Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].N1C=CC=CC=1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21].CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Temperature: 0 °C
Yield: 72.1 %

Procedure:
Add 4-chloro-3-(trifluoromethyl)aniline (1.0 g, 5.1 mmol) and pyridine (1.0 g, 12.8 mmol) in DCM (10 mL), stir well and cool to 0° C. Add phenyl chloroformate (1.04 g, 6.6 mmol) at 0° C. After addition, stir the reaction at room temperature for 1 hr. TLC (EtOAc:PE=1:2) shows the reaction is complete. Wash the organic layer with 1M HCl solution (20 mL) and brine (20 mL) respectively. Dry over anhydrous Na2SO4; concentrate under reduced pressure to give the target compound (1.16 g) which is used without further purification. MS: (M+1): 316.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:21][C:22](=[O:39])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([N:32]2[CH:36]=[CH:35][N:34]=[C:33]2[S:37][CH3:38])[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([N:32]5[CH:36]=[CH:35][N:34]=[C:33]5[S:37][CH3:38])[CH:27]=4)[CH2:23][C:22](=[O:39])[NH:21][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1
Reactant: CSc1nccn1-c1cccc(C(=O)CC(=O)Nc2cc(-c3ccc(F)cc3)ccc2NC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nccn1-c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from (4′-fluoro-3-{3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example K87) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (104 mg).
Reaction SMILES: [C:1]([OH:12])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:21])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]O>>[C:1]([O:12][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]([CH3:21])[CH3:13])(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCOCCO
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)OCCOCCN(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(2-(dimethylamino)ethoxy)ethanol as starting materials to give the aimed compound.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:12]=[N:13][C:14]([CH3:18])=[C:15]([F:17])[CH:16]=1)C1C=CC=CC=1>[Pd]>[F:17][C:15]1[CH:16]=[C:11]([NH2:10])[CH:12]=[N:13][C:14]=1[CH3:18]
Reactant: Cc1ncc(NC(=O)OCc2ccccc2)cc1F
Agent: [Pd]
Product: Cc1ncc(N)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask is charged with (5-fluoro-6-methyl-pyridin-3-yl)-carbamic acid benzyl ester (0.20 g, 0.23 mmol) and 10% Pd/C (0.09 g, 0.08 mmol). The atmosphere is evacuated and refilled with Ar three times. To this mixture is added MeOH (10 mL). The reaction mixture is placed under an atmosphere of H2 and stirred at room temperature for 1 h. The mixture is filtered through a syringe filter and concentrated under reduced pressure to provide 5-fluoro-6-methyl-pyridin-3-ylamine as a solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([OH:17])=O)=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][CH:26]1[CH2:31][NH:30][CH2:29][CH:28]([CH3:32])[NH:27]1>>[CH3:25][CH:26]1[NH:27][CH:28]([CH3:32])[CH2:29][N:30]([C:15]([C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[N:6][C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)=[CH:8]3)=[O:17])[CH2:31]1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CC1CNCC(C)N1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CC(C)NC(C)C4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 2,6-Dimethyl-piperazine to give (3,5-Dimethyl-piperazin-1-yl)-[1-isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-methanone. LC-MS: m/e 423 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1([C:19]2[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3].[C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)#[N:28].C([O-])([O-])=O.[Na+].[Na+].CCO>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.O>[CH2:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1([C:19]2[CH:24]=[CH:23][C:22]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:27]#[N:28])[CH:34]=3)=[CH:21][CH:20]=2)[CH2:14][CH2:13][N:12]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:11][CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COC(=O)NCC1(c2ccc(I)cc2)CCN(CC2CC2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)COC(=O)NCC1(c2ccc(-c3cccc(C#N)c3)cc2)CCN(CC2CC2)CC1
Temperature: 25 °C
Yield: 24.2 %

