Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Li].[CH2:3](OCC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:23]([CH3:36])=[C:24]([CH3:35])[C:25]4[O:29][C:28]([CH3:31])([CH3:30])[C:27](=[O:32])[C:26]=4[C:33]=3[CH3:34])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1>C1COCC1.O>[CH3:30][C:28]1([CH3:31])[C:27]([CH3:3])([OH:32])[C:26]2[C:33]([CH3:34])=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([O:9][CH3:8])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)[C:23]([CH3:36])=[C:24]([CH3:35])[C:25]=2[O:29]1
Reactant: CCOCC
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C)(O)C(C)(C)O4)CC2)cc1
Reaction time: 0.17 h
Yield: 96.3 %

Procedure:
A solution of methyllithium in diethyl ether (1.14 M, 5.60 mL, 6.38 mmol) was added dropwise to a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (2.00 g, 5.06 mmol) obtained in Reference Example 13 in THF (20 ml) under ice cooling and the mixture was stirred for 10 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was crystallized from hexane to obtain 2.00 g (yield 96%) of the title compound. mp. 139–141° C.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[O:24]1[CH2:29][CH2:28][CH:27]([CH:30]=O)[CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.O1CCCC1>[F:1][C:2]1[C:3]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:30][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C=C(c2c(F)cccc2N2CCNCC2)CC(C)(C)C1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)C=C(c2c(F)cccc2N2CCN(CC3CCOCC3)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a mixture of 1-[3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperazine (115 mg, 0.363 mmol) produced in Example (97d), tetrahydropyran-4-carbaldehyde (62 mg, 0.543 mmol) and tetrahydrofuran (7 mL) were added sodium triacetoxyborohydride (154 mg, 0.726 mmol) and acetic acid (0.021 mL, 0.363 mmol) in that order, followed by stirring for 1 hour and 30 minutes at room temperature. Ethyl acetate, saturated aqueous solution of sodium hydrogencarbonate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 108 mg of 1-[3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]-4-(tetrahydropyran-4-ylmethyl)piperazine as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:8]([CH:11]=1)[C:9]#[N:10])(=[O:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1.C(N(CCCC)CCCC)CCC.Cl>O.C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([C:25]([OH:30])([C:26]([F:27])([F:28])[F:29])[CH2:2][C:1]([C:4]2[CH:5]=[CH:6][C:7]([N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[C:8]([CH:11]=2)[C:9]#[N:10])=[O:3])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: CC(=O)c1ccc(-n2cncn2)c(C#N)c1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: Cl
Solvent: CCCCN(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 60 °C
Reaction time: 24 h
Yield: 56 %

Procedure:
1.00 g (4.71 mmol) of 5-acetyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile, 1.15 g (4.71 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 2.30 g of toluene and 0.26 g (1.41 mmol) of tributylamine were fed and the mixture was stirred for 24 hours at 60° C. The mixture was cooled to room temperature, and a separation operation was performed by adding 20 ml of toluene and an aqueous solution prepared with 0.15 g (1.41 mmol) of 35% hydrochloric acid and 10 ml of water. The toluene phase was washed with 10 ml of water. After removing the solvent by distilling under reduced pressure, the residue was purified by silica gel column chromatography to obtain 1.20 g of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 56.0%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:10]=1)C1C=CC=CC=1.C(O)C.C1COCC1.[H][H]>[Pd].CN(C=O)C>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[N:16]=[CH:15][N:14]=1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OCCCN4CCOCC4)c23)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OCCCN4CCOCC4)c23)c1
Yield: 29.3 %

Procedure:
