Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[N:12]2)[CH2:7][CH2:6]1.I[C:26]1[CH:31]=[N:30][C:29]([NH2:32])=[C:28]2[O:33][C:34]([C:36]3[CH:45]=[CH:44][CH:43]=[C:42]4[C:37]=3[CH:38]=[CH:39][N:40]=[CH:41]4)=[CH:35][C:27]=12.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH:41]1[C:42]2[C:37](=[C:36]([C:34]3[O:33][C:28]4=[C:29]([NH2:32])[N:30]=[CH:31][C:26]([C:14]5[CH:13]=[N:12][N:11]([CH:8]6[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:9]6)[CH:15]=5)=[C:27]4[CH:35]=3)[CH:45]=[CH:44][CH:43]=2)[CH:38]=[CH:39][N:40]=1
Reactant: COCCN1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(I)c2cc(-c3cccc4cnccc34)oc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCCN1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnccc56)cc34)cn2)CC1
Temperature: 100 °C
Yield: 6.3 %

Procedure:
A vial was charged with 1-(2-methoxyethyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine (32.4 mg, 96.8 μmol) and 4-iodo-2-(isoquinolin-5-yl)furo[2,3-c]pyridin-7-amine (25.0 mg, 64.6 μmol) in 1,4-dioxane (0.43 mL) and H2O (0.1 mL), potassium carbonate (13 mg, 97.0 μmol) and (1,1′-bis(diphenylphosphino)ferrocene) palladium dichloride (5 mg, 6 μmol) was evacuated and filled with argon three times. The mixture was heated in a microwave reactor at 100° C. for 40 min. The reaction mixture was partitioned between EtOAc and brine/water and separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography (0 to 10% 7 N NH3/MeOH:EtOAc) afforded 1.9 mg (6%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 9.33 (s, 1 H), 8.57 (d, J=6.06 Hz, 1 H), 8.49 (d, J=6.06 Hz, 1 H), 8.34 (dd, J=7.33, 1.26 Hz, 1 H), 8.23 (d, J=8.34 Hz, 1 H), 8.13 (s, 1 H), 7.92 (d, J=9.09 Hz, 2 H), 7.82 (t, J=7.71 Hz, 1 H), 7.49 (s, 1 H), 4.25 (dt, J=15.54, 7.89 Hz, 1 H), 3.58 (t, J=5.56 Hz, 2 H), 3.37 (s, 3 H), 3.15 (d, J=12.13 Hz, 2 H), 2.66 (t, J=5.56 Hz, 2 H), 2.26-2.35 (m, 2 H), 2.13-2.20 (m, 4 H); MS (ESI): 469.23 [M+H]+; HPLC tR=0.77 min (TOF: polar—3 min).
Reaction SMILES: O[CH2:2][C:3]([CH3:14])([CH3:13])[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH3:15][C:16]1([CH3:28])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[N:25][NH:26][CH:27]=2)[O:17]1.C(P(CCCC)(CCCC)=CC#N)CCC>C1(C)C=CC=CC=1>[CH3:13][C:3]([CH3:14])([CH2:2][N:26]1[CH:27]=[C:23]([B:18]2[O:17][C:16]([CH3:28])([CH3:15])[C:20]([CH3:22])([CH3:21])[O:19]2)[CH:24]=[N:25]1)[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(CO)CNC(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(CNC(=O)OC(C)(C)C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
A solution of tert-butyl (3-hydroxy-2,2-dimethylpropyl)carbamate (1.000 g, 4.92 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.145 g, 5.90 mmol) and 2-(tributylphosphoranylidene)acetonitrile (1.425 g, 5.90 mmol) were stirred together in toluene (20 ml) at 90° C. overnight. The reaction mixture was concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[NH2:14][C:15]1[C:19]2[CH:20]=[C:21]3[C:34](=[C:35]([F:36])[C:18]=2[O:17][N:16]=1)[N:33]1[CH2:37][C@@H:38]([CH3:42])[O:39][C@@H:40]([CH3:41])[C@@H:32]1[C:23]1([C:28](=[O:29])[NH:27][C:26](=[O:30])[NH:25][C:24]1=[O:31])[CH2:22]3>C(Cl)CCl>[F:36][C:35]1[C:18]2[O:17][N:16]=[C:15]([NH:14][C:7](=[O:9])[CH3:8])[C:19]=2[CH:20]=[C:21]2[C:34]=1[N:33]1[CH2:37][C@@H:38]([CH3:42])[O:39][C@@H:40]([CH3:41])[C@@H:32]1[C:23]1([C:28](=[O:29])[NH:27][C:26](=[O:30])[NH:25][C:24]1=[O:31])[CH2:22]2
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H]1CN2c3c(cc4c(N)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Temperature: 130 °C
Reaction time: 12 h

