Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][N:33]=2)[CH2:31][CH2:30]1>>[CH:29]1([C:32]2[N:33]=[CH:34][C:35]([C:2]3[C:3]([N:22]4[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]4)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]4[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=4)=[O:8])[CH:21]=3)=[CH:36][CH:37]=2)[CH2:31][CH2:30]1
Reactant: CC1(C)OB(c2ccc(C3CC3)nc2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccc(C3CC3)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 75 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and 2-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford an off-white solid. UPLC-MS (condition 1) tR=2.30 min, m/z=499.0 [M+H]+, m/z=497.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.04 (m, 4H) 1.49-1.62 (m, 1H) 1.77-1.88 (m, 1H) 2.10-2.19 (m, 1H) 2.18-2.26 (m, 1H) 2.99 (dd, J=11.00, 6.85 Hz, 1H) 3.09-3.20 (m, 2H) 3.21-3.29 (m, 1H) 3.29-3.41 (m, 2H) 4.60 (br. s, 1H) 7.29-7.40 (m, 3H) 7.64 (dd, J=8.07, 2.20 Hz, 1H) 7.85 (d, J=9.05 Hz, 2H) 7.99 (d, J=2.20 Hz, 1H) 8.45 (d, J=2.20 Hz, 1H) 8.73 (d, J=2.20 Hz, 1H) 10.14 (s, 1H).
Reaction SMILES: BrC[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13]C)=[CH:10][CH:11]=2)[O:6][C:5](=[O:15])[C:4]=1[C:16]1[C:17]([O:24][CH3:25])=[N:18][C:19]([O:22]C)=[N:20][CH:21]=1.B(Br)(Br)Br>C(Cl)CCl>[OH:22][C:19]1[N:20]=[CH:21][C:16]2[C:4]3[C:5](=[O:15])[O:6][C:7]4[C:12](=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=4)[C:3]=3[CH2:25][O:24][C:17]=2[N:18]=1
Reactant: COc1ccc2c(CBr)c(-c3cnc(OC)nc3OC)c(=O)oc2c1
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: O=c1oc2cc(O)ccc2c2c1-c1cnc(O)nc1OC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromomethyl-3-(2,4-dimethoxy-pyrimidin-5-yl)-7-methoxy-chromen-2-one (200 mg, 0.492 mmoL) in ClCH2CH2Cl (5 mL) at room temperature was added BBr3 (1.0 N, 2.50 mmoL, 2.5 mL). The result reaction mixture was stirred at room temperature for 30 min and then heated to reflux overnight. The reaction was cooled down and the solvent was removed in vacuo. The residue was dissolved in 10% K2CO3 in MeOH:acetone (˜1:1, 10 mL) at 0° C., stirring was kept for another 2 hours. The solvent was evaporated to dryness, the residue was dissolved in water (15 mL) and then acidified with dilute hydrochloric acid to about pH 4. The precipitated brown solid was isolated by filtration, washed with water and dried to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:46])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]([N:15]([CH3:44])[CH:16]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][C:33]([NH:36]C(=O)OC(C)(C)C)=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:14])[C:6]=2[CH:45]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:36][C:33]1[CH:32]=[CH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([CH:16]([N:15]([CH3:44])[C:13](=[O:14])[CH2:12][N:7]3[C:6]4[CH:45]=[C:2]([Cl:1])[C:3]([Cl:46])=[CH:4][C:5]=4[O:10][CH2:9][C:8]3=[O:11])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:25][CH:26]=2)=[CH:35][CH:34]=1
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Yield: 100.6 %

