Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:37])[C@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C1C=CC=CC=1.C1COCC1.OO.[Li+].[OH-:46]>O>[C:28]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:29]=[CH:30][C:25]([CH2:24][C@H:15]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14]([OH:37])=[O:46])=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.6 %

Procedure:
To a stirred solution of (R)-tert-butyl 4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-(biphenyl-4-ylmethyl)-4-oxobutanoate (1.20 g, 2.402 mmol) in a mixed solvent of THF (20 mL) and water (5 mL), a solution of aqueous H2O2 (0.960 mL, 9.61 mmol) and aqueous LiOH (4.80 ml, 4.80 mmol) is added at 0° C. during 5 minutes. After stirring for 1.5 hour, the reaction is quenched with saturated aqueous Na2SO3 (10 mL) at 0° C., and allowed to stir for 10 minutes at the same temperature. The reaction mixture is warmed up to ambient temperature while stirring for 0.5 hour. Then, saturated aqueous NaHCO3 and brine are added to the mixture. The product is extracted with ethyl acetate, washed with aqueous 1M HCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 120 g of silica gel (heptane/EtOAc=75:25 to 0:100) to give (R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (765 mg, 93%). HPLC retention time=1.63 minutes (condition D); MS=338.6 (m−1); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (s, 9 H) 2.41 (A of ABX, Jab=16.67 Hz, Jax=4.55 Hz, 1 H) 2.52-2.67 (B of ABX, Jab=16.75 Hz, Jbx=8.45 Hz, 1 H) 2.74-2.89 (m, 1 H) 3.06-3.22 (m, 2 H) 7.22-7.29 (m, 2 H) 7.30-7.37 (m, 1 H) 7.43 (t, J=7.58 Hz, 2 H) 7.53 (d, J=8.1 Hz, 2 H) 7.57 (d, J=7.8 Hz, 2 H).
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][C:4]=1[CH2:5][C:6]1[N:15]2[N:16]=[C:17]([NH2:19])[N:18]=[C:14]2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.COC1C=C(C=C(OC)C=1)CC1N2N=C(N)N=C2C2C=CC=CC=2N=1>>[NH2:19][C:17]1[N:18]=[C:14]2[N:15]([C:6]([CH2:5][C:4]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:3]=3[OH:2])=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=32)[N:16]=1
Reactant: COc1ccc(OC)c(Cc2nc3ccccc3c3nc(N)nn23)c1
Agent: COc1cc(Cc2nc3ccccc3c3nc(N)nn23)cc(OC)c1
Product: Nc1nc2c3ccccc3nc(Cc3cc(O)ccc3O)n2n1
Yield: 41 %

Procedure:
Operating as in Example 39, but employing 5-(2,5-dimethoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, prepared as described in Example 6, instead of 5-(3,5-dimethoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine, the title compound was obtained in 41% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:20]([F:23])([F:22])[F:21])([O:15][Si](C)(C)C)[CH:10]([C:24]([F:27])([F:26])[F:25])[CH2:9][CH2:8][C:7]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([F:28])[CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([C:20]([F:22])([F:23])[F:21])([OH:15])[CH:10]([C:24]([F:27])([F:25])[F:26])[CH2:9][CH2:8][C:7]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)c2[nH]c3c(Cl)cc(F)cc3c2CCC1C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OC1(C(F)(F)F)c2[nH]c3c(Cl)cc(F)cc3c2CCC1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
8-Chloro-6-fluoro-1,2-bis(trifluoromethyl)-1-(trimethylsilyloxy)-2,3,4,9-tetrahydro-1H-carbazole (0.2 g, 0.44 mmol) was dissolved in THF (10 mL) and KOH (0.125 g, 2.2 mmol), water (2 mL), was added. The reaction mixture was stirred at room temperature for 2 h, diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over Na2SO4, concentrated in vacuo and purified by column chromatography [EtOAc-hexane (1:19) as eluant] to obtain the title compound (0.070 g, 42%) (HPLC 99%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.49 (br s, 1H), 7.26-7.23 (d, J=11.0 Hz, 1H), 7.14-7.11 (dd, J=8.5, 2.0 Hz, 1H), 3.71-3.67 (m, 1H), 2.60-2.57 (m, 1H), 5.54 (s, 1H), 2.40-2.37 (m, 1H), 2.30-2.24 (m, 1H), 2.10-2.07 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]=[C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][O:7][C:8](=[O:10])[CH3:9]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][O:7][C:8](=[O:10])[CH3:9]
Reactant: COC(=O)C=C(COC(C)=O)c1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)CC(COC(C)=O)c1ccccc1
Yield: 92.2 %

