Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[S:33][CH:34]=[CH:35][N:36]=1)[CH3:29]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[O:26])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Reactant: CCNCc1nccs1
Product: CCN(Cc1nccs1)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with ethyl-thiazol-2-ylmethyl-amine
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CC[CH2:17][CH2:16]1.C([Mg]Cl)=C>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[CH:16]=[CH2:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: C1CCOC1
Agent: C=C[Mg]Cl
Solvent: CCCCCC
Product: C=C[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 22 h
Yield: 48 %

Procedure:
In an argon atmosphere, 6.54 g (28.1 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 20 mL of hexane and after adding a vinyl magnesium chloride tetrahydrofuran solution (1.61 mol/L, 34.5 mL, 55.5 mmol), the resulting solution was stirred at room temperature for 22 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 85° C./6.1×102 Pa) to obtain 1,3-di-tert-butyl-2-vinyl-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)CHCH2) as a yellow liquid (yielded amount: 3.01 g, yield: 48%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]2[C:17](=O)[CH2:16][CH2:15][CH2:14][C:13]2=[O:19])=[CH:10][C:9]([CH3:20])=[C:8]2[C:3]=1[CH:4]([O:23][CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][S:7]2(=[O:22])=[O:21].C(N(CC)CC)C>ClCCCl>[Cl:1][C:2]1[C:11]([C:12]2[C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH:17]=2)=[CH:10][C:9]([CH3:20])=[C:8]2[C:3]=1[CH:4]([O:23][CH:24]([CH3:26])[CH3:25])[CH2:5][CH2:6][S:7]2(=[O:22])=[O:21]
Reactant: Cc1cc(C2C(=O)CCCC2=O)c(Cl)c2c1S(=O)(=O)CCC2OC(C)C
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C2=CCCCC2=O)c(Cl)c2c1S(=O)(=O)CCC2OC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
0.5 Gram of 5-chloro-8-methyl-6(1,3-dioxocyclohexan-2-yl)-4-(2-propoxy)thiochroman-1,1-dioxide (Compound No. 15 in Table 38) prepared in Preparation Example 6 was dissolved in 5 ml of 1,2-dichloroethane, and 0.12 g of triethylamine was added. The mixture was stirred at room temperature for 1 hour. A formed crystal was recovered by filtration to give, as an end product, 0.3 g of Compound No. 251 shown in Table 48 (yield 65%). Table 60 shows the physical property date of the obtained compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCNCC1
Yield: 13 %

Procedure:
20 g of anhydrous piperazine was dissolved in 1,000 ml of tetrahydrofuran and then 33.6 g of stearoyl chloride was added dropwise thereto under stirring and under cooling with ice. The mixture was stirred under cooling with ice for 1 h and tetrahydrofuran was distilled off under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue. After extraction with 200 ml of chloroform three times, the extract was washed with a saturated aqueous solution of common salt and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=9/1) to obtain 5.1 g of the intended product.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CO.N[C:9]([CH2:15][OH:16])([CH2:13][OH:14])[C:10]([OH:12])=O.C(=O)([O-])[O-].[Na+].[Na+].C=O.ON1[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2N=N1>>[C:29]1([C:9]([CH2:13][OH:14])([CH2:15][OH:16])[C:10]([NH2:1])=[O:12])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N[C@@H](CO)C(=O)O
Reactant: NC(CO)(CO)C(=O)O
Reactant: On1nnc2ccccc21
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: NC(=O)C(CO)(CO)c1ccccc1