Procedure:
Pyridine (0.01 mL, 0.2 mmol) and acetic anhydride (0.10 mL, 0.14 mmol) were added sequentially to a solution of (2R,4S,4aS)-rel-8-amino-11-fluoro-2,4-dimethyl-1,2,4,4a-tetrahydro-2′H,6H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Example 1, 54 mg, 0.13 mmol) in ethylene dichloride, and the mixture was stirred at 130° C. for 12 hours. After cooling to room temperature, solvent was removed, and the residue was purified over a silica gel flash column using a gradient of methanol in chloroform to give the title compound as a racemic mixture in the form of a yellow solid. Yield: 7.5 mg, (13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11](O)=[O:12].C(N(CC)CC)C.C(OC(Cl)=O)(C)C.C1(C)C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=C(O)CCc1c(Cl)cccc1Cl
Agent: CC(C)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCc1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A solution of 3-(2,6-dichlorophenyl)propanoic acid (5.00 g, 22.8 mmol) in THF (114 mL) was stirred at room temperature as triethylamine (3.2 mL, 22.8 mmol) was added. The solution was then cooled in an ice/water bath before the addition of a 1 M solution of isopropylchloroformate in toluene (22.8 mL, 22.8 mmol). After 30 minutes the mixture was filtered into a mixture of sodium borohydride (1.13 g, 30 mmol) in water (8 mL). The resulting mixture was stirred in an ice/water bath and allowed to warm slowly to room temperature. The mixture was allowed to stir at room temperature overnight, then was filtered. The filtrate was partitioned between brine and ethyl acetate. The organic layer was dried with MgSO4, filtered, and concentrated. The residue was purified by chromatography (silica gel, 3:7 ethyl acetate:hexanes) to provide the title compound (3.85 g, 77% as ·0.17 EtOAc). 1H NMR (d6-DMSO): 7.41 (d, J=8 Hz, 2H), 7.22 (t, J=8 Hz, 1H), 4.57 (t, J=5 Hz, 1H), 3.48-3.43 (m, 2H), 2.88-2.84 (m, 2H), 1.65-1.58 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1)[C:29](O)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=[C:26]([O:25][CH3:24])[CH:27]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: COc1cc(OC)cc(C(=O)O)c1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cc(OC)cc(OC)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,5-dimethoxy-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.80 mmol) and 3,5-dimethoxy benzoic acid (161 mg, 0.87 mmol). The title compound was obtained as powder (62 mg, 16%).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][CH:13]=2)[CH:5]=1.[OH-].[Na+]>O.C(O)C>[C:15]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:24])=[O:2])=[CH:13][CH:14]=1
Reactant: COC(=O)c1cccc(COc2ccc(-c3ccccc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(COc2ccc(-c3ccccc3)cc2)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To the above benzoic acid methyl ester (12.3 g, 40.0 mmol) suspended in a mixture of water (125 ml) and ethanol (125 ml) was added sodium hydroxide (4.80 g, 0.12 mol) and the reaction mixture was heated at 60° C. for 20 h. The volatiles were evaporated in vacuo and to the residue was added water (50 ml) followed by concentrated hydrochloric acid to pH=1. The resulting mixture was stirred at room temperature for 20 h and the precipitate was filtered off and washed with water (3×25 ml), suspended in diethyl ether (100 ml) and stirred for 2 h. The precipitate was filtered off and dried in vacuo at 50° C. which afforded 10.23 g (81%) of 3-(biphenyl-4-yloxymethyl)benzoic acid as a solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[F:10][C:11]([Si](C)(C)C)([F:16])[C:12]([F:15])([F:14])[F:13].[F-].[K+].N>[Cu](I)I.CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]([F:16])([F:10])[C:12]([F:15])([F:14])[F:13])=[CH:3][CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: I[Cu]I
Agent: N
Agent: [F-]
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2.00 g 4-iodo-anisol, 2.00 g pentafluoroethyl-trimethylsilane, 0.60 g potassium fluoride, 2.43 g copper iodide and 15 ml N,N-dimethylformamide is stirred overnight at 80° C. Then the mixture is stirred for a further 36 h at 80° C., while a further 2.00 g pentafluoroethyl-trimethylsilane are added after 4 h, 12 h and 24 h. After cooling to ambient temperature 2 M aqueous ammonia solution is added and the mixture is filtered. The filtrate is extracted with ethyl acetate, and the combined organic extracts are dried (Na2SO4) and evaporated down. The residue is chromatographed on silica gel with petroleum ether/ethyl acetate (9:1) as eluant.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].[NH:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10](=O)[C:11]([O:13][CH3:14])=[O:12]>CO>[CH3:2][O:3][N:4]=[C:10]([C:6]1[NH:5][CH:9]=[CH:8][CH:7]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CON
Reactant: COC(=O)C(=O)c1ccc[nH]1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc[nH]1

