Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([NH:7][C:8](=[O:12])[CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[H-].[Na+].[C:19](O)(=[O:22])[C:20]#[CH:21].C(F)(=O)C1C=CC=CC=1.C(F)(=O)C#C>O1CCCC1>[C:10]([C:9](=[C:19]([OH:22])[CH:20]=[CH2:21])[C:8]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)=[O:12])#[N:11]
Reactant: N#CCC(=O)Nc1ccc(C(F)(F)F)cc1
Reactant: C#CC(=O)O
Agent: C#CC(=O)F
Agent: O=C(F)c1ccccc1
Agent: [H-]
Solvent: C1CCOC1
Product: C=CC(O)=C(C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 g (0.22 mole) of 4'-trifluoromethyl-cyanoacetanilide in 150 ml of dry tetrahydrofuran were stirred at room temperature under nitrogen and treated with 2.0 g (0.066 mole) of sodium hydride 80% oil dispersion. The suspension was stirred for 1 hour at room temperature and then was cooled to -70° C. The flask was equipped with an acetone/dry ice condenser and used as the collecting flask from a distillation apparatus charged with 3.01 ml (0.05 mole) of propiolic acid and 15 g of benzoyl fluoride (0.12 mole), as described in J.A.C.S. (1974), Vol. 96 (18), p. 5855 to 5859. The distillation flask was heated in an oil bath at 50° C. and the liberated propynoyl fluoride passed via an air condenser directly into the cold solution of the carbanion. The mixture was stirred at -70° C. for 1 hour and was then quenched by pouring onto a mixture of dilute hydrochloric acid/ice. The mixture was extracted with ethyl acetate and the extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure and triuration with diethyl ether gave colorless crystals of the title compound. Chromatography of the mother liquors over silica gel, eluting with dichloromethane isolated 2.49 g (40%) of the remainder of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:27]4[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=4)[CH:3]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Reactant: OB(O)c1cccnc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cccnc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.4) (0.21 g, 0.5 mmol) and commercially available 3-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.12 g, 57%). MS (ISP) 412.3 [(M+H)+]; mp 162° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(O)=O.[Na+].[CH:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=1)=[CH2:42].[Na+].[Cl-]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=[C:2](/[CH:42]=[CH:41]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=2)[N:7]=1
Reactant: C=Cc1ccccn1
Reactant: Cc1cc(N2CCCC2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Cc1cc(N2CCCC2)nc(/C=C/c2ccccn2)n1
Temperature: 130 °C
Yield: 19.5 %

Procedure:
To a stirred solution of 100 mg (0.5 mmol) of 2-chloro-4-methyl-6-pyrrolidin-1-yl-pyrimidine in 0.5 ml DMF under an argon atmosphere were added at RT 67 mg (0.25 mmol) tris-(o-tolyl)phosphine, 5.5 mg (0.025 mmol) palladium(II) acetate, 17 mg (0.2 mmol) NaHCO3 followed by 263 mg (2.5 mmol) 2-vinylpyridine. The mixture was heated at 130° C. for 48 h, cooled to RT and 1.5 ml saturated aqueous NaCl solution was added. The mixture was extracted 4-times with 2 ml EtOAc/Et2O (2/1), the combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4 and concentrated in vacuo. The residue was applied to a silica gel column with hexane/EtOAc as eluent (gradient: 1/1 to 1/9). Combination of the purified fractions and concentration in vacuo gave 26 mg (20%) of the desired (E)-4-methyl-2-(2-pyridin-2-yl-vinyl)-6-pyrrolidin-1-yl-pyrimidine as yellow solid. ISP mass spectrum, m/e: 267.3 (M+1 calculated for C16H18N4: 267).
Reaction SMILES: [C:1]([O:9][C@H:10](CO)[C@@:11]1([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:19][CH:14](OC(=O)C)[C@H:13]([O:20][C:21](=[O:23])[CH3:22])[C@H:12]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:44]1[CH:52]=[C:50]([CH3:51])[C:48](=[O:49])[NH:47][C:45]1=[O:46].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[C:21]([O:20][C@@H:13]1[C@@H:12]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:11]([CH2:32][O:33][C:34](=[O:41])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:19][C@H:14]1[N:44]1[CH:52]=[C:50]([CH3:51])[C:48](=[O:49])[NH:47][C:45]1=[O:46])(=[O:23])[CH3:22]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: CC(=O)OC1O[C@](COC(=O)c2ccccc2)([C@@H](CO)OC(=O)c2ccccc2)[C@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: CC#N
Product: CC(=O)O[C@H]1[C@H](n2cc(C)c(=O)[nH]c2=O)OC(COC(=O)c2ccccc2)(COC(=O)c2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a stirred suspension of the anomeric mixture 3 (7.26 g, 0.013 mol) and thymine (3.25 g, 0.028 mol) in anhydrous acetonitrile (80 cm3) was added N,O-bis(trimethylsilyl)acetamide (19.1 cm3, 0.077 mol). The reaction mixture was stirred at 60° C. for 1 h and then cooled to 0° C. Trimethylsilyl triflate (4.1 cm3, 0.023 mol) was added drop-wise during 10 min and the mixture was subsequently heated for 22 h under reflux. After cooling to room temperature, a saturated aqueous solution of sodium hydrogen carbonate (30 cm3) was added and extraction was performed using dichloromethane (100 cm3×3). The combined organic phase was washed with saturated aqueous solutions of sodium hydrogen carbonate (30 cm3×3) and brine (50 cm3×3), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane/methanol (0.5–2.0% methanol, v/v) as eluent to give nucleoside 4 (6.88 g, 85%) as a white solid material after evaporation of the solvents under reduced pressure.
Reaction SMILES: [N:1]1([C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[C:17](=[O:26])[C:16]=1[C:27]#[N:28]>C1(C)C=CC=CC=1>[CH3:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[O:8])[CH2:2][CH2:3]2)=[C:16]([C:27]#[N:28])[C:17]1=[O:26]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: Cn1c(=O)c(C#N)c(Cl)c2ccccc21
Solvent: Cc1ccccc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3cccs3)CC2)c2ccccc21
Temperature: 120 °C
Yield: 97.7 %

