Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Cl:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>ClC(Cl)C.O1CCCC1.ClCCl.O1CCCC1>[Cl:7][C:8]1[C:9]([C:10]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:11])=[CH:13][CH:14]=[CH:15][N:16]=1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1cccnc1Cl

Procedure:
134 ml (1.4 mole) of 2-amino 2-methyl propanol are dissolved in 600 ml of a dichloroethane/tetrahydrofuran mixture (85/15 v/v) and the solution is cooled in an ice/sodium chloride bath. 70.4 g (0.4 mole) of 2-chloro nicotinic acid chloride, prepared as described in Example 1 and dissolved in 770 ml of a dichloromethane/tetrahydrofuran mixture (85/15 v/v) are added such that the temperature is maintained at or below 0° C.
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:33])[C:9]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1>CC(CC)=O>[ClH:1].[CH3:33][N:8]([CH3:7])[C:9]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Agent: COc1ccc(NC(=O)CC2CCC(c3ccccc3)(N(C)C)CC2)cc1
Solvent: O
Solvent: CCC(C)=O
Product: Cl

Procedure:
Chlorotrimethylsilane (0.097 ml) and water (7 μl) were added to a solution of the less polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-(4-methoxy-phenyl)-acetamide (255 mg, 0.7 mmol) in ethyl methyl ketone (2 ml). The hydrochloride was extracted as an oil with hexane and isolated in a quantitative yield.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]=1.[CH2:13](Br)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.CN(C)C=O>O>[C:16]1([C:14]2[N:1]=[C:2]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[NH:5][C:4](=[O:12])[N:3]3[CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1nc(=O)[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ccccc2c2nc(-c3ccccc3)cn12
Temperature: 120 °C

Procedure:
1.61 g (0.01 mol) of 4-amino-2-quinazolinone and then 2.2 g (0.011 mol) of phenacyl bromide are added to 25 ml of dimethylformamide. The mixture is heated at 120° C. (external heating) for 3 hours, then left to cool and water is added. The brown precipitate formed is filtered out (1.34 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:13][O:14][C:15](=[O:19])[CH2:16][NH:17][CH3:18].C(N(CC)CC)C.O>ClCCCl>[CH3:13][O:14][C:15](=[O:19])[CH2:16][N:17]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)CN(C)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
In 1,2-dichloroethane (50 ml) were suspended p-nitro-benzaldehyde (5 g), sarcosine methyl ester hydrochloride (4.6 g) and triethylamine (4.6 ml), and to the mixture was added, under ice-cooling, triacetoxy sodium boron hydride (9.8 g). Under nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. To the mixture was added water, and the mixture was concentrated, neutralized with sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give N-(4-nitrobenzyl)sarcosine methyl ester (6.3 g) as colorless oil.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8](=[O:24])/[CH:9]=[CH:10]/[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)([O:5][CH3:6])=[O:4]>CO.[Pd]>[CH3:1][O:2][P:3]([CH2:7][C:8](=[O:24])[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][CH2:16]1)([O:5][CH3:6])=[O:4]
Reactant: COP(=O)(CC(=O)/C=C/C1CCN(C(=O)OC(C)(C)C)CC1)OC
Agent: [Pd]
Solvent: CO
Product: COP(=O)(CC(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1)OC

Procedure:
A solution of 5.443 g (15.062 mM) of tert-butyl (E)-4-[4-(dimethoxyphosphoryl)-3-oxo-1-butenyl]piperidine-1-carboxylate in 50 ml of methanol was subjected to hydrogenation using 3 g of 10% palladium-on-carbon (50% hydrous) as a catalyst at room temperature and atmospheric pressure until the starting material had been no longer detected. The catalyst was removed by filtration with the aid of celite and the catalyst was washed with methanol. The filtrate and washes were pooled and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate:1/1 to ethyl acetate) to provide the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]1([S:9]([C:12]2[C:16](S(C3C=CC=CC=3)(=O)=O)=[N:15][O:14][N+:13]=2[O-:26])(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:27]([CH:34]([CH:36]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[OH:37])[OH:35])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C1COCC1>[OH:37][C@H:36]([C@@H:34]([O:35][C:16]1[C:12]([S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:10])=[O:11])=[N+:13]([O-:26])[O:14][N:15]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39]
Reactant: O=S(=O)(c1ccccc1)c1no[n+]([O-])c1S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(O)C(O)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](O)[C@@H](Oc1no[n+]([O-])c1S(=O)(=O)c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
50% NaOH solution (1.2 g-30 mmol) is added in the course of ½ hour to a solution of 3,4-bis(phenylsulphonyl)-1,2,5-oxadiazole 2-oxide (7 g-19 mmol) and di-tert-butyl tartrate (5 g-19 mmol) in 100 ml of anhydrous THF. After stirring for 5 hours, the solvent is evaporated off to dryness and the residue is taken up in water and ethyl acetate. The organic fraction is dried with Na2SO4 and evaporated to dryness and subsequently purified by flash chromatography, using a (98:2) dichloromethane/ethanol mixture as eluant, to yield the expected product in the form of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([CH2:14][OH:15])[CH:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[C:11]([CH:14]=[O:15])[CH:10]=[C:9]2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Product: Cc1c(C=O)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1