Procedure:
In Scheme B serine is converted to 2-amino-3-hydroxy-2-hydroxymethylpropionic acid by reaction with aqueous sodium carbonate containing an excess of formaldehyde. From that point the synthesis is conducted as set out in Scheme A. However, it is preferable to activate 2-amino-3-hydroxy-2-hydroxymethylpropionic acid with 1-hydroxy benzotriazole to facilitate condensation with p- N,N-bis(2-chloroethyl)!phenylendediamine. The product, 2-amino-N- p-bis(2-chloroethyl)amino!phenyl-3-hydroxy-2-hydroxymethylpropionamide, is isolated as the hydrochloride salt. As in Scheme A, the hydrochloric acid may be replaced with those indicated acids.
Reaction SMILES: [P:1]([O:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:20][OH:21])([O:7][CH2:8][CH:9]=[CH2:10])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.CC(O)C>CC(C)=O.O>[CH2:4]([O:3][P:1]([O:11][CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C:20]([OH:24])=[O:21])([O:7][CH2:8][CH:9]=[CH2:10])=[O:2])[CH:5]=[CH2:6]
Reactant: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1CO
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: O
Product: C=CCOP(=O)(OCC=C)OCc1c(C)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of diallyl 2-(hydroxymethyl)-6-methylbenzyl phosphate (1.22 g, 4.02 mmol) obtained from Example 22-(4) in acetone (25 ml) was cooled to 0° C., and Jones reagent (a mixture of chromic anhydride (5.34 g) and concentrated sulfuric acid (4.6 ml) diluted with water to 20 ml total volume; 6 ml, ca. 16 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours, and then 2-propanol (1 ml) was added thereto to stop the reaction. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give an oily residue. The residue was dried using a vaccum pump, and then subjected to chromatography on a silica gel (50 g) column (eluent; ethyl acetate:dichloromethane=1:1) to afford the title compound (905.3 mg, 71% yield) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:13])([CH2:11][OH:12])[CH2:9][OH:10])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1COCC1.O>[OH:10][CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][CH:6]=1)([OH:13])[CH2:11][OH:12]
Reactant: Nc1ccc(C(O)(CO)CO)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(C(O)(CO)CO)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a stirred solution of 2-(4-aminophenyl)propane-1,2,3-triol (900 mg, 4.918 mmol, 1.0 eq) in THF/H2O/sat. NaHCO3 (4 mL: 2 mL: 4 mL) was added phenyl chloroformate (0.68 mL, 5.367 mmol, 1.1 eq) at 0° C. and the mixture was stirred at RT for 0.5 h, then the THF was evaporated, the residue was diluted with EtOAc (20 mL), washed with water (20 mL) followed by brine and the solvent evaporated. The resulting residue was purified by CC using MeOH/CHCl3 (1:19) as eluent to get phenyl 4-(1,2,3-trihydroxypropan-2-yl)phenylcarbamate (900 mg, 60%, white solid; TLC system: MeOH/CHCl3 (1:9), Rf: 0.4).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[NH:8]3.[H-].[Na+].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.O>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:5]2[C:6]=1[C:7](=[O:13])[N:8]3[CH2:1][CH2:2][CH2:6][CH2:7][N:20]1[C:16](=[O:26])[C:17]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:18]2[C:19]1=[O:21]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1nc2cccc3[nH]c(=O)c1n23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3n(CCCCN4C(=O)c5ccccc5C4=O)c(=O)c1n23
Yield: 122.1 %

Procedure:
To a suspension of 8.66 g (50 mmol) of 1,2-dihydro-3-methyl-1,4,7b-triazacyclopent[cd]inden-2-one in 100 ml of DMF was added, while stirring under ice-cooling, 2.20 g (55 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added 14.10 g (50 mmol) of phthalimide, which was stirred for 6 hours at 100° C. After cooling, the reaction mixture was then poured into water, extracted with chloroform. The extract solution was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give 11.43 g of the desired compound (61.1%, pale yellow solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([OH:14])[C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7].[C:15](=O)([O-])[O-].[K+].[K+].ICI.Cl>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]2[O:14][CH2:15][O:13][C:12]=12)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(O)c(O)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ICI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)c2c(c1)OCO2
Reaction time: 24 h

Procedure:
Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.93 g, 4.6 mmol) and potassium carbonate (3.2 g, 23.4 mmol) in acetone (25 mL) and dimethylformamide (25 mL). Add diiodomethane (6.3 g, 23.3 mmol). Heat to reflux. After 24 hours, cool in an ice bath, acidify with a 1 M aqueous hydrochloric acid solution (35 mL), and extract twice with ethyl acetate. Combine the organic layers and extract with brine. Dry over MgSO4, filter, and concentrate in vacuo to give methyl 3-methoxy-4,5-methylenedioxybenzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH:5]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>ClCCCl>[CH:20]([C:16]1[CH:15]=[C:14]([N:13]2[CH2:12][CH2:11][N:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([O:2][CH3:1])=[O:23])[C:24]2=[O:25])[CH:19]=[CH:18][CH:17]=1)([CH3:21])[CH3:22]
Reactant: COC(=O)c1cccc(NCCNc2cccc(C(C)C)c2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COC(=O)c1cccc(N2CCN(c3cccc(C(C)C)c3)C2=O)c1
Temperature: 90 °C
Yield: 85.4 %