Procedure:
To a solution of 1,1-dimethylethyl {4′-[1-[[(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetyl](methyl)amino]-2-(4-morpholinyl)ethyl]-4-biphenylyl}carbamate (0.64 g, 0.96 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (4 mL). The resultant mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give 0.55 g (100%) of the title compound as tan solid MS (ES) m/e 569.4 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:20])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([CH3:19])[CH:12]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[N:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:46]3[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=3)[CH:3]=2)=[O:20])=[CH:12][C:13]=1[CH3:19]
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(C(=O)C(=O)c2cccc(Br)c2)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C(=O)C(=O)c2cccc(-c3ccncc3)c2)cc1C
Temperature: 100 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
A solution of 1-(3-bromo-phenyl)-2-(4-methoxy-3-methylphenyl)ethane-1,2-dione (0.25 g, 0.75 mmol) in dioxane is treated sequentially with tri-o-tolylphosphine (57 mg, 0.187 mmol), palladium (II) acetate (21 mg, 0.093 mmol), pyridine-4-boronic acid (139 mg, 1.125 mmol) and H2O, stirred at 100° C. for 4 h, cooled to room temperature and filtered. The filtrate is evaporated in vacuo. The resultant residue is purified by flash chromatography on silica gel (hexanes/EtOAc 3/7 as eluent), to afford the title compound as a yellow solid, 0.145 g (58% yield), identified by HNMR and mass spectral analyses. MS m/e (M+H)+ 332; 1H NMR (400 MHZ, CDCl3) δ 2.28 (s, 3H) 3.95 (s, 3H) 6.94 (d, 1H) 7.68 (m, 3H) 7.84 (m, 2H) 7.88 (m, 1H) 8.08 (m, 1H) 8.30 (m, 1H) 8.75 (m, 2H).
Reaction SMILES: C1(C)C=CC=CC=1.S(=O)(=O)(O)O.[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][OH:23])=[CH:16][CH:15]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:41])([CH2:39][CH3:40])[CH2:37]O)=[CH:32][CH:31]=1>O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:41])([CH2:39][CH3:40])[CH2:37][O:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:17]3[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=3)[CH:20]=2)=[CH:32][CH:31]=1
Reactant: OCc1cccc(Oc2ccc(F)cc2)c1
Reactant: CCC(C)(CO)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C)(COCc1cccc(Oc2ccc(F)cc2)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
To 20 ml of toluene were added 2 ml of concentrated sulfuric acid, 2.7 g of 3-(4-fluorophenoxy)benzyl alcohol and 2.3 g of 2-(4-fluorophenyl)-2-methylbutyl alcohol, and the mixture was refluxed for 6 hours (water formed by reaction was removed). The mixture was cooled to room temperature, and water was added to the mixture and the toluene layer was separated, washed with water, dried, and evaporated under reduced pressure, and the obtained crude ether was purified by column chromatography on 100 g of silica gel (1:1 mixed solvent of toluene and n-hexane was used as eluent) to give 2.2 g of the desired ether (the yield was 46% of the theoretical yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2OC(=O)[NH:13][C@H:12]2[CH3:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>[Pd].CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C@@H:12]([NH2:13])[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1NC(=O)O[C@H]1c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@H](N)Cc1ccc(C(C)(C)C)cc1

Procedure:
A mixture of 1 g (4.3 mmole) (4S,5S)-5-(4-tert-butylphenyl)-4-methyl-oxazolidin-2-one p(see preparation 4, step 2), 2 g (31.74 mmole) ammonium formate and 0.1 g 10% palladium on carbon in 25 mL methanol was heated under reflux for 2 hrs. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between 10 mL 10% sodium carbonate and 25 mL ethyl acetate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. The title compound was isolated as the hydrochloride salt from diethyl ether, 0.93 g (95%), m.p. 259.5-261.3° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C:25](=O)[CH2:24]3)=[CH:19][CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH:25]2[CH2:26][CH2:27][N:23]([C:20]3[CH:19]=[CH:18][C:17]([N:11]4[CH2:10][CH2:9][C:8]5[C:13](=[CH:14][CH:15]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=5)[C:12]4=[O:16])=[CH:22][CH:21]=3)[CH2:24]2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CCC(=O)C3)cc1)C2=O
Reactant: C1CCNC1
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CCC(N4CCCC4)C3)cc1)C2=O

Procedure:
According to Method J, 6-butoxy-2-[4-(3-oxo-pyrrolidin-1-yl)-phenyl]-3,4-dihydro-2H-isoquinolin-1-one was reacted with pyrrolidine. In this way the product was obtained with molecular weight 433.60 (C27H35N3O2); MS (ESI): 434 (M+H+).
Reaction SMILES: [C:1](I)([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2].[C:15]([O:18][CH:19]=C)(=[O:17])[CH3:16]>>[C:1]([CH2:19][O:18][C:15]([CH3:16])=[O:17])([C:4]([C:7]([C:10]([F:13])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)I
Reactant: C=COC(C)=O
Product: CC(=O)OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
By the reaction of C4F9I with vinyl acetate under the conditions of Examples 3 to 7 there is obtained: ##STR7##
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].CC(C)([O-])C.[K+].F[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][N:21]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:19]=2)=[CH:14][CH:13]=1.O>CS(C)=O>[F:26][C:23]([F:24])([F:25])[C:20]1[NH:21][N:22]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:2][CH2:1][CH2:3][NH2:4])=[CH:13][CH:14]=2)[CH:19]=1
Reactant: NCCO
Reactant: Fc1ccc(-c2cc(C(F)(F)F)n[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NCCOc1ccc(-c2cc(C(F)(F)F)[nH]n2)cc1
Temperature: 65 °C
Yield: 34.3 %