Procedure:
To a flask containing [1-cyclopropylmethyl-4-(4-iodo-phenyl)-piperidin-4-ylmethyl]-carbamic acid isobutyl ester (0.061 g, 0.13 mmol) was added Pd(PPh3)4 (0.015 g, 0.013 mmol, 10 mol %), 3-cyanophenylboronic acid (0.03 g, 0.2 mmol, 1.5 eq.) and Na2CO3 (0.212 g, 2 mmol). The mixture was suspended in toluene (3 mL), EtOH (1.5 mL) and H2O (1.0 mL) and heated to 80° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (10 mL) and saturated Na2CO3 (10 mL). The organic layer was washed with saturated Na2CO3 (3×10 mL) and saturated brine (2×10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. This was purified by HPLC to give the title compound [4-(3′-cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-ylmethyl]-carbamic acid isobutyl ester as a brown solid (0.014 g, 24%). MS (ESI): 446.3/447.3 (M+1).
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:12]1CCC[CH2:13]1.C(OCC)C.C([Li])CCC.CN(C1C=CC=CN=1)C=O>O1CCCC1>[C:1]1([C:7]2[O:11][C:10]([CH:13]=[O:12])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnco2)cc1
Reactant: C1CCOC1
Agent: CN(C=O)c1ccccn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1ncc(-c2ccccc2)o1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 5-phenyloxazole (0.192 g) in 2:1 tetrahydrofuran/diethyl ether (7 mL) was cooled to −78° C., and treated with n-butyl lithium (0.582 mL) dropwise under Argon. The mixture was stirred for 30 minutes at −78° C., at this time a solution of N-methyl-N-(pyridin-2-yl) formamide (0.270 g) in tetrahydrofuran (2.6 mL) was added dropwise to the solution. After stirring at −78° C. for 30 minutes, the mixture was allowed to warm up to room temperature and stirring continued overnight. The mixture was quenched by the addition of water and extracted with ethyl acetate. The combined extracts were washed with 10% hydrochloric acid, saturated aqueous solution of sodium bicarbonate and brine, dried and concentrated in vacuo and purified by column chromatography on silica gel (10-50% ethyl acetate in hexane) to provide the title compound (0.016 g) with the following physical data.
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:29][CH2:30][CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34]>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([NH:36][S:33]([CH2:32][CH2:31][CH2:30][Cl:29])(=[O:35])=[O:34])=[O:27])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NS(=O)(=O)CCCCl
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)CCCCl

Procedure:
Prepared by coupling 2e and 3-chloropropanesulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (65%); 1H NMR (d6-DMSO) δ 11.83 (s, 1H), 7.54 (d, J=15.7 Hz, 1H), 7.34–7.09 (m, 10H), 6.87 (d, J=8.1 Hz, 2H), 6.70 (d, J=7.3 Hz, 1H), 6.51 (d, J=15.7 Hz, 1H), 3.72 (t, J=6.4 Hz, 2H), 3.54 (t, J=6.4 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.26 (t, J=7.0 Hz, 2H), 2.08 (m, 4H); APcI m/z: 504 (M−H−).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6](/[CH:10]=[CH:11]/[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:5]([CH3:25])[CH:4]=1)#[N:2].C(=O)([O-])[O-:27].[K+].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.O>[NH2:2][C:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6](/[CH:10]=[CH:11]/[CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)=[C:7]([CH3:9])[CH:8]=1)=[O:27]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(C#N)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(N)=O)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 738 %

Procedure:
To a suspension of 133 mg of tert-butyl 4-[(E)-2-(4-cyano-2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate in 5 ml of acetone and 2 ml of water, 146 mg of hydrogen peroxide-urea complex and 7 mg of potassium carbonate were added, followed by stirring overnight. Then, 221 mg of hydrogen peroxide-urea complex was added and the mixture was stirred overnight, and 293 mg of hydrogen peroxide-urea complex was further added, followed by stirring for 4 days. An aqueous solution of sodium sulfate was added to the reaction mixture and extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform-methanol) to give 134 mg of tert-butyl 4-{(E)-2-[4-(aminocarbonyl)-2,6-dimethylphenyl]vinyl}piperidine-1-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([CH3:16])[N:3]=1.[I:17][C:18]1[N:19]=[CH:20][NH:21][CH:22]=1>>[Cl:15][C:10]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([N:21]3[CH:22]=[C:18]([I:17])[N:19]=[CH:20]3)[CH:7]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Ic1c[nH]cn1
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(Cl)n1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-methylpyridine (example A.51) (3.5 g, 12.8 mmol) and commercially available 4-iodo-imidazole (2.99 g, 15.4 mmol) according to the general procedure IVa. Obtained as a light grey solid (0.90 g, 16%). MS (ISP) 430.0 [(M+H)+], 432.1 [(M+2+H)+] and 434.0 [(M+4+H)+].
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[B:13](OC)([O:16]C)[O:14]C.Cl>C1COCC1.O.C1COCC1>[F:6][C:7]1[C:12]([B:13]([OH:16])[OH:14])=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Fc1ccccn1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: OB(O)c1cccnc1F
Temperature: -78 °C
Reaction time: 4 h