Procedure:
Piperazine-1-yl-thiophen-2-yl-methanone (600 mg, 3.06 mmol) was added to a solution of Compound 3 (319 mg, 1.46 mmol) in toluene (40 mL) and heated overnight at 120° C. The solvent was removed under vacuum. The residue was suspended in water, sonicated, and filtered to yield 540 mg (98%) of white solids. M.P. 247° C. 1H NMR (DMSO-d6): δ 3.58 (s, 3H), 3.63 (m, 4H), 3.92 (m, 4H), 7.16 (t, J=4.8 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.48 (d, J=3.5 Hz, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.75 (t, J=7.25, 2H), 7.79 (d, J=4.8 Hz, 1H) 7.92 (d, J=7.5 Hz, 1H). EIMS m/z 379 (M+1), 401 (M+23). Anal. (C20H18N4O2S) C, H, N.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)C(O)=O.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O.CC(C)=O>[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([N:1]=[C:2]=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=C=O
Reactant: C[Si](C)(C)c1c(F)cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)c1c(F)cccc1N=C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of the Intermediate Isocyanate was carried out via a Curtius rearrangement. See Capson, T. L. et al., Tetrahedron Lett., 25, 3515 (1984) and references herein. To a solution of the compound prepared in (2) (3.03 g, 14.3 mmol) in CH2Cl2 (20 mL) was added oxalylchloride (1.30 mL, 15.0 mmol) and the resulting mixture was stirred 3 h at room temperature. The residue obtained after evaporation of the solvent was diluted with THF (10 mL) and injected with vigorous stirring to a ice-cooled solution of NaN3 (3.70 g, 57 mmol) in H2O (20 mL) and acetone (50 mL). After 15 min at 0° C. and 1 min at room temperature, the solution was extracted with Et2O (4×50 mL) and dried (Na2SO4). The residue obtained after evaporation of solvents was refluxed in toluene for 1 h 30 to provide, upon solvent removal, 2.85 g (79%) of a slightly yellow oil: IR (neat, cm−1) 2269, 1598, 1433, 1252, 1228, 846, 788; 1H NMR (300 MHz, CDCl3) δ 0.38 (d, J=1.9 Hz, 9 H), 6.82 (br t, J=8.3 Hz, 1 H), 6.90 (br d, J=8.2 Hz, 1 H), 7.25 (ddd, J1=J2=8.1 Hz, J3=6.6 Hz, 1 H); 13C NMR (75 MHz, CDCl3) δ 0.4, 112.6 (d, JCF=26 Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, JCF=241 Hz).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]([N:15]([CH2:28][CH2:29][OH:30])[CH2:16][CH:17]([OH:27])[C:18]2[N:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[S:21][CH:22]=2)[CH3:14])=[CH:8][CH:7]=1)(O)=[O:2].B#B.C(OCC)(=O)C.CO>O1CCCC1>[OH:2][CH2:1][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]([N:15]([CH2:28][CH2:29][OH:30])[CH2:16][CH:17]([OH:27])[C:18]2[N:19]=[C:20]([C:23]([F:25])([F:24])[F:26])[S:21][CH:22]=2)[CH3:14])=[CH:10][CH:11]=1
Reactant: CC(Cc1ccc(OCC(=O)O)cc1)N(CCO)CC(O)c1csc(C(F)(F)F)n1
Agent: B#B
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC(Cc1ccc(OCCO)cc1)N(CCO)CC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 71 by reaction of N-[2-(4-carboxymethoxyphenyl)-1-methylethyl]-N-(2-hydroxyethyl)-2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine in tetrahydrofuran with diborane in tetrahydrofuran and purification of the base on a silica gel column using an ethyl acetate/methanol=20:1 as eluant.