Procedure:
Following a procedure similar to that described in Example 49(i), but using 1-(4-fluorophenyl)-4-hydroxymethyl-5-methyl-2-(4-methylsulfonylphenyl)pyrrole (prepared as described in Example 47) and manganese dioxide as starting materials, the title compound was obtained as a white powder (yield 98%), melting at 167-169° C.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:2]1.C([Li])CCC.CCCCCC.[Si:29](Cl)([CH3:32])([CH3:31])[CH3:30].[Cl-].[NH4+]>C(OCC)C.O>[CH3:30][Si:29]([CH3:32])([CH3:31])[CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:2]1
Reactant: C1=C(CCc2ccccn2)c2ccccc2C1
Reactant: C[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: C[Si](C)(C)C1C=C(CCc2ccccn2)c2ccccc21
Temperature: -90 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
2-[2-(1H-inden-3-yl)ethyl]pyridine (14.88 g, 0.0637 mol) was dissolved in 190 ml of diethylether. The resulting solution was cooled to −90° C. and then 15% n-butyllithium in hexane (42.08 ml, 67.3 mmol) added. The resulting mixture was stirred at this temperature for an additional 30 min and then allowed to reach room temperature. After additional stirring for 1 h at room temperature, the mixture was cooled to −90° C. and was then treated with a solution of SiMe3Cl (9.4 ml, 74 mmol) in 10 ml of diethylether. The resulting mixture was allowed to warm to room temperature and then stirred for 12 h. Then the mixture was first treated with water and then aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase extracted three times with diethylether. The combined organic phase was washed with brine and dried over MgSO4. After filtration, the solvent was removed from the filtrate to give 15.97 g (81%) of 2-{2-[1-(trimethylsilyl)-1H-inden-3-yl]ethyl}pyridine as an oil, which was used in the next stage without separation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:5]=[C:6]([S:8]CC[Si](C)(C)C)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])[CH:5]=[C:6]([SH:8])[CH:7]=1
Reactant: C[Si](C)(C)CCSc1cc(F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: OC(c1cc(F)cc(S)c1)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Yield: 44.2 %