Procedure:
In a flame-dried, round-bottomed flask, ethanolamine (836 mg, 13.7 mmol) was dissolved in dimethylsulfoxide (2.7 ml), and potassium tert-butoxide (95%, 1.54 g, 13.7 mmol) was added to the solution. This mixture was stirred at about 65° C. for about ten minutes, and then 5-(4-fluoro-phenyl)-3-trifluoromethyl-1H-pyrazole (630 mg, 2.74 mmol) was added. The dark-colored solution was heated to about 85° C. for about eighteen hours, and was then allowed to cool to room temperature. Water was added, and the resulting tan-colored solid was collected by filtration. This crude product was purified by column chromatography (5% methanol/dichloromethane to 20% methanol/dichloromethane) to afford the product as a white solid (255 mg, 25% yield). LRMS ([M+H]+)=272.2.
Reaction SMILES: [Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6](Cl)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][SH:31])=[CH:25][CH:24]=1.COC(=O)C(SCCC1C=CC(F)=CC=1)CC1C=CC(C(C)(C)O[SiH2]C(C)(C)C)=CC=1>>[Cl:1][C:2]([Cl:21])([Cl:20])[CH2:3][O:4][C:5](=[O:19])[CH:6]([S:31][CH2:30][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccc(CC(Cl)C(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Fc1ccc(CCS)cc1
Agent: COC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)SCCc1ccc(F)cc1
Product: O=C(O)Cc1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1

Procedure:
The title compound was prepared from 3-(4-carboxymethyl-phenyl)-2-chloro-propionic acid 2,2,2-trichloro-ethyl ester (1.17 g, 3.13 mmol) and 2-(4-fluoro-phenyl)-ethanethiol (0.53 g, 3.44 mmol) as described for 3-[4-(tert-butyl-dimethyl-silanyloxy-methyl)-phenyl]-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid methyl ester. After purification by flash chromatography with n-heptane/EtOAc 10:1 as the eluent the product was obtained as a solid (611 mg, 39.6%). 1H NMR (300 MHz, CDCl3): δ 7.09-7.23 (m, 6H), 6.94-6.99 (m, 2H), 4.65-4.77 (q, 2H), 3.56-3.61 (m, 3H), 3.18-3.28 (dd, 1H), 2.78-3.02 (m, 5H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[S:18][CH:19]=2)=[CH:9][C:8]=1[CH3:30])C.[Li+].[OH-]>>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C:17]2[S:18][CH:19]=[C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:31][CH2:32][CH3:33])[C:4]([OH:34])=[O:3])=[C:8]([CH3:30])[CH:9]=3)[N:16]=2)=[CH:25][CH:24]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2csc(-c3ccc(C(C)(C)C)cc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(4-tert-butyl-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless foam.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])[CH2:18][C:19]3[CH:24]=[CH:23][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:21][CH:20]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl[C:36]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:34])[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:36]4[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38][N:37]=4)=[CH:23][CH:24]=3)=[N:14][CH:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2)CC1
Reactant: Cc1cc(Cl)ncn1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4cc(C)ncn4)cc3)nc2)CC1
Temperature: 110 °C

Procedure:
A mixture of N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide 196-1 (20 mg, 0.04 mmol), 4-chloro-6-methylpyrimidine 198-1 (8 mg, 0.06 mmol) Pd(PPh3)4 (2 mg, 0.002 mmol) and K3PO4 (25 mg, 0.12 mmol) in dioaxane (0.6 mL) was flushed with nitrogen and heated to 110° C. for 2 hours. The salt was removed by filtration and the filtrate was taken to dryness by rotary evaporation. The residue was purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(6-methylpyrimidin-4-yl)phenyl)acetamide 198. MS m/z 431.20 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.59 (s, 1H), 8.16 (d, 2H), 8.04 (d, 1H), 7.98 (s, 1H), 7.92 (m, 1H), 7.51 (d, 2H), 7.45-7.40 (m, 2H), 3.77 (s, 2H), 3.58 (b, 2H), 3.15 (b, 2H), 3.08 (b, 2H), 2.55 (s, 3H), 2.53 (s, 2H), 2.04 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH2:20][OH:21])[CH:5]=[CH:4][C:3]1=2>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1([CH3:22])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:20]=[O:21])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C3=C(CO)CCCC3)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C3=C(C=O)CCCC3)ccc21