Procedure:
97.5 g (1.2 eq) of methoxyamine hydrochloride are added to a solution of 148.8 g (0.97 mol) of methyl pyrrol-2-ylglyoxylate (prepared by a method similar to that described by B. Lindstrbm et al., Acta Chem. Scand. 27 (1973), 7) in 1 l of methanol, and the solution is refluxed for 2.5 hours. After evaporation in a rotary evaporator, the residue is taken up in ethyl acetate and the solution is washed with water, dried and evaporated down. 81 g (46%) of the pyrrole remained in the form of an oil.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:26])[C:13]([N:23]([CH3:25])[CH3:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:51]I>C(Cl)Cl>[I:51][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:26])[C:13]([N:23]([CH3:25])[CH3:24])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1
Reactant: II
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCO)cc1)N(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCI)cc1)N(C)C
Temperature: 20 °C
Reaction time: 0.33 h

Procedure:
14.5 g (0.041 mol) of 1-[4-(3-Hydroxypropylamino)phenyl]-2-dimethylamino-2-benzyl-butan-1-one, 6.96 g (0.1 mol) of imidazole and 26.8 g (0.1 mol) of triphenyl phosphine are dissolved in 100 ml of methylene chloride. To the solution are added 20.8 g (0.082 mol) of iodine and stirred at room temperature (about 20° C.) for 20 min. 200 ml of methylene chloride are added to the reaction mixture and washed with aqueous solution of sodium sulfite and water, and dried over MgSO4. After distilling off the methylene chloride, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:4) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.82-1.88 (m, 1H), 2.02-2.35 (m, 3H), 2.35 (s, 6H), 3.17 (d, 1H), 3.20 (d, 1H), 3.27 (t, 2H), 3.34-3.37 (m, 2H), 4.17 (br, 1H), 6.53 (d, 2H), 7.15-7.28 (m, 5H), 8.32 (d, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11](C#N)=[CH:10][CH:9]=1.[CH3:20][O:21]C1C=CC(B(O)O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].FC1C=C(C2C(=O)N3C=CSC3=NC=2C)C=C(F)C=1>C1(C)C=CC=CC=1.O.C(O)C>[CH3:20][O:21][C:11]1[CH:14]=[CH:15][C:8]([C:7]2[C:6](=[O:16])[N:5]3[CH:17]=[CH:18][S:19][C:4]3=[N:3][C:2]=2[CH3:1])=[CH:9][CH:10]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(C)nc3sccn3c2=O)cc1
Yield: 78.9 %