Procedure:
To a solution of 5-fluoro-3-(hexafluoro-2-hydroxyprop-2-yl)-1-(2-trimethylsilylethylthio)benzene (1 g, 2.54 mmol Step 2) in dry DMF (20 mL) was added tetrabutylammonium fluoride (1M in THF) (Aldrich) (6.4 mL, 6.4 mmol) and the reaction mixture was heated at 60° C. for 30 min.. The reaction mixture was then added to H2O and extracted with EtOAc. The combined organic phase were washed with brine, dried and evaporated to give a residue which was chromatographed on silica gel eluting with 8:2 mixture of hexane:EtOAc to afford the title compound (330 mg, 44%).
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:46]=[CH:45][C:9]([CH2:10][N:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]3[C:20]([NH:27][C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:21][CH:22]=[C:23]([CH:26]=3)[CH:24]=[O:25])[N:13]=2)=[CH:8][CH:7]=1.[Cl-].[NH4+].O>C1COCC1>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:46][CH:45]=2)[C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]3[CH:26]=[C:23]([CH:24]([OH:25])[CH3:1])[CH:22]=[N:21][C:20]=3[NH:27][C:28]3[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:13]=2)=[CH:42][CH:41]=1
Reactant: C[Mg]Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Methylmagnesium bromide (1.4 M in 3:1 toluene/THF) (Aldrich, St. Louis, Mo.; 1.787 mL, 2.502 mmol) was added (dropwise, over 10 min) to a yellow-brown solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (Example 144, Step 1; 451.7 mg, 0.782 mmol) in THF (5.0 mL) at 0° C., and the resulting brown solution was stirred at 0° C. for 1 h. Saturated ammonium chloride (10 ml) and water (10 ml) were then added, THF was removed in vacuo, and the resulting mixture was extracted with EtOAc (2×60 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Trituration of the residue with hexanes (10 mL) furnished 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (331.1 mg, 0.558 mmol, 71.3% yield) as a yellow-brown solid. m/z (ESI, +ve) 594.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]2[O:9][C:10](=[O:12])[CH3:11])[C:5]2[CH:21]=[C:22]([Cl:26])[C:23]([Cl:25])=[CH:24][C:4]=2[N:3]=1.[CH:27]([Sn](CCCC)(CCCC)CCCC)=[CH2:28].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[Cl:25][C:23]1[C:22]([Cl:26])=[CH:21][C:5]2[N:6]([C@@H:7]3[O:19][C@H:18]([CH3:20])[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]3[O:9][C:10](=[O:12])[CH3:11])[C:2]([CH:27]=[CH2:28])=[N:3][C:4]=2[CH:24]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=Cc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 90 °C
Yield: 51.1 %

Procedure:
2-Bromo-5,6-dichloro-1-(2,3-di-O-acetyl-5-deoxy-beta-D-ribofuranosyl)-1H-benzimidazole (0.22 g, 0.47 mmol), vinyltributyltin (Aldrich, 0.5 ml, 2.4 mmol), tetrakis(triphenylphosphine)palladium(0) (Aldrich, 0.054 g, 0.047 mmol) and DMF (Aldrich Sure Seal, 5 mL) were combined and flushed with argon for 30 min. The solution was warmed to 90° C. After 1 h the DMF was distilled off under reduced pressure. The residue was taken up in ethyl acetate (50 mL) and extracted with 20 mL of saturated NH4Cl. The organic layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column (2.5×14 cm, 230-400 mesh) with 1:40 methanol:dichloromethane to give the title compound (0.1 g, 0.24 mmol, 51%); MS (ES+): m/z (rel. intensity) 436 (100, M++Na); 1H NMR (DMSO-d6) δ8.06 (s,1H, ArH), 7.97 (s, 1H, ArH), 7.10 (dd, 1H, CH, J=11 Hz, J=16.8 Hz), 6.50 (dd, 1H, CH, J=1.8 Hz, J=16.8 Hz), 6.32 (d, 1H, CH, J=6.9 Hz), 5.85 (dd, 1H, CH, J=1.8 Hz, J=11 Hz), 5.51 (apparent triplet, 1H, CH, J=7.0 Hz), 5.27 (apparent triplet, 1H, CH, J=6.5 Hz), 4.27-4.18 (m, CH, 1H), 2.15 (s, 3H, OAc), 1.99 (s, 3H, OAc), 1.53 (d, 3H, CH3, J=6.3 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9]>>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][CH3:6])[CH2:9][CH2:8][C:7]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CC(=O)OCC
Reactant: CCCCNC
Product: CCCCN(C)CCC(=O)OCC
Yield: 87.2 %

Procedure:
A stirred mixture of N-methyl-n-butylamine (42.8 g., 0.49 mole) and ethyl acrylate (55 g., 0.54 mole) was heated at 80°-90° C for 20 hours. Excess acrylate was evaporated under reduced pressure, and the residue distilled to give 80.0 g (87%) of the title compound, b.p. 97° C at 12 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[C:17]([CH3:26])=[C:18]([S:22]([NH:14][C:11]2[S:12][CH:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[N:10]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COc1ccc(-c2csc(N)n2)cc1
Product: COc1ccc(-c2csc(NS(=O)(=O)c3cccc(Cl)c3C)n2)cc1

