]([CH3:22])[N:9]=2)=[C:4]([F:17])[CH:3]=1
Reactant: Fc1cc(Cl)ccc1-c1cc(OC(F)F)[nH]n1
Reactant: COS(=O)(=O)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: Cn1nc(-c2ccc(Cl)cc2F)cc1OC(F)F
Reaction time: 1 h
Yield: 92.5 %

Procedure:
11.6 g of the 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1H-pyrazole (purity 86%) obtained in step 1.2 were initially charged in 100 ml of toluene. 6.2 g of dimethyl sulfate were added dropwise, and the mixture was heated at reflux for 3 h. After cooling, 25 ml of saturated aqueous NH4Cl solution were added, the mixture was stirred for 1 h and the organic phase was separated off and washed with water until neutral. Drying over Na2SO4 and concentration gave 11.3 g of 3-(4-chloro-2-fluorophenyl)-5-difluoromethoxy-1-methyl-1H-pyrazole as an oil of a purity of 82.4% (GC). Yield: 88.6%
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.[C:13](OCC)(=[O:17])[CH2:14][CH2:15][CH3:16]>C1COCC1>[CH3:7][C:5]1[N:6]=[C:2]([CH2:1][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[S:3][CH:4]=1
Reactant: Cc1csc(C)n1
Reactant: CCCC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC(=O)Cc1nc(C)cs1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
3.00 g (26.5 mmol) of 2,4-dimethylthiazole are dissolved in 30 ml of abs. THF and, at −78° C., 11.7 ml (29.2 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for 2 hours, 5.23 g (45.1 mmol) of ethyl butyrate are added as solution in 15 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. The crude product is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 5:1). 3.0 g (62% of theory) of the title compound are obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=1[CH3:8].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:24]([C:23]1[CH:26]=[CH:27][C:20]([O:19][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]=2[CH3:8])=[CH:21][CH:22]=1)=[O:25]
Reactant: COC(=O)c1cccc(-c2nc(CCl)c(C)o2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2nc(COc3ccc(C=O)cc3)c(C)o2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
A mixture of methyl 3-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)benzoate (2.0 g), 4-hydroxybenzaldehyde (0.87 g), potassium carbonate (0.98 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 3-{4-[(4-formylphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate as colorless crystals (2.33 g, yield 94%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[N:16]([CH3:31])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([Cl:30])[N:18]=3)[C:10]([CH3:33])([CH3:32])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:19]1[N:18]=[C:17]2[C:22]([N:23]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3([CH3:33])[CH3:32])[N:16]2[CH3:31])=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=1
Reactant: Cn1c(CN2CCN(C(=O)OC(C)(C)C)CC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(CN2CCNCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Reaction time: 1 h

Procedure:
To a solution of 4-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (288 mg, 0.60 mmol) in DCM (30 mL) was added TFA (3 mL) and the mixture stirred at r.t for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording the title compound as a white solid (199 mg, 87%). 1H NMR (CDCl3, 400 MHz): δ 4.26 (4 H, brd s), 3.84-3.77 (9 H, m), 2.84 (2 H, t, J=4.87 Hz), 2.74 (2 H, s), 2.43 (2 H, t, J=4.89 Hz), 1.21 (6 H, s).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.N1C=CC=CC=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O>[C:24]([O:1][CH2:2][C:3]1([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:4][CH2:5][C:6](=[O:9])[CH2:7][CH2:8]1)(=[O:26])[CH3:25]
Reactant: COc1ccc(C2(CO)CCC(=O)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C2(COC(C)=O)CCC(=O)CC2)cc1
Reaction time: 20 h
Yield: 68 %

Procedure:
The 4-hydroxymethyl-4-(4-methoxyphenyl)cyclohexanone is dissolved in 12 ml. of pyridine and 6 ml. of acetic anhydride. After about 20 hours of standing at room temperature, the mixture is poured into ice and water. The gum that precipitates is extracted with ether. The organic layer is washed successively with water, 2.5 N hydrochloric acid, water, sodium bicarbonate solution and brine, and evaporated to dryness. The solid residue is recrystallized from a mixture of ether and Skellysolve B to give 2.95 g. (68% yield) of 4-acetoxymethyl-4-(4-methoxyphenyl)cyclohexanone, having a melting point of 86.5° to 88°C.
Reaction SMILES: [NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH2:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:30])=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.CN1CCOCC1.ClC(OCC(C)C)=O>CN(C=O)C>[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[NH:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:2]([C:8]([NH:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:30])=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1)=[O:10])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Agent: CC(C)(C)OC(=O)N[C@@H](CCC(N)=O)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)ccc12

Procedure:
Boc-Gln-AMC was prepared by coupling anhydrous Boc-Gln-OH (7.03 g, 28.5 mmol) to 7-amino-4-methylcoumarin (AMC) by the mixed anhydride coupling procedure outlined above. First, a solution of a mixed anhydride of Boc-Gln-OH was prepared by reacting Boc-Gln-OH with an equivalent of N-methylmorpholine and an equivalent of isobutyl chloroformate, and the resulting solution was added to AMC (5.00 g, 28.5 mmol) dissolved in 30 mL DMF. After the resulting reaction was complete, the reaction mixture was filtered and the filtrate concentrated. Product (5 g) was separated from the filtrate and dissolved in 75 mL hot methanol. This solution was then concentrated to about 30 mL and cooled. Solid AMC was separated from the solution by filtration, and the remaining filtrate was further concentrated to a volume of about 5 mL. This concentrated solution was then diluted with 30 mL chloroform, and the resulting solution applied to a 4 cm column containing about 30 g silica gel. Residual AMC was eluted from the column with additional chloroform, and product Boc-Gln-AMC (0.97 g) was then recovered from the column by elution with 2% methanol in chloroform. Recrystallization of product from methanol provided 0.46 g of purified Boc-Gln-AMC, mp 260.5-207°. TLC with methanol:chloroform (1:9) indicated a single spot, Rf 0.28.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:22]2[CH2:24][CH2:23]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:8]=1[CH2:9][O:10][CH3:11].[CH2:25]([O:27][C:28](=[O:41])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:34]=1[CH3:40])([CH3:31])[CH3:30])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:25]([O:27][C:28](=[O:41])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:2][C:3]2[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:5][C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:8]=2[CH2:9][O:10][CH3:11])=[CH:35][C:34]=1[CH3:40])([CH3:30])[CH3:31])[CH3:26]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
A solution of 200 mg (0.56 mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 134 mg (0.56 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 237 mg (0.73 mmol) cesium carbonate in 3 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 257 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy-2-methyl-propionic acid ethyl ester could be isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[S:13]1[CH:17]=[CH:16][N:15]=[C:14]1[CH:18]=O.C>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][C:18]([C:14]3[S:13][CH:17]=[CH:16][N:15]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: O=Cc1nccs1
Agent: C
Product: O=[N+]([O-])c1cc2oc(-c3nccs3)nc2cc1Cl
Yield: 63 %

Procedure:
To a flask equipped with a vigreux column was added 2-amino-4-chloro-5-nitro-phenol, thiazole-2-carbaldehyde, Darco KB and xylenes. The mixture was then refluxed overnight and the mixture was cooled, filtered and the solvent removed under vacuum. The resultant solid was recrystallized from Et2O to yield 4.76 g (63%) of a yellow colored solid.