Procedure:
To the solution of 3-[2-(3-isopropylphenylamino)ethylamino]benzoic acid methyl ester (0.83 g, 2.7 mmol) prepared above in dry 1,2-dichloroethane (5.0 mL) was added, under nitrogen, 1,1′-carbonyldiimidazole (0.65 g, 4.0 mmol). The mixture was then heated at 90° C. for 24 h. After cooling to room temperature, the mixture was washed with water, diluted HCl, water and brine, then dried over anhydrous Na2SO4 and concentrated. The crude product was obtained after the removal of the solvent and further purified by column chromatography (silica gel, hexanes:ethyl acetate, 9:1) to give methyl 3-[3-(3-isopropylphenyl)-2-oxo-imidazolidin-1-yl]benzoate as colorless needles (0.78 g, 85.7%). MS (ES+) m/z: 339.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=S.CN(C)C=O.[C:28](=[O:31])([O-:30])[O-].[K+].[K+].N#CBr.[C:37]([O:40]CC)(=[O:39])[CH3:38]>CCOCC>[C:37]([OH:40])(=[O:39])/[CH:38]=[CH:2]\[C:28]([OH:30])=[O:31].[CH3:22][N:19]1[CH2:20][CH2:21][N:16]([C:14]2[N:3]3[CH:4]=[CH:5][N:1]=[C:2]3[CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:13]=2)[CH2:17][CH2:18]1
Reactant: CN1CCN(C(=S)Nc2ccccc2Cc2ncc[nH]2)CC1
Reactant: O=C([O-])[O-]
Reactant: CCOC(C)=O
Agent: N#CBr
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCN(C2=Nc3ccccc3Cc3nccn32)CC1
Product: O=C(O)/C=C\C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The mixture of 315 mg of 1-[2-(2-imidazolylmethyl) phenylthiocarbamoyl]-4-methylpiperazine, 3.3 ml of dimethylformamide, 276 mg of potassium carbonate, 116 mg of cyanogen bromide and 50 mg of 8-crown-6 ether is stirred at room temperature under nitrogen for 3 hours. It is diluted with ethyl acetate, washed with saturated aqueous sodium chloride, dried and evaporated. The residue is dissolved in acetone, the solution treated with 116 mg of maleic acid and diluted with diethyl ether, to yield 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c]-[1,3] benzodiazepine monomaleate of example 1.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][C:7]([Cl:11])=[C:6]([Cl:12])[C:5]=1[CH2:13]C(OC(C)(C)C)=O)([O-:3])=[O:2].[NH3:21]>COCCO.O.C(OCC)(=O)C>[NH2:21][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:13])[C:6]([Cl:12])=[C:7]([Cl:11])[CH:8]=1
Reactant: N
Reactant: CC(C)(C)OC(=O)Cc1c(Cl)c(Cl)cc(Cl)c1[N+](=O)[O-]
Solvent: O
Solvent: COCCO
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(Cl)cc(N)c1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of t-butyl (2-nitro-3,5,6-trichlorophenyl)acetate (123 g, 0.361 mol) and saturated aqueous ammonia (300 mL) in 2-methoxy ethanol (360 mL) was heated in an autoclave at 150° C. for 72 hours. The resulting viscous, black mixture was diluted with water (1 L) and ethyl acetate (1 L) and filtered through Arbocel filter aid. The dark red filtrate was separated, and the aqueous layer extracted with ethyl acetate (2×1 L). The combined organic solutions were washed with brine (1 L), dried (MgSO4) and evaporated onto silica gel (70-200μ, 200 g). The silica gel was applied to the top of a chromatography column containing silica gel (40-60 μ, 800 g). Elution with hexane/ethyl acetate (98:2-92:8) gave 3-amino-5,6-dichloro-2-nitrotoluene (EP-A-0385850) as a bright orange solid (39.7 g), which was contaminated with 5-amino-3,6-dichloro-2-nitrotoluene (14%). This mixture was carried onto the next step without further purification. 1H NMR (300 MD, CDCl3) 2.48 (3H, s), 4.80 (2H, s), 6.82 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[S:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][CH2:3]1.[C:17]1([N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][Cl:32])[CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:1]=[C:2]1[CH:8]([C:9]([O:11][CH3:12])=[O:10])[S:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[O:4][CH:3]1[CH2:31][CH2:30][CH2:29][N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1.[ClH:32]
Reactant: COC(=O)C1Sc2ccccc2OCC1=O
Reactant: ClCCCN1CCN(c2ccccc2)CC1
Product: COC(=O)C1Sc2ccccc2OC(CCCN2CCN(c3ccccc3)CC2)C1=O
Product: Cl