Procedure:
800 ml (1.28 mol) of n-BuLi (1.6M in hexane) are added to a solution of 188 ml (1.32 mol) of TMP in 1,000 ml of THF at -78° C. under argon. After the mixture has been stirred for 45 minutes at this temperature, 120.4 g (1.24 mol) of 2-fluoropyridine in 200 ml of THF are added in the course of 3 minutes. After the mixture has been stirred for 4 hours at -78° C., a solution of 128.8 g (1.24 mol) of trimethyl borate in 200 ml of THF is added dropwise in the course of 20 minutes. Then, 200 ml of a 1: 1 mixture of water/THF is added at 25° C., and 256 ml of concentrated HCl are added dropwise, with ice-cooling. The organic phase is separated off, and the aqueous phase is washed twice using Et2O, filtered and concentrated in vacuo. Crude yield 148.2 g.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.[C:33]1([C:39]2[O:40][C:41]([C:47]([F:50])([F:49])[F:48])=[C:42]([C:44](Cl)=[O:45])[N:43]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl.C(OCC)(=O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:44]([C:42]4[N:43]=[C:39]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[O:40][C:41]=4[C:47]([F:49])([F:50])[F:48])=[O:45])=[CH:17][N:16]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1
Reactant: O=C(Cl)c1nc(-c2ccccc2)oc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(N2CCC(c3cccc(C(F)(F)F)c3)CC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamine (400 mg, 1.24 mmol) in methylene chloride (10 mL) was added diisopropylethylamine (0.60 mL, 3.30 mmol) followed by 2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl chloride (300 mg, 1.10 mmol). The reaction was stirred at room temperature for 24 hours and then diluted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum. The residue was purified by HPLC to yield 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [4-(3-trifluoromethyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-amide as a light purple solid. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C28H22F6N4O2 (m/e) 560, obsd 561 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1>C(O)(=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]#[N:10])[CH:13]=[CH:17][CH:16]=[CH:15]1
Reactant: COC1CCC(OC)O1
Reactant: N#CCc1ccccc1N
Solvent: CC(=O)O
Product: N#CCc1ccccc1-n1cccc1

Procedure:
Under inert atmosphere a solution of 500 mg (3.783 mmol) of 2-Aminophenylacetonitrile and 1 mL (7.566 mmol) of 2,5-Dimethoxytetrahydrofuran in 5 mL of acetic acid was heated to 60° C. for 2 hours. After cooling the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on SiO2 using cyclohexane/ethyl acetate mixture of increasing polarity (from 100% cyclohexane to 100% ethyl acetate) as eluent. The title compound was obtained as a light yellow oil (470 mg, 68.2%).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:6][C:3]=1[C:4]#[N:5].[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[C:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:32][C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([F:24])[CH:26]=2)[N:9]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Cl
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nc1Oc1ccc(F)c(F)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To the product of Example 131 (250 mg, 0.6984 mmol) was added 3,4-difluorophenol (273 mg, 2.095 mmol), Cs2CO3 (683 mg, 2.096 mmol) and toluene (4.5 mL) before heating to 100° C. After stirring 16 hours the reaction solution was filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 10% ethyl acetate/hexane affording the product. MS (electrospray) m/e 453.0 MH+ (Rt=4.4 min LC/MS).
Reaction SMILES: [O:1]=[C:2]([C@@H:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[S:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[N:21]=2)=[CH:12][CH:11]=1)[CH3:9])[CH2:3][C:4](OC)=[O:5].[OH-].[Na+].Cl.[NH2:29]O.Cl>CO.CO.O>[F:23][C:22]([F:24])([F:25])[C:20]1[N:21]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([C@H:8]([C:2]3[O:1][N:29]=[C:4]([OH:5])[CH:3]=3)[CH3:9])=[CH:15][CH:14]=2)[S:18][CH:19]=1
Reactant: COC(=O)CC(=O)[C@H](C)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H](c1ccc(Nc2nc(C(F)(F)F)cs2)cc1)c1cc(O)no1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a cooled (−30° C.) solution of the intermediate 7a, methyl (4R)-3-oxo-4-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)pentanoate, (372 mg, 1 mmol) in CH3OH (0.5 ml), a solution of NaOH (42 mg, 1.05 mmol) in CH3OH (4 ml) was added by dripping. The resulting mixture was stirred for 10 min, then a mixture of hydroxylamine hydrochloride (133 mg, 2 mmol) and NaOH (83 mg, 2 mmol) in CH3OH/water (4 ml/0.5 ml) was added at the same temperature. After stirring for 2 h at −30° C., the reaction mixture was poured into 37% HCl (1.5 ml) and the resulting mixture was heated at 80° C. for 2 h. After cooling at room temperature and solvents evaporation, the crude was diluted with water and extracted with EtOAc (3×10 ml). The combined organic extracts were dried over anhydrous Na2SO4, evaporated and purified by flash chromatography (n-hexane/EtOAc 8:2; 1% AcOH) to afford pure 5-[(1R)-1-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)ethyl]isoxazol-3-ol (10) (202 mg, 0.57 mmol) as a pale yellow solid (57%). [α]D=−40 (c=1.4; CH3OH); 1H-NMR (CDCl3): δ 10.70 (bs, 1H, OH), 9.15 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.25 (d, 2H, J=7 Hz), 7.00 (s, 1H), 5.70 (s, 1H), 3.80 (q, 1H, J=7 Hz), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:6][CH2:5][C:4](=O)[CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C([O-])(=O)C.[NH4+:18]>CCO>[NH2:18][C:4]1[CH2:5][CH2:6][C:2]([CH3:13])([CH3:1])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)C1C(=O)CCC1(C)C
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOC(=O)C1=C(N)CCC1(C)C
Temperature: 85 °C
Yield: 86.1 %