Procedure:
A mixture of 4-acetoxy-3-phenyl-but-2-enoic acid methyl ester, (1.0 g, 4.27 mmol), 10 wt. % palladium on activated carbon (1.0 g), acetic acid (10 mL) is shaken under an atmosphere of hydrogen on a Parr® Shaker. The mixture is filtered through a pad of Celite® and rinsed with methanol. The solution is concentrated in vacuo to yield 0.93 g (92%) of the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][C:8]=1[CH2:17][CH2:18][CH3:19])(=O)=O.[O:22]1CCO[CH:23]1[C:27]1[CH:28]=[CH:29][C:30]([CH3:36])=[C:31](B(O)O)[CH:32]=1>>[CH3:36][C:30]1[C:29]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:16])[CH2:14][CH3:15])=[CH:9][C:8]=2[CH2:17][CH2:18][CH3:19])=[CH:28][C:27]([CH:23]=[O:22])=[CH:32][CH:31]=1
Reactant: CCCc1cc(C(=O)CC)ccc1OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(C2OCCO2)cc1B(O)O
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(C=O)ccc1C

Procedure:
In a manner similar to that of Example 1(g), by reacting 2 g (6.2 mmol) of 4-propionyl-2-propylphenyl 1,1,1-trifluoromethanesulfonate with 1.2 g (8 mmol) of 5-[1,3]dioxolan-2-yl-2-methylphenylboronic acid, and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (90/10), 1.42 g (78%) of product are obtained in the form of a pale yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][C:11](=[CH2:14])[CH2:12][OH:13])=[O:8].[CH2:15]([N:28]=[C:29]=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:15]([NH:28][C:29]([O:13][CH2:12][C:11](=[CH2:14])[CH2:10][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCCN=C=O
Reactant: C=C(CO)COC(=O)CCCCCBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(COC(=O)CCCCCBr)COC(=O)NCCCCCCCCCCCCC
Temperature: 22 °C
Reaction time: 23 h

Procedure:
3-(6-Bromohexanoyloxy)-2-methylenepropan-1-ol (from Preparation 44) (0.58 g), tridecyl isocyanate (0.55 g) and 4-dimethylaminopyridine (0.05 g) were mixed in methylene chloride (3 ml). After stirring for 23 hours at 22° C. the mixture was filtered, and the filtrate was purified through a column of silica gel 60 (70-230 mesh, 4 g) eluting with ether/chloroform 1:1. Further purification was achieved by chromatography on Waters PrepLC®/System 500A using a prepPAK®-500/SILICA cartridge with ether/chloroform/pentane 1:1:4 as eluent.
Reaction SMILES: [N:1]1[CH:6]=[C:5](/[CH:7]=[N:8]/[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:20])([F:19])[F:18])[CH:11]=2)[CH:4]=[N:3][CH:2]=1.[C:21]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:22][C:23]([CH3:25])=O>[Cl-].[Zn+2].[Cl-]>[CH2:28]([O:27][C:21]([C:22]1[C:7]([C:5]2[CH:6]=[N:1][CH:2]=[N:3][CH:4]=2)=[N:8][N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]([F:18])([F:19])[F:20])[CH:11]=2)[C:23]=1[CH3:25])=[O:26])[CH3:29]
Reactant: CCOC(=O)CC(C)=O
Reactant: FC(F)(F)Oc1cccc(N/N=C/c2cncnc2)c1
Agent: [Cl-]
Agent: [Zn+2]
Product: CCOC(=O)c1c(-c2cncnc2)nn(-c2cccc(OC(F)(F)F)c2)c1C
Temperature: 170 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
A mixture of N-[1-pyrimidin-5-yl-meth-(E)-ylidene]-N′-(3-trifluoromethoxy-phenyl)-hydrazine (215 mg, 0.76 mmol) and zinc chloride (208 mg, 1.52 mmol) in 2 ml ethyl acetoacetate was heated at 170° C. for 3 h and stirring was continued for 20 h at room temperature. Ethyl acetoacetate was distilled (Kugelrohr distillation, 90° C., 10-40 mbar) and the residue was purified by column chromatography (EtOAc:n-heptane 4:1) to afford the title compound as a yellow oil (89 mg, 30%). MS: 393.0 (MH+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[C:13]([F:18])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].[CH:19]12CC(C=C1)C=[CH:20]2>O1CCOCC1>[F:18][C:13]1[CH:12]=[C:11]([N:7]2[CH2:6][C@H:5]([CH2:4][N:1]3[CH:20]=[CH:19][N:3]=[N:2]3)[O:9][C:8]2=[O:10])[CH:16]=[CH:15][C:14]=1[I:17]
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: C1=CC2C=CC1C2
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Temperature: 100 °C