Procedure:
The title compound was prepared from 4-(4-methoxy-phenyl)-thiazol-2-ylamine and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (58.0 mg) with purity >90%. MS (pos) m/z 395.2.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])[CH2:8][CH2:7]1)=[O:5].[NH2:26][CH:27]1[CH:34]2[CH2:35][C:30]3([CH2:37][OH:38])[CH2:31][CH:32]([CH2:36][CH:28]1[CH2:29]3)[CH2:33]2>>[OH:1][CH2:2][C:3]([CH3:25])([CH3:24])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18]([NH:26][CH:27]2[CH:28]3[CH2:36][CH:32]4[CH2:31][C:30]([CH2:37][OH:38])([CH2:35][CH:34]2[CH2:33]4)[CH2:29]3)=[O:19])[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)(CO)C(=O)N1CCC(CCOc2cccc(C(=O)O)c2)CC1
Reactant: NC1C2CC3CC1CC(CO)(C3)C2
Product: CC(C)(CO)C(=O)N1CCC(CCOc2cccc(C(=O)NC3C4CC5CC3CC(CO)(C5)C4)c2)CC1

Procedure:
Prepared from 3-{2-[1-(3-hydroxy-2,2-dimethyl-propionyl)-piperidin-4-yl]-ethoxy}-benzoic acid and 4-amino-1-hydroxymethyladamantane to give the title compound as a mixture of two isomers. 1H NMR (400 MHz, CDCl3) δ: 7.31-7.38 (m, 2H), 7.24-7.29 (m, 1H), 7.02 (d, 1H), 6.31-6.43 (m, 1H), 4.33-4.45 (m, 2H), 4.17-4.24 (m, 1H), 4.07 (t, 2H), 3.49 (s, 2H), 3.26 (d, 2H), 2.74-2.87 (m, 2H), 2.12-2.19 (m, 2H), 2.01-2.05 (m, 1H), 1.42-1.93 (m, 15H), 1.27 (s, 6H), 1.14-1.23 (m, 2H).
Reaction SMILES: C(#N)C.[N:4]1[NH:5][N:6]=[N:7][C:8]=1[CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:11]1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>C(N(CC)CC)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:6]2[N:5]=[N:4][C:8]([CH2:9][C@H:10]3[CH2:15][CH2:14][C@H:13]([O:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:12][CH2:11]3)=[N:7]2)=[CH:29][CH:28]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O[C@H]1CC[C@H](Cc2nn[nH]n2)CC1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nnc(C[C@H]3CC[C@H](OC(=O)c4ccccc4)CC3)n2)cc1
Temperature: 25 °C

Procedure:
To an acetonitrile (20 mL) suspension of trans-benzoic acid 4-(2H-tetrazol-5-ylmethyl)-cyclohexyl ester (1.34 g) obtained in Example (44b), triethylamine (0.68 mL) and 4-methoxybenzyl chloride (0.70 mL) were added at room temperature. The reaction mixture was heated to reflux for 2 hours, cooled to room temperature, concentrated, then diluted with ethyl acetate, and filtered. The filtrate was washed with 1 N hydrochloric acid, then dried over sodium sulfate, and then concentrated. The residue was purified by column chromatography (hexane/ethyl acetate) to obtain the title compound (610 mg, 32%) as a colorless oil.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[C:35]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=3[O:33][C:32]2=[O:41])=[CH:27][CH:26]=1)(O)=[O:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:40][C:37]1[CH:38]=[CH:39][C:34]2[O:33][C:32](=[O:41])[CH:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:21])=[CH:30][CH:29]=3)[C:35]=2[CH:36]=1
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc2c(c1)C(c1ccc(OCC(=O)O)cc1)C(=O)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)COc1ccc(C2C(=O)Oc3ccc(C)cc32)cc1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
A mixture of 5.0 g (18.5 mmol) of 1-octadecanol, 5.0 g (16.8 mmol) of 3-(4-carboxymethoxyphenyl)-5-methylbenzofuran-2-one (Compound (101), Example 1) and 1.0 g (5.3 mmol) of p-toluenesulfonic acid is stirred at 200° C. under a slight vacuum (150 mmHg) for about 1 hour. The reaction mixture is then diluted with 60 ml of ligroin and cooled with ice/water. The precipitated product is filtered. Crystallisation of the residue due from ligroin given 7.5 g (81%) of 5-methyl-3-(4-n-octadecyloxycarbonylmethoxyphenyl)benzofuran-2-one, melting pint 85°-87° C. (Compound (105), Table 1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[CH:25]=[C:24]([Br:26])[CH:23]=[C:22]([N+:27]([O-])=O)[C:21]=2[S:30][C:31](=[O:35])N(C)C)[C:11]1=[O:36])[CH2:7][CH2:8][CH3:9])[CH3:2].C(O)C.[Sn](Cl)(Cl)(Cl)Cl>C(OC(=O)C)C>[CH2:1]([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:21]3[S:30][C:31](=[O:35])[NH:27][C:22]=3[CH:23]=[C:24]([Br:26])[CH:25]=2)[C:11]1=[O:36])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc([N+](=O)[O-])c2SC(=O)N(C)C)c2ccccc21
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3[nH]c(=O)sc23)c2ccccc21
Temperature: 75 °C
Yield: 57.9 %