Procedure:
The title compound was prepared by coupling reaction of Step 2 intermediate from Intermediate 4 (6.8 g, 23.271 mmol) with 4-methoxyphenylboronic acid (4.95 g, 32.490 mmol) in the presence of Pd[(C6H5)3P]4 (1.076 g, 0.931 mmol) and sodium carbonate (14.812 g, 139.071 mmol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, step 3 yielded 5.0 g of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.83 (s, 3H), 6.92-6.96 (m, 3H), 7.20-7.23 (m, 2H), 7.94 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 273.51 (M+H)+.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]([O:9][CH:10]([Cl:12])[CH3:11])=[O:8].N1C=CC=CC=1>ClCCl>[C:7](=[O:8])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][CH:10]([Cl:12])[CH3:11]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OC(C)(C)C

Procedure:
In a reactor cooled to +5° C., there are introduced 600 ml of dicloromethane, 43.7 g (0.59 mole) of tert-butanol and 94.7 g (0.66 mole) of α-chloroethyl chloroformate. 57 g (0.72 mole) of pyridine are then added dropwise and with stirring while the temperature is maintained at between 10° and 20° C. The mixture is stirred for 4 hours at room temperature.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([O:25]C(C)(C)C)=[O:24])=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[C:8]1(=[C:14]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added dropwise to 68 (210 mg, 0.519 mmol) dissolved in CH2Cl2 (2 mL) at 0° C. The reaction mixture was stirred at RT for 3 h and the volatiles were removed under reduced pressure. The residue was chromatographed on silica gel (20:1 CH2Cl2:MeOH) and recrystallized (EtOAc:hexanes) to afford 138 mg (76%) of 69 as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ1.51 (br s, 6H), 2.13 (m, 4H), 2.30 (s, 3H), 6.35 (d, J=16.0 Hz, 1H), 6.66 (d, J=8.2 Hz, 2H), 6.82-6.91 (m, 4H), 7.59 (d, J=7.9 Hz, 1H), 7.75 (d, J=16.0 Hz, 1H), 9.31 (s, 1H), 12.36 (br s, 1H). LRMS (ESI): m/z 349 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:15][CH2:14][C:9]2([O:13]CCO2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].Br[CH2:25][CH2:26][O:27][CH3:28].Cl>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:25][CH2:26][O:27][CH3:28])[CH2:7][CH2:8][C:9](=[O:13])[CH2:14][CH2:15]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: COCCBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCOC)CCC(=O)CC1
Temperature: -5 °C
Reaction time: 2.5 h

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decane-8-carboxylic acid ethyl ester (39.5 g) in THF (200 ml) was added dropwise over a period of 45 minutes at −5° C. (ice/methanol bath) to a solution of lithiumdiisopropylamide (2M in THF, 184.3 mL) in THF (300 ml). Stirring was continued for 2.5 hours at 0° C. The reaction mixture was cooled to −5° C. and 2-bromoethyl-methylether (34.6 ml) was added dropwise over a period of 30 minutes. Stirring was continued for 12 hours at RT. The reaction mixture was cooled to 0° C. and aqueous HCl (25%, 300 ml) was added dropwise over a period of 45 minutes to pH 1. Stirring was continued for 2 hours at RT. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a yellow liquid (25.2 g). MS (EI)=288.0 [M+].
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([O:13][CH2:14][CH3:15])(=[O:12])[C:7]([O:9]CC)=O.Cl>C(OCC)C>[O:9]=[C:7]([CH:1]([CH3:3])[CH3:2])[C:6]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(C)C
Temperature: -70 °C