Procedure:
(5R)-5-(Azidomethyl)-3-(3-fluoro-4-iodophenyl)-1,3-oxazolidin-2-one (Intermediate 5, 30.3 g, 72.9 mmol) was stirred in 1,4-dioxane. Bicyclo[2.2.1]hepta-2,5-diene (40.3 g, 437 mmol) was added and the reaction was heated at 100° C. overnight. The resulting brown mixture was filtered and the desired product was obtained as a light brown solid (14.8 g).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([Li])CCC>CCCCCC>[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:8](=[O:10])[CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:12][CH:11]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)COc1ccc(F)cc1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Product: O=C(COc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
The target compound (2.76 g) was obtained as colorless crystals by carrying out the reaction and the post-treatment according to Reference example 20(a) using 4-fluorophenoxyacetic acid (1.70 g), oxalyl chloride (2.18 ml), (S)-4-benzyl-2-oxazolidinone (1.77 g) and a solution of n-butyl lithium in hexane (1.61N, 7.14 ml).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([Cl:13])([Cl:12])[Cl:11])[CH:3]=1.[N-:14]=[N+]=[N-].[Na+].O.[BH4-].[Na+]>CN(C=O)C.CO>[NH2:14][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]([C:10]([Cl:13])([Cl:12])[Cl:11])[CH:3]=1
Reactant: Clc1cc(C(Cl)(Cl)Cl)nc(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(C(Cl)(Cl)Cl)nc(Cl)c1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
To a solution of 4,5,6-trichloro-2-trichloromethylpyridine (2 g, 6.7 mmol) in aqueous DMF was added NaN3 (0.5 g, 7.7 mmol). The resulting mixture was heated at 70° C. for 2 hr, added to H2O and extracted (3x) with Et2O. Organic layer was concentrated to yield a white solid, which was dissolved in 10 mL of MeOH. Excess NaBH4 was added and the reaction mixture was stirred at room temperature for 0.5 hr. This material was added to H2O, extracted (3×) with Et2O, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed several times with hexane to give 1.3 g of 4-amino-5,6-dichloro-2-trichloromethylpyridine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](O)=[O:8])=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.S(Cl)([Cl:16])=O>CCCCCC>[CH3:1][N:2]1[C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: Cn1nc(C(F)(F)F)cc1C(=O)Cl
Yield: 67.3 %

Procedure:
A mixture of 0.19 g of 1-methyl-3-trifluoromethyl-1H-pyrazole-5-carboxylic acid, 0.15 g of thionyl chloride and 5 ml of hexane was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.14 g of 1-methyl-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride. To a mixture of 0.22 g of N-(2-aminobenzoyl)-N′-ethoxycarbonylhydrazine and 10 ml of pyridine was added 0.14 g of the resulting 1-methyl-3-trifluoromethyl-1H-pyrazole-5-carbonyl chloride and the mixture was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and a deposited precipitates were collected by filtration to obtain 0.23 g of the present compound (3) of the formula:
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:16])[CH2:14][OH:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]1=2.C(#N)C.[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C>O>[C:24]([O:15][CH2:14][CH:13]([C:11]1[CH:10]=[CH:9][C:8]2[C:2](=[O:1])[C:3]3[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=3[CH:5]=[CH:6][C:7]=2[CH:12]=1)[CH3:16])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC(CO)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(=O)OCC(C)c1ccc2c(=O)c3ccccc3ccc2c1
Reaction time: 1 h