Procedure:
The above alcohol is stirred with excess manganese dioxide in methylene chloride for 5 hours. The reaction mixture is dried over sodium sulfate, filtered, and evaporated to give 2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-cyclohexene carboxaldehyde.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH2:11])[N:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O-:14])=[O:13]>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([NH:11][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])(=[O:22])=[O:23])=[O:26])[N:3]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: Cc1nc(N)nc2c1CCC2
Solvent: ClCCl
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])nc2c1CCC2
Yield: 60.9 %

Procedure:
To a dry, stirred solution of 10 g of 6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-amine in 800 ml of methylene chloride at ambient temperature and pressure was added 14.9 g of 2-nitrobenzenesulfonylisocyanate. The resulting mixture was stirred at reflux temperature (42°) for 2 hours after which the methylene chloride was removed under reduced pressure. The resulting solid was triturated with methanol or 1-chlorobutane and filtered to yield 15 g of N-[(6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-yl)aminocarbonyl]-2-nitrobenzene-sulfonamide, m.p. 202°-205°. The product showed characteristic absorption bands in the infrared spectrum at 1675 cm-1 and at 1.7, 3.2 and 7.7 to 8.5 ppms by nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:12][S:11][CH2:10][C@H:2]1[C:3]([NH:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].FC(F)(F)C(O)=O>>[NH:1]1[CH2:12][S:11][CH2:10][C@H:2]1[C:3]([NH:5][C:6]([CH3:9])([CH3:7])[CH3:8])=[O:4]
Reactant: CC(C)(C)NC(=O)[C@@H]1CSCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)[C@@H]1CSCN1
Yield: 94 %

Procedure:
To 3.25 g (11.3 mmol) of Boc-Thz-NH-tBu, 15 ml (195 mmol) of trifluoroacetic acid was added under ice cooling and the resultant mixture was stirred at that temperature for 30 min and evaporated. The residue was washed with hexane by decantation and partitioned between chloroform and 1N NaOH aqueous solution. The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give 2.00 g (Y. 94%) of H-Thz-NH-tBu which was convened to Qoa--Mta--AHPBA--Thz--NH-tBu by a similar method with processes 3-5 of Example 3.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH2:32]C)(C(O)=O)[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].N1CCC(C[C:41]([OH:43])=[O:42])CC1.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([CH2:32][C:41]([OH:43])=[O:42])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Reactant: O=C(O)CC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [Na+]
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCC(CC(=O)O)CC4)ccc3c2)CC1
Yield: 60 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using Piperidin-4-yl-acetic acid (0.0554 g, 0.387 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.100 g, 0.322 mmol) and Sodium triacetoxyborohydride (0.212 g, 0.9 mol) to give 85 mg {1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-piperidin-4-yl}-acetic acid (60%). ESI-LCMS (438 M+H). 1H NMR (DMSO-d6, 400 MHz): Shift (ppm) 7.71-8.01 (m, 3H), 7.43 (d, J=2.0 Hz, 2H), 7.10-7.30 (m, 1H), 4.38 (d, J=4.8 Hz, 3H), 3.28-3.55 (m, 2H), 2.82-3.14 (m, 2H), 2.20 (d, J=6.3 Hz, 4H), 1.85 (br. s., 5H), 1.38 (br. s., 7H), 0.89 (s, 9H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23]OC)=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C2C(=CC(OCC)=C([N+]([O-])=O)C=2)N=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH2:22][CH3:23])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COCCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N
Agent: CCOc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Product: CCOc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1N