A mixture of 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-(3-morpholinopropoxy)quinazoline (0.185 g), 10% palladium on charcoal catalyst (0.018 g), ethanol (2.5 ml), THF (2.5 ml) and DMF (1 ml) was stirred under an atmosphere pressure of hydrogen for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.045 g); NMR Spectrum: (DMSOd6) 2.05 (m, 2H), 2.35 (br s, 4H), 2.45 (t, 2H), 3.55 (t, 4H), 3.8 (s, 3H), 4.42 (t, 2H), 6.7 (d, 2H), 7.45 (d, 1H), 8.3 (s, 1H), 8.45 (s, 1H), 10.05 (s, 1H); Mass Spectrum: M+H+ 445.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:9](=[O:11])[NH:10][C:5]2=[N:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:26]3[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=3)=[CH:3][N:4]=[C:5]2[NH:10][C:9]1=[O:11])([O-:21])=[O:20]
Reactant: O=c1[nH]c2ncc(Br)nc2n1Cc1cccc([N+](=O)[O-])c1
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3[nH]c(=O)n(Cc4cccc([N+](=O)[O-])c4)c3n2)cc(OC)c1OC
Temperature: 95 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of 6-bromo-1-(3-nitrobenzyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one (95 mg, 0.27 mmol), 3,4,5-trimethoxyphenyl boronic acid (65 mg, 0.30 mmol) and potassium carbonate (120 mg, 0.88 mmol) in degassed 20% aq. dioxane (2.5 mL) was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (24 mg, 0.029 mmol) under an argon atmosphere. The mixture was stirred at 95° C. overnight, then cooled to room temperature and concentrated under reduced pressure. Purification of the resultant residue by flash chromatography [silica gel; hexanes/ethyl acetate (2:1)] afforded 1-(3-nitrobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one as a white solid (82 mg, 70%). 1H NMR (300 MHz, CDCl3): δ 8.48 (t, J=2.2 Hz, 1H), 8.19 (dd, J=7.5 and 2.2 Hz, 1H), 7.91 (dd, J=7.5 and 2.2 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.16 (s, 2H), 5.30 (s, 2H), 4.00 (s, 6H), 3.92 (s, 3H). MS: 438.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])=[O:4].Cl.[CH3:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17].C1(C)C=CC=CC=1.O>CCOCC>[CH3:15][N:16]([CH2:18][CH2:19][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[C:2]([F:12])([F:13])[F:1])[CH3:17]
Reactant: O=C(c1ccccc1O)C(F)(F)F
Reactant: CN(C)CCCl
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccccc1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 2-trifluoroacetylphenol (380 mg, 2.0 mmol), 2-[N,N-dimethylamino]ethyl chloride, hydrochloride (432 mg, 6.0 mmol) potassium carbonate (1.38 g, 10 mmol) and toluene (5 ml) was refluxed for 3.5 h. After cooling to r.t., the mixture was treated with water and ether. The organic layer was washed twice with brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (acetone/ether 1:1 to 1:0) to give the title compound (375 mg, 72%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[F:18][C:19]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:20]=1[C:21]#[N:22].C([O-])(O)=O.[Na+].N#N>O1CCOCC1.O.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>[NH2:8][C:6]1[N:7]=[C:2]([C:25]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([F:18])[CH:26]=2)[CH:3]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:5]=1
Reactant: Nc1nc(Cl)cc(NCc2ccccc2Cl)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(NCc3ccccc3Cl)nc(N)n2)cc1F
Temperature: 100 °C
Yield: 50.7 %

Procedure:
A mixture of 6-chloro-N4-[(2-chlorophenyl)methyl]-2,4-pyrimidinediamine (1.2 g, 4.46 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.32 g, 5.35 mmol) in 1,4-dioxane (14.6 mL) and a solution of NaHCO3 (3.12 mmol) in water (20 mL) was protected with N2. Pd(Ph3P)4 (100 mg, 0.087 mmol) was added, and the reaction mixture was heated at 100° C. for 16 hours. The mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by SiO2 chromatography (1:2 THF:petroleum ether) to afford the title compound (800 mg) as a yellow solid. LC-MS (ES) m/z=354 [M+H]+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH3:41][NH:42][CH2:43][C:44]1[S:48][C:47]2[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=2[C:45]=1[CH3:53].CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:42]([CH3:41])[CH2:43][C:44]2[S:48][C:47]3[CH:49]=[CH:50][CH:51]=[CH:52][C:46]=3[C:45]=2[CH3:53])=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc(N)c(CN3CCN(C)CC3)c2)sc2ccccc12