Procedure:
0.5 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propan-1-ol is dissolved in 15 ml. of acetonitrile and 2 ml. of acetyl chloride and 1.3 ml. of triethylamine are added to the solution. After 1 hour, the mixture is poured into water and extracted with ethyl acetate. The extract is dried and evaporated, then dissolved in ether and passed through a silica gel column, and the eluate evaporated to afford 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)prop-1-yl acetate [an oil, nmr spectrum in deuterochloroform relative to tetramethylsilane, 1.33 (doublet, CH3), 1.98 (singlet, acetoxy), 4.23 (doublet, CH2) and 7.02 ppm (singlet, 10H, 11H); mass spectrum: 306 (M+), 246, 234].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH:11][CH3:12])=[C:6]([Cl:13])[C:5]=1[NH2:14].[C:16](O)(=O)C.C(N)=N.CCOC(C)=O>CCO>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:14])=[C:6]([Cl:13])[C:7]2[N:11]([CH3:16])[CH:12]=[N:10][C:8]=2[CH:9]=1)=[O:15]
Reactant: CNc1c(N)cc(C(=O)OC)c(N)c1Cl
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cc2ncn(C)c2c(Cl)c1N
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 1 g (4.35 mmol) of 2,5-diamino-3-chloro-4-methylamino-benzoic acid methyl ester in 153 ml of EtOH, is added 700 mg (6.53 mmol) of formamidine acetate. The mixture is stirred at a temperature of 80° C. for 24 hours. EtOAc is added and the organic phase is washed once with H2O and once with brine. Then the organic layer is dried on Na2SO4, filtrated and concentrated. After purification by flash chromatography on silica gel 0.68 g (2.84 mmol, 65%) of a dark violet solid were obtained. LC/MS: 240/242 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH3:21])=[O:5])[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:47])C(=O)C1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][Br:47])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Temperature: 0 °C

Procedure:
To a solution of 200 g of commercially available 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester in 1.6 L of dichloromethane were added 20.5 g of benzoyl peroxide and 124 g of NBS. The resulting mixture was refluxed in the dark for 22 h. After cooling to 0° C., the mixture was filtered. The filtrate was concentrated to half volume under reduced pressure, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a white solid. The solid was recrystallized in 900 mL of diisopropyl ether 80/dichloromethane 20 to give a first crop of 101 g of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester. The filtrate was concentrated under reduced pressure then recrystallized in 300 mL of diisopropyl ether 90/dichloromethane 10 to give a second crop of 72 g. A total of 173 g of 4-bromomethyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester was obtained as a white solid. 4 WO02067912
Reaction SMILES: [CH2:1]1[C:4]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][O:5]2)[CH2:3][NH:2]1.Br[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][OH:28])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[OH:28][CH2:27][CH2:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][CH2:18][N:2]1[CH2:3][C:4]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][CH2:6][O:5]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CCOC2(CNC2)C1
Reactant: OCCc1cccc(CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC2(CN(CCc3cccc(CCO)c3)C2)C1
Temperature: 60 °C

Procedure:
A mixture of tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate (0.49 g) (example 176 step c), 2-(3-(2-bromoethyl)phenyl)ethanol (0.738 g) [Organometallics 2002, 21(20), 4217] and potassium carbonate (1.187 g) in acetonitrile (30 mL) and water (0.5 mL) was heated at 60° C. for 24 hours. The mixture was cooled to RT and filtered. The solvent was passed through a 10 g SCX cartridge and further acetonitrile then eluted through. The cartridge was then eluted with a 10% solution of 880 ammonia in acetonitrile (80 mL) to bring off product. The solvents were evaporated under reduced pressure and the residue was diluted with acetonitrile and then evaporated to dryness to afford the subtitled compound. Yield 0.610 g.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[O:13])=O)C.[Li+].[BH4-].C(OCC)(=O)C>O1CCOCC1>[OH:3][CH2:4][CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=[O:13]
Reactant: CCOC(=O)Cn1ccccc1=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=c1ccccn1CCO
Reaction time: 0.08 h
Yield: 41.3 %