Procedure:
Starting material: N4-(3-chloro-4-fluorophenyl)-7-ethoxyquinazoline-4,6-diamine was prepared according to the same method of the preparation of N4-(3-chloro-4-fluorophenyl)-7-(2-methoxy)ethoxyquinazoline-4,6-diamine in WO2008/33747, but starting material was 4-chloro-7-ethoxy-6-nitro-quinazoline (Bioorg. Med. Chem, 2007, 15, 3635-3648); other materials were prepared as example 1.
Reaction SMILES: [Al].II.[CH2:4](Br)[C:5]#[CH:6].[Cl:8][C:9]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:10]=1[O:11][CH2:12][CH2:13][C:14]([CH3:24])([CH3:23])[C:15](=[O:22])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1.[Cl-].[NH4+]>O1CCCC1.[Hg](Cl)Cl>[Cl:8][C:9]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:10]=1[O:11][CH2:12][CH2:13][C:14]([CH3:24])([CH3:23])[C:15]([CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)([OH:22])[CH2:6][C:5]#[CH:4]
Reactant: C#CCBr
Reactant: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)Cn1cncn1
Agent: Cl[Hg]Cl
Agent: II
Agent: [Al]
Solvent: C1CCOC1
Product: C#CCC(O)(Cn1cncn1)C(C)(C)CCOc1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 12 h
Yield: 74.8 %

Procedure:
1.58 g (0.058 mol) of aluminum (in the form of flakes) are covered with a layer of 7.3 ml of tetrahydrofuran, and a catalytic amount (0.05 g) of mercury(II) chloride and an iodine crystal are added. After the mixture has stood for 12 hours at 20° C., 10.3 g (0.087 mol) of propargyl bromide in 11 ml of tetrahydrofuran are added dropwise at 60° C. The mixture is then cooled to -60° C., and a solution of 17.1 g (0.05 mol) of 5-(2,4-dichlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-pentan-2-one in 20 ml of tetrahydrofuran is added dropwise. The mixture is allowed to warm up to 0° C. and is kept for a further hour at this temperature, and 22 ml of a saturated, aqueous ammonium chloride solution are added. Thereafter, the mixture is filtered, the filtrate is evaporated down in vacuo and the residue is taken up in 200 ml of ethyl acetate. After the solution has been washed with three times 100 ml of water, the organic phase is dried over sodium sulphate and then evaporated down in vacuo. Residues of solvent are removed at 50° C. and 0.01 mbar. 14.3 g (74.8% of theory) of 7-(2,4-dichlorophenoxy)-5,5-dimethyl-4-(1,2,4-triazol-1-yl-methyl)-hept-1-in-4-ol are obtained as a brownish oil of refractive index nD20 =1.5642.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C1C(=O)N([Br:19])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:19][C:10]1[C:2]([CH3:1])=[C:3]([CH:7]=[CH:8][C:9]=1[CH3:11])[C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)O)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C(=O)O)c(C)c1Br
Temperature: 50 °C

Procedure:
2,4-Dimethylbenzoic acid (7.00 g, 46.6 mmol) and NBS (12.4 g, 69.9 mmol) were dissolved in TFA (150 mL). The mixture was then heated at 50° C. for overnight. Analysis by LC as well as TLC (hexanes/EtOAc=1/1) indicated that reaction had gone to completion. The solvent was removed in vacuo and the resulting residue was dissolved in DCM, absorbed onto silica gel, and loaded onto a silica MPLC column for separation. The desired product was separated using the solvent system of hexanes/EtOAc (1/1) to yield 3-bromo-2,4-dimethylbenzoic acid. The undesired isomeric 5-bromo-2,4-dimethylbenzoic acid was also isolated. 1H-NMR (CDCl3, 500 MHz), δ 7.868 (d, J=7.5 Hz, 1H), 7.2 (d, J=7.5 Hz, 1H), 2.793 (s, 3H), 2.526 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH3:2].[Br:13]Br.S([O-])([O-])=O.[Na+].[Na+]>>[Br:13][C:5]12[CH2:11][CH:9]3[CH2:8][CH:7]([CH2:12][C:3]([CH2:1][CH3:2])([CH2:10]3)[CH2:4]1)[CH2:6]2
Reactant: BrBr
Reactant: CCC12CC3CC(CC(C3)C1)C2
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: CCC12CC3CC(CC(Br)(C3)C1)C2
Yield: 83 %

Procedure:
Mix 0.034 mol of ethyl adamantane with a ten times excess of bromine (0.33 mol). Heat slowly and stir under reflux for 4 hrs. Then allow to cool and pour onto ice water. Decompose the excess bromine with sodium sulfite until discoloration of the aqueous solution. Subsequently extract with ether, wash the combined organic phases with sodium bicarbonate solution, dry with magnesium sulfate, filter and evaporate to dryness under vacuum. Recrystallize the residue from methanol. (Yield: 83%).