Procedure:
Isopropylmagnesium chloride (2.0M in ether, 200 mmol) was added to a solution of diethyl oxalate (29.23 g, 20.0 mmol) in dry diethyl ether (100 ml) at −70° C. over a period of one hour. The mixture was stirred at −70° C. for a further half an hour and then poured immediately into a vigorously stirred suspension of ice (80 g), diethyl ether (100 ml) and concentrated HCl (18 ml). The aqueous phase was separated out and the organic phase washed with water (100 ml) and then dried (MgSO4) and the solvent was removed in order to leave the desired product in the form of a colourless oil.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.[CH:21]1([C:24]2[C:25]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[CH2:23][CH2:22]1>>[CH:21]1([C:24]2[C:25]([N:34]3[CH2:39][CH2:38][N:37]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:20])=[CH:8][C:9]=4[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:36][CH2:35]3)=[N:26][CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=2)[CH2:22][CH2:23]1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Product: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 79.5 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (271 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 87, the title compound (455 mg) was obtained.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[O-:19][CH2:20][CH3:21].[Na+].[Na]>C(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([O:19][CH2:20][CH3:21])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Yield: 95 %

Procedure:
2-Chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g) was added to an ethanol solution of sodium ethoxide prepared from sodium (0.35 g) and ethanol (15 ml), and stirred under reflux for 30 minutes. The solvent was evaporated, and water was added to the residue, which was then acidified with 2N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-ethoxy-5-oxazolepropionic acid (1.40 g, 95%). This was recrystallized from ethanol to give colorless prisms. mp 148-149° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][N:22]=[C:16]2[CH2:15]1)=[O:13].[F:29]C1C=CC(B(O)O)=CC=1.C1(B(O)O)C=CC=CC=1.CCCC(C)C>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[N:21][N:22]=[C:16]2[CH2:15]1)=[O:13]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccccc2)C1
Reactant: OB(O)c1ccc(F)cc1
Agent: OB(O)c1ccccc1
Solvent: CCCC(C)C
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccc(F)cc2)C1

Procedure:
7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-(4-fluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine was prepared in a manner analogous to that described above for 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (Example 13), but using (4-fluorophenyl)boronic acid (commercially available e.g. from Alfa Aesar or ABCR) in the place of phenylboronic acid, and using MDAP followed by isohexane trituration rather than MDAP.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22].[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27]Br>>[F:24][C:25]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:26]=1[CH2:27][O:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:12][CH2:13]2)=[O:7])=[CH:4][C:3]=1[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1O
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(F)cc1F
Yield: 74.8 %

Procedure:
As in the case of Example 18, 1-(4-hydroxy-3-isobutylbenzoyl)-4-isobutylpiperazine (1.60 g) was benzylated with 2,4-difluorobenzyl bromide (1.24 g), thereby yielding 1.67 g of the aimed compound.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:33][CH3:34])=[CH:30][CH:31]=2)[N:26]=[CH:25][N:24]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]2[C:32]([C:23]([N:18]3[CH2:19][CH2:20][CH:15]([N:5]4[C:6](=[O:14])[C:7]5[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=5)[N:3]([CH3:2])[C:4]4=[O:21])[CH2:16][CH2:17]3)=[N:24][CH:25]=[N:26]2)=[CH:31][CH:30]=1
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Agent: Br
Product: COc1ccc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)ncnc2c1
Yield: 22 %

Procedure:
The procedure similar to that described in Example 57 was repeated, except that 354.0 g (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide (Compound v) obtained in Example 41 was used and 4-chloro-7-methoxyquinazoline was used in place of 4-chloro-6,7-dimethoxyquinazoline. As a result, 96.2 mg (yield: 22%) of Compound 85 was obtained as white crystals.
Reaction SMILES: [CH:1](=[CH:10][C:11](=[O:13])[CH3:12])[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.CCOCC.C([O-])(=O)C>[Pt]=O>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:1][CH2:10][C:11](=[O:13])[CH3:12]
Reactant: COc1ccccc1C=CC(C)=O
Agent: O=[Pt]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: COc1ccccc1CCC(C)=O
Yield: 45 %

Procedure:
The crude o-anisalacetone is hydrogenated (100 g/l liter of ether acetate and 1 g of platinum oxide) and then distilled to give 1.25 moles (45%) of 1-(o-methoxyphenyl)-3-butanone, bp 90°-110° C., 0.15 mm Hg.