Procedure:
In 100 ml of dioxane, was dissolved N-ethoxycarbonylmethyl-2-pyridone (3.62 g, 20 mmol). To the solution was added 90% LiBH4 (0.96 g, 40 mmol) and the mixture was refluxed for 20 minutes. Subsequently, ethyl acetate (20 ml) was added to the mixture and the refluxing was carried out for five minutes. The reaction mixture was evaporated to dryness and water was added to the residue. The aqueous solution was extracted with chloroform (three times), dried, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, to thereby obtain the title compound (1.15 g, yield 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[C:4]([F:25])[CH:3]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4nc(C)c(C)cc4C)CC3)c(F)c2)C1=O
Yield: 52.1 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (406 mg) described in Preparation Example 128 and 1-acetylimidazolidin-2-one (192 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (236 mg) was obtained.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[OH:19][C:20]([CH3:26])([CH3:25])[C:21]([NH:23][NH2:24])=[O:22]>>[OH:19][C:20]([CH3:26])([CH3:25])[C:21]([NH:23]/[N:24]=[C:9]1\[C:7](=[O:8])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:16]2[C:11]\1=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)=[O:22]
Reactant: CC(C)(O)C(=O)NN
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Product: CCCCCN1C(=O)/C(=N\NC(=O)C(C)(C)O)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and 2-hydroxy-2-methylpropanohydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.36 to 1.39 (m, 4H), 1.59 (s, 6H), 1.87 (m, 3H), 2.63 (s, 1H), 3.68 (t, 2H), 3.87 (s, 3H), 6.41 (d, 1H), 6.61 (dd, 1H), 7.73 (d, 1H), 13.71 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[CH:7][CH:8]=1.[Br:10]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:10][C:6]1[NH:5][C:4](=[O:9])[C:3]([O:2][CH3:1])=[CH:8][CH:7]=1
Reactant: COc1ccc[nH]c1=O
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-methoxy-2(1 h)-pyridone (1.00 g, 7.99 mmol, AstaTech, Inc) in DCM (26 mL) at 0° C. was slowly added bromine (0.819 mL, 15.98 mmol). After addition, the mixture was stirred at rt for 18 h. The mixture was then cooled to 0° C. and saturated aqueous NaHCO3 (4 mL) was slowly added. The mixture was then stirred at rt for 30 min. The organic layer was collected and the aqueous layer was extracted with EtOAc (1×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was then dissolved in MeOH (20 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The solid mixture was purified by silica gel flash column chromatography (solid loading, 0%-100% EtOAc/hexane) to give the title compound as a tan solid. MS (ESI, positive ion) m/z: 204, 206 (M+H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[N:9]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]#[N:15])[CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OCCCc1cccc(C#N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: N#Cc1cccc(CCCO)n1
Temperature: 25 °C
Reaction time: 22 h
Yield: 92.3 %

Procedure:
3-(6-Cyano-2-pyridyl)propyl acetate (3.0 g, 14.7 mmol) was dissolved in methanol (15 ml), and potassium carbonate (0.08 g, 0.58 mmol) was added thereto. The reaction mixture was stirred at room temperature for 22 hrs and concentrated to give the titled compound (2.2 g, 92%).
Reaction SMILES: C[Al](C)C.[CH:5]1([CH2:8][NH2:9])[CH2:7][CH2:6]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[C:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[N:23][O:24][C:25]=2[CH3:26])=[N:15][CH:14]=1.O>O1CCOCC1>[CH:5]1([CH2:8][NH:9][C:12](=[O:11])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[C:22]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=4)=[N:23][O:24][C:25]=3[CH3:26])=[N:15][CH:14]=2)[CH2:7][CH2:6]1
Reactant: NCC1CC1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 600 μL, 1.2 mmol) was added dropwise (exothermic) to a solution of cyclopropylmethylamine (85 mg, 103 μL, 1.2 mmol) in dioxane (7.5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) in dioxane (4 mL) was added. The resulting mixture was then heated at 85-95° C. overnight and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (78 mg, 68%) which was obtained as an off white solid. MS: m/e=382.3 [M+H]+.