Yield: 46 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (101 mg, 46%) was prepared as a light, yellow powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.6 (br s, 1H), 8.27 (s, 1H), 8.16 (s, 1H), 7.87 (d, J=7.6 Hz, 1H), 7.73 (d, J=7.1 Hz, 1H), 7.52-7.28 (m, 5H), 7.11 (d, J=15.3 Hz, 1H), 5.11-4.89 (m, 2H), 3.55 (br s, 2H), 3.37-3.23 (m, 4H), 3.14 (s, 2H), 3.10-2.92 (m, 5H), 2.72 (s, 3H), 2.42 (s, 3H); MS (ESI) m/e 450 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=3[NH:8][C:7](=[O:16])[C:6]=12.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[NH2:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([O:15][CH2:27][CH2:28][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:10][C:9]=3[NH:8][C:7](=[O:16])[C:6]=12
Reactant: COc1cccc(-n2nc3c(c2N)c(=O)[nH]c2cc(O)ccc23)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-n2nc3c(c2N)c(=O)[nH]c2cc(OCCN4CCOCC4)ccc23)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of 3-amino-2-(3-methoxyphenyl)-7-hydroxy-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (150 mg), 4-(2-chloroethyl)morpholine hydrochloride (109 mg), potassium carbonate (163 mg), potassium iodide (5 mg) and N,N-dimethylformamide (5 mg) was stirred at 80° C. for 3 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography. To the concentrated residue of fraction was added ethyl acetate. The precipitated solid was collected by filtration, washed with ethyl acetate, and dried to obtain the target compound (73 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[H-].[Na+].Cl[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[CH:26]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]([O:48][CH3:49])=[O:47])=[CH:42][CH:41]=1)[CH2:27][CH2:28][C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1.[I-].[K+].[Cl-].[NH4+]>CN(C=O)C>[CH3:49][O:48][C:46]([C:43]1[CH:44]=[CH:45][C:40]([CH2:39][CH:26](/[CH:25]=[CH:24]/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:4]2[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]2=[O:8])[CH2:27][CH2:28][C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=2)=[CH:41][CH:42]=1)=[O:47]
Reactant: CN1CCCNC1=O
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCCN(C)C2=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 36.4 mg (0.319 mmol) of 1-methyltetrahydropyrimidin-2-one [CAS Reg. No. 10166-54-8] is initially charged in 1.5 ml of dry DMF, and 13.1 mg (0.328 mmol) of sodium hydride (60% in paraffin oil) are added. The mixture is stirred at room temperature for 45 min. The reaction solution is then cooled to 0° C. and a solution of 50 mg (0.091 mmol) of methyl 4-{(4E)-5-{2-[(5-chloropentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 32A) in 1.5 ml of dry DMF is added. This is followed by the addition of 1.5 mg (0.9 μmol) of potassium iodide. The mixture is stirred at room temperature for 1.5 h. The reaction solution is then carefully poured into 15 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. This gives 47 mg (0.075 mmol, 82% of theory) of a colorless oil which is reacted without further purification.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:13]([OH:38])[CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=2[C:27]2[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=2[O:36][CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:41](C(OC(C)(C)C)=O)[C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:45]([O:44][C:42](=[O:41])[N:15]([CH2:14][CH:13]([C:5]1[CH:4]=[C:3]([C:2]([F:39])([F:40])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1)[OH:38])[CH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:19][C:18]=1[C:27]1[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[CH:29][C:28]=1[O:36][CH3:37])([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNCC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)ethanol (Example 6 Step B, 325.0 mg, 0.561 mmol) in CH2Cl2 (15 mL) was added BOC2O (122 mg, 0.561 mmol) and DIPEA (98 μL, 0.561 mmol). The reaction was stirred at room temperature. After 5 hours, additional BOC2O (50 mg, 0.229 mmol) and DIPEA (50 μL, 0.287 mmol) were added. The reaction was stirred at room temperature for 48 hours. The reaction was then concentrated to ˜2 mL, diluted with hexanes (8 mL) and purified by flash chromatography with 10 to 20% EtOAc/hexanes to afford tert-butyl{2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxyethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.38 (25% EtOAc/hexanes). LCMS=580.3 (M+1−BOC)+. 