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[CH3:31][C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]3[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[O:12][C:11]3=[O:30])[CH3:9])=[CH:4][CH:3]=2)[CH:35]=[CH:34][N:33]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCNS(C)(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and 2-methylpyridine-4-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=0.988 min, m/z=508.2; 1H NMR (CDCl3) 1.36 (m, 1H), 1.51 (d, 3H), 1.70 (m, 1H), 1.96 (m, 2H), 2.17 (m, 1H), 2.26 (m, 2H), 2.59 (s, 3H), 2.86 (m, 4H), 3.02 (m, 2H), 4.19 (m, 1H), 5.62 (m, 1H), 6.96 (d, 2H), 7.19 (m, 3H), 7.26 (d, 2H), 7.29 (m, 4H), 8.47 (d, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:37][C:38](OCC)=[O:39])[CH:36]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:20])C1C=CC=CC=1.[Cl-].[Li+].[BH4-].[Na+]>O1CCCC1.C(O)C>[OH:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:31][C:32]1[CH:33]=[N:34][N:35]([CH2:37][CH2:38][OH:39])[CH:36]=1)[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)=[O:20]
Reactant: CCOC(=O)Cn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1ccc(N(Cc2cnn(CCO)c2)C(=O)C2CCCc3c(O)cccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
Ethyl 2-(4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}pyrazol-1-yl)acetate (1.0 g) was dissolved in tetrahydrofuran:ethanol (1:2) solution (10 mL), and lithium chloride (0.30 g) and sodium borohydride (0.27 g) were added. The mixture was stirred at room temperature for 3 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the obtained residue (0.91 g) was reacted and treated in the same manner as in Example 17 to give 5-hydroxy-N-{[1-(2-hydroxyethyl)pyrazol-4-yl]methyl}-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.25 g). melting point: 110-114° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH2:4][OH:5])[CH3:2].[H-].[Na+].[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15](F)[C:12]=1[C:13]#[N:14]>C1COCC1>[NH2:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([O:5][CH2:4][CH:3]([CH2:6][CH3:7])[CH2:1][CH3:2])[C:12]=1[C:13]#[N:14]
Reactant: CCC(CC)CO
Reactant: N#Cc1c(N)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)COc1cccc(N)c1C#N
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 2-ethylbutan-1-ol (1.02 g, 10.0 mmol) in dry THF (60 mL) was carefully added NaH (60% in mineral oil, 480 mg, 12.0 mmol) in small portions at 0° C. under nitrogen. The reaction mixture was stirred at 0° C. under nitrogen for 2 hrs. To this solution was added 2-amino-6-fluorobenzonitrile (1.36 g, 10.0 mmol), and the reaction solution was stirred at 0° C.—RT for 2 hrs, and then at 65° C. overnight under nitrogen. The reaction was cooled down to room temperature then quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4. Filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: 20% EtOAc in hexanes) to give the title compound as colorless oil (1.29 g, 59%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, J=8 Hz, 6H), 1.55-1.43 (m, 4H), 1.73-1.65 (m, 1H), 3.90 (d, J=4 Hz, 2H), 4.10 (brs, 2H), 6.25 (d, J=8 Hz, 1H), 6.34 (d, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9]O)=[C:4]([F:11])[CH:3]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][Cl:14])=[CH:6][C:7]=1[F:8]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(F)c(Cl)cc1F
Product: Fc1cc(CCl)c(F)cc1Cl
Temperature: 100 °C
Yield: 34 %