Procedure:
Methyl 3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate was condensed with 3-(4-phenylpiperazin-1-yl)propyl chloride in the same manner as in Reference Example 1 to isolate methyl 3-oxo-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate as hydrochloride. Recrystallization from methanol yielded white crystals, melting point 176°-178° C.
Reaction SMILES: [C:1]1([CH:7](Br)[CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][NH:23][CH3:24]>>[CH3:22][N:23]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[CH3:24]
Reactant: CNC
Reactant: FC(F)(F)c1ccc(OCCC(Br)c2ccccc2)cc1
Product: CN(C)C(CCOc1ccc(C(F)(F)F)cc1)c1ccccc1

Procedure:
Still following the above procedure, 1-phenyl-3-(p-trifluoromethylphenoxy)propylbromide was reacted with dimethylamine in a sealed vessel at 150° C. for a period of 8 hours. N,N-dimethyl 1-phenyl-3-(p-trifluoromethylphenoxy)-propylamine thus formed was converted to the hydrochloride salt by the addition to the reaction mixture of 100 ml. of 10% aqueous HCl. The hydrochloride salt was isolated therefrom and melted at 178°-180° C. after recrystallization from an ethyl acetate-hexane solvent mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].BrC[C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: BrCc1ccncc1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCc3ccncc3)cc2)c2ccccc21
Reaction time: 0.5 h

Procedure:
The phenol was dissolved in DMF (5 mL) at room temperature. Sodium hydride (60% in oil) was added and the mixture allowed to stir 30 min. 4-Bromomethyl-pyridine was added and the reaction was allowed to stir over night. Ethanol was added and the reaction was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (2/98 methanol/dichloromethane—5/95 methanol/dichloromethane gradient) to afford the product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:74]([NH2:78])([CH3:77])([CH3:76])[CH3:75]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:78][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CC(C)(C)N
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC(C)(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.9 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and t-butylamine (8.71 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.6 mg, 51%). LC-MS m/z 629 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[C:10](OC1C=CC=CC=1)(=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>C(O)C>[OH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[C:10]1[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[N:1]=1
Reactant: Cc1ccc(O)c(N)c1
Reactant: O=C(Oc1ccccc1)c1ccccc1O
Solvent: CCO
Product: Cc1ccc2oc(-c3ccccc3O)nc2c1
Temperature: 200 °C

Procedure:
A mixture of 2-amino-p-cresol (10.0 g, 0.081 mole) and phenyl salicylate (17.4 g, 0.08 mole) was heated under nitrogen atmosphere in an oil bath at 200° C. for 1½ h. To the cooled reaction mixture ethanol was added and the product filtered off under suction. The product was dried under vacuum at 75° C., and then purified by column chromatography (dichloromethane). The eluent containing the product was concentrated and ethanol added to the residue to give a bright white crystalline solid. The product was suction filtered and dried under vacuum at 75° C. Yield 7.4 g (40%). M.p 138° C. (DSC, onset). Elemental analysis: Found, C 74.62, H 4.86 and N 6.32%. C14H11NO2 requires C 74.65, H 4.92 and N 6.22%.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][NH:8][C:9](=[O:36])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:34])[C:17]([OH:33])([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28](=[O:30])[N:27]([CH3:31])[C:26]=3[CH:32]=2)[C:18]([F:21])([F:20])[F:19])=[C:12]([Cl:35])[CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:35][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[CH:16]([CH3:34])[C:17]([OH:33])([C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28](=[O:30])[N:27]([CH3:31])[C:26]=2[CH:32]=1)[C:18]([F:20])([F:21])[F:19])[C:9]([NH:8][CH2:7][C:6]([OH:37])=[O:5])=[O:36]
Reactant: CC(c1ccc(C(=O)NCC(=O)OC(C)(C)C)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccc(C(=O)NCC(=O)O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.4 %

Procedure:
{3-Chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydrobenzooxazol-5-yl)-propyl]-benzoylamino}-acetic acid tert-butyl ester (20 mg, obtained in Example 231) was dissolved in dry dichloromethane (1.0 mL) and trifluoroacetic acid (0.41 mL) was added. The mixture was then allowed to stir at r.t. for 12 hours. The reaction mixture was concentrated in vacuo and the residue was further purified by repeated evaporation from ether (2 times), methanol (2 times) and again dichloromethane (2 times) to give the title compound {3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydrobenzooxazol-5-yl)-propyl]-benzoylamino}-acetic acid as a colorless solid (18 mg). MS (m/e, ISP neg. ion)=485.1 [M−H+].