Procedure:
(S)-3-[3-(5-Bromo -2-dimethylcarbamoylsulfanyl-3-nitro-benzyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (70 mg, 0.11 mmol) is suspended in ethylacetate (0.5 mL)/ethanol (0.5 mL) and then tin chloride (133 mg, 0.6 mmol) is added. The resulting suspension is equipped with a reflux condenser and heated to 75° C. for 1 hour. Upon completion the reaction is cooled to room temperature and the solvents evaporated in vacuo. The resulting solid is taken up in ethyl acetate and the product is filtered. The solvent is evaporated in vacuo and the resulting solid is purified via prep reverse phase LC to give 33 mg (54%) of the title compound. LCMS (ESMS): m/z 519.7 (M+H+).
Reaction SMILES: CN([CH2:4][CH:5]1[CH2:12][N:11]2[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]1=[O:13])C.[C-:14]#[N:15].[K+]>>[C:14]([CH2:4][CH:5]1[CH2:12][N:11]2[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]1=[O:13])#[N:15]
Reactant: CN(C)CC1Cn2cccc2C1=O
Reactant: [C-]#N
Agent: [K+]
Product: N#CCC1Cn2cccc2C1=O
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To 100 ml H2O0 were added 8.6% of compound 2 and 5.2 g KCN. The solution was gently heated to 100° C. and kept stirring for 10 minutes. After cooling to r.t., the reaction mixture was extracted with CH2CI2 (60×3). Evaporated the solvent, 6 g oil was obtained. Purified by column chromatography on silica gel, 4 g of compound 8 was obtained as white powder, mp 68° C., yield 68%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[O:17])[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:27]C(=O)OCC1C=CC=CC=1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:27][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:15][C:16](=[O:17])[N:18]([CH3:26])[CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:14]=2)=[CH:7][C:2]=1[F:1]
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ncn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)c(F)c3)ncn2)CC1
Reaction time: 10 h

Procedure:
Benzyl N-(2-fluoro-4-{6-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyrimidin-4-yloxy}phenyl)carbamate (189 mg) was dissolved in tetrahydrofuran (20 ml). After adding 20% palladium hydroxide-carbon (104 mg), the mixture was stirred for 10 hours under a hydrogen atmosphere. The catalyst was filtered and washed with ethyl acetate. The filtrate and the washings were combined and concentrated under reduced pressure to provide crude 3-[6-(4-amino-3-fluorophenoxy)pyrimidin-4-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea as a colorless oil [ESI-MS (m/z): 375[M+H]+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9]\[CH2:10][OH:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:39][C:40](=[O:53])[C@@H:41]([O:50][CH2:51][CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=1)[CH3:38].N(C(OCC)=O)=NC(OCC)=O>>[CH2:37]([O:39][C:40](=[O:53])[C@@H:41]([O:50][CH2:51][CH3:52])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)/[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:45][CH:44]=1)[CH3:38]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: OC/C=C(/c1ccccc1)c1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/c2ccccc2)c2ccc(F)cc2)cc1)OCC
Yield: 73 %

Procedure:
Reaction of (Z)-3-(4-fluorophenyl)-3-phenyl-prop-2-en-1-ol (200 mg, 0.88 mmol), triphenylphosphine (242 mg, 0.92 mmol), (2S)-2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (200 mg, 0.84 mmol) and diethyl azodicarboxylate (160 mg, 0.92 mmol) in an identical manner to example 1 gave the title compound (275 mg, 73%).