Procedure:
A mixture of ethyl 2,2-dimethyl-5-oxocyclopentanecarboxylate (3.426 g) and ammonium acetate (14.33 g) in EtOH (100 mL) was heated at 85° C. (bath) for 1 hour. The contents were concentrated. The residue was partitioned between water and DCM. The organic phase was separated. The aqueous solution was extracted with DCM. The combined DCM solutions were washed with water and dried (Na2SO4). Upon filtration and concentration, solid ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate (2.933 g) was yielded. The ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate was mixed with ammonium formate (5.054 g) and formamide (7 mL) and heated at 150° C. for 16 hours. The mixture was diluted with water and extracted with 5:1 DCM-IPA. The combined extracts were dried (Na2SO4) and concentrated to give 5,5-dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one as a viscous oil (1.185 g). 5,5-Dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (1.063 g) was dissolved in acetonitrile (20 mL) with POCl3 (1.78 mL). The mixture was heated at 80° C. for 10 hours. The mixture was cooled to 0° C. 50% KOH (15.3 mL) was added dropwise. t-Butyl piperazine-1-carboxylate (3.615 g) was added. The mixture was heated at 80° C. for 24 hours. The contents were concentrated. Water was added. The mixture was extracted with DCM (2×) and dried (Na2SO4). The crude material was purified with flash chromatography to give tert-butyl 4-(5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.021 g). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.57 (s, 1H), 3.56-3.54 (m, 4H), 3.37-3.34 (m, 4H), 2.90 (t, J=7.3 Hz, 2H), 1.89 (t, J=7.3 Hz), 3H)1.48 (s, 9H), 1.40 (s, 6H). MS: 333.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]1([Si:22]2([CH2:35][CH2:36][CH3:37])[CH2:27][CH2:26][CH:25]([CH:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([Si:22]2([CH2:35][CH2:36][CH3:37])[CH2:27][CH2:26][CH:25]([CH:28]3[CH2:33][CH2:32][CH:31]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Fc1ccc(-c2ccc([Mg]Br)cc2)cc1
Reactant: CCC[Si]1(c2ccccc2)CCC(C2CCC(=O)CC2)CC1
Product: CCC[Si]1(c2ccccc2)CCC(C2CCC(c3ccccc3-c3ccc(F)cc3)CC2)CC1

Procedure:
In the same manner as in Example 6, 25 g of 4-(4-fluorophenyl)phenylmagnesium bromide was reacted with 31.5 g of 4-(4-phenyl-4-n-propyl-4-silacyclohexyl)cyclohexanone and the resultant alcohol was dehydrated, followed by catalytic reduction to obtain 4-(4-phenyl-4-n-propyl-4-silacyclohexyl)cyclohexyl-4'-fluorobiphenyl. The biphenyl product was then reacted with iodine monochloride, followed by reduction with lithium aluminohydride to obtain 14.4 g (yield: 36%) of the intended product. The product was subjected to NMR and IR analyses with the results shown below.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[C:25]([Cl:26])=[CH:24][C:23]2[C:18](=[C:19]([CH2:27][N:28]([CH3:30])[CH3:29])[CH:20]=[CH:21][CH:22]=2)[CH:17]=1)=O)C.O>C1COCC1>[Cl:26][C:25]1[C:16]([CH2:14][OH:13])=[CH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:27][N:28]([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cc2c(CN(C)C)cccc2cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)Cc1cccc2cc(Cl)c(CO)cc12
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
Diisobutylaluminium hydride (1 M in THF, 4.2 ml, 4.1 mmol, 9.0 equiv) was added to a solution of 3-chloro-8-dimethylaminomethyl-naphthalene-2-carboxylic acid ethyl ester (133 mg, 0.46 mmol) in 3.2 ml anhydrous THF at 0° C. After 15 minutes at 0° C., TLC analysis revealed complete conversion of starting material. Water (30 ml) was added, and the mixture was extracted with EtOAc (2×100 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (gradient of CH2Cl2/MeOH 97:3 to 90:10) afforded the title compound (109 mg, 96%, mixture of 2 regioisomers) as a colorless oil. Data for (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-methanol: 1H NMR (400 MHz, CDCl3): δ=8.36 (s, 1H), 7.85 (s, 1H), 7.74 (dd, J=7.1/1.9 Hz, 1H), 7.44-7.39 (m, 2H), 4.94 (s, 2H), 4.06 (s, 2H), 2.45 (s, 6H). MS (ES+): 250 (M+H)+.