1H NMR (CD2Cl2, 500 MHz) δ 7.78 (s, 1H), 7.54-7.67 (m, 4H), 7.23-7.33 (m, 2H), 6.90-6.95 (m, 2H), 3.15-4.82 (m, 9H), 2.87 (m, 1H), 1.19-1.43 (m, 15H).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]([C:12](=[O:28])[CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:10]([CH2:29][CH3:30])[N:9]=[C:8]2[CH2:31][CH2:32][CH3:33])=[C:4]([F:36])[CH:3]=1.[C:37]([NH:41][S:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1B(O)O)(=[O:44])=[O:43])([CH3:40])([CH3:39])[CH3:38].C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1.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>[C:37]([NH:41][S:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:11]([C:12](=[O:28])[CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:10]([CH2:29][CH3:30])[N:9]=[C:8]2[CH2:31][CH2:32][CH3:33])=[C:4]([F:36])[CH:3]=1)(=[O:44])=[O:43])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCCc1nc(CC)c(C(=O)COc2ccccc2Oc2ccccc2)n1Cc1ccc(Br)cc1F
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc(CC)c(C(=O)COc2ccccc2Oc2ccccc2)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 40.3 %

Procedure:
From 0.16 g (0.29 mmol) of 1-(4-bromo-2-fluorobenzyl)-2-(n-propyl)-4-ethyl-5-(2-(phenoxy)phenoxy)acetyl-1H-imidazole, using 0.12 g (0.47 mmol) of 2-(t-butylamino)sulfonylphenyl boronic acid, 0.12 g (0.86 mmol)potassium carbonate, 0.016 g (0.05 mmol) tetrabutylammonium bromide, 0.02 g (0.02 mmol) tetrakis(triphenylphosphine)palladium(0), with 1 mL of water and 2 mL of toluene as solvent, 0.08 g (40%) of the title compound was obtained following the procedure of Example 3, Part F, after purification by preparative TLC (silica gel; 20% acetone, 30% ethyl acetate, 50% hexane). 1H NMR (300 MHz, CDCl3): δ 0.97 (m, 12H, overlapping t-butyl singlet and methyl triplet); 1.32 (t, 3H, J=7.3 Hz); 1.72 (m, 2H); 2.63 (t, 2H, J=7.3 Hz); 2.83 (q, 2H, J=7.3 Hz); 3.57 (s, 1H); 5.06 (s, 2H); 5.58 (s,2H); 6.61 (t, 1H, J=8.1 Hz); 6.87-7.09 (m, 7H); 7.12 (d, 1H, J=8.1 Hz); 7.23-7.29 (m,5H); 7.51 (m, 2H); 8.15 (d, 1H, J=7.7 Hz). ##STR107##
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:22]([C:21]4[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=4[Cl:19])=[O:23])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Cc1cc2c(C)noc2cc1-c1ccc(N)nc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(C)noc2cc1-c1ccc(NC(=O)c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 5-(3,5-dimethylbenzo[d]isoxazol-6-yl)-2-pyridylamine (105) (14.5 mg, 0.06 mmol) in 1 ml DCM was added 2-chlorobenzoyl chloride (16 μl, 0.12 mmol) followed by addition of DIEA (63 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(3,5-dimethylbenzo[d]isoxazol-6-yl)(2-pyridyl)](2-chlorophenyl)carboxamide (106) (17.1 mg, yield: 75.4%, purity>95%) as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:19])[CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2[CH2:26][CH2:27][CH2:28][CH2:29][C:21]1=2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:12])=[CH:7][C:5]([N:6]2[C:23](=[O:24])[C:22]3[CH2:26][CH2:27][CH2:28][CH2:29][C:21]=3[C:20]2=[O:25])=[C:4]([F:19])[CH:3]=1
Reactant: CCCCCOC(=O)COc1cc(N)c(F)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCOC(=O)COc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of the compound (II) (12.0 g), 3,4,5,6-tetrahydrophthalic anhydride (7.56 g), triethylamine (0.4 g) and toluene (50 g) was heated under reflux for 10 hours. The reaction mixture was cooled to room temperature and washed with water. The toluene layer was separated and concentrated under reduced pressure. Analysis of the resulting product revealed that it contains the compound (I) in a purity of about 77% and a large amount of a compound of the following formula as the impurity: ##STR6## Purification of the above product by silica gel column chromatography gave the compound (I) (13.7 g).