Procedure:
Step B A mixture of (4-chloro-2,5-difluoro-phenyl)-methanol (5.5 g, 32 mmol) in thionyl chloride (25 mL) was heated at refluxing (100° C.) for 30 min. The mixture was cooled to room temperature and concentrated. The residue was diluted with ethyl acetate, washed with saturated aqueous NaHCO3 solution, water, brine, dried over MgSO4, and concentrated to give 1-chloro-4-chloromethyl-2,5-difluoro-benzene as a yellow oil (2.1 g, 34%).
Reaction SMILES: [N+:1]([C:4]([CH3:17])([CH3:16])[CH2:5][O:6][CH:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8]1([CH3:15])[CH3:14])([O-])=O>CO.[Ni]>[NH2:1][C:4]([CH3:17])([CH3:16])[CH2:5][O:6][CH:7]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8]1([CH3:15])[CH3:14]
Reactant: CC1(C)CCC(C)(C)C1OCC(C)(C)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CC(C)(N)COC1C(C)(C)CCC1(C)C

Procedure:
1-(2-Nitro-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane is dissolved in methanol and hydrogenated at 50 psi with Raney nickel T-1 as a catalyst. The reaction mixture is filtered through Celite and evaporated to yield 1-(2-amino-2-methylpropoxy)-2,2,5,5-tetramethylcyclopentane.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][C:6]1=[O:15])([CH3:4])([CH3:3])[CH3:2].C(C1C=C(C(C)(C)C)C=CC=1O)(C)(C)C>[Ni]>[C:1]([CH:5]1[CH2:10][CH:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:8][CH2:7][CH:6]1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)C(C(C)(C)C)C1
Agent: [Ni]
Agent: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Product: CC(C)(C)C1CCC(O)C(C(C)(C)C)C1

Procedure:
The 2,4-di-tert-butylcyclohexanone can be synthesized, for example, by the following manner. 2,4-Di-tert-butylphenol (IV), which is commercially available at a low price, is hydrogenated by using a nickel catalyst to give 2,4-di-tert-butylcyclohexanol (VII). Then the compound (VII) is oxidized to give the aimed compound (I). The hydrogenation of the compound (IV) can be readily carried out without using any solvent or by using an alcohol such as methanol or a hydrocarbon such as hexane at a temperature of approximately 140° to 230° C. for approximately 3 to 24 hours. Examples of the nickel catalyst include Raney nickel and stabilized nickel. This nickel catalyst can be appropriately used in an amount of 0.01 to 5% based on the compound (IV). The oxidation of the compound (VII) into the compound (I) can be carried out by using a copper/chromium or copper/zinc dehydrogenation catalyst in the absence of any solvent at a temperature of approximately 150° to 250° C. for approximately 3 to 20 hours. The catalyst can be appropriately employed in an amount of approximately 0.1 to 10% by weight based on the compound (VII). Alternatively the compound (VII) can be readily oxidized by a conventional method for oxidizing a secondary alcohol into a ketone, such as Jones oxidation, Oppenauer oxidation, manganese dioxide oxidation or chromic acid oxidation.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][C@H:25]([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:6]2[CH:5]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:3]=[C:2]([Cl:1])[N:7]=2)[C@H:25]([CH3:29])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Fc1ccc(-c2cc(Cl)nc(Cl)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1cc(-c2ccc(F)cc2)nc(Cl)n1

Procedure:
Heat a mixture of 2,4-dichloro-6-(4-fluoro-phenyl)-pyrimidine (2.8 g, 11.52 mmol), 3-(R)-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.42 g, 12.1 mmol), and K2CO3 (3.2 g, 23.0 mmol) in DMA at 60° C. for 16 h. Dilute with water, extract with EtOAc, and wash with brine. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue by flash column eluting with EtOAc-Hexanes (1:4) to afford the title compound as a white solid.
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][C@H:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])[CH:14]([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+]>CO>[N+:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C@@H:13]([OH:12])[CH:14]([CH3:15])[CH3:16])([O-:25])=[O:24]
Reactant: CC(C)[C@H](OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)[C@H](O)c1ccccc1[N+](=O)[O-]
Yield: 97.1 %

Procedure:
(S)-1-(2-Nitrophenyl)-2-methyl-propyl (1S)-camphanate (0.717 g, 1.90 mmol) was dissolved in hot methanol (40 mL) and K2CO3 (0.380 g, 2.74 mmol) was added. The mixture was heated to reflux for one hour, then cooled down, concentrated in vacuo, and diluted with diethyl ether (100 mL). The organic phase was washed with water (20 mL), dried over anhydrous Na2SO4, and purified by silica gel column chromatography to yield (S)-1-(2-nitrophenyl)-2-methyl-propanol (0.360 g, 97%) as a light yellow oil. 1H NMR was identical to that of the racemic alcohol.
Reaction SMILES: C(N(CC)CC)C.C(O)(C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.Br[CH2:24][C:25](=[O:28])[CH2:26][CH3:27]>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH2:21][CH2:24][C:25](=[O:28])[CH2:26][CH3:27])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: CCC(=O)CBr
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CCC(=O)CCC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
Anhydrous zinc chloride (3.71 g, 27.2 mmol) was placed into a round bottom flask and dried by melting under vacuum at 250-350° C. for 15 minutes. After cooling under vacuum to room temperature, benzene (15 ml.), triethylamine (2.7 ml, 19.42 mmol) and tert-butanol (1.83 ml, 19.42 mmol) were successively added. The mixture was stirred until zinc chloride was fully dissolved (approx. 2 hour) and 1-(4-chlorophenyl)ethan-1-one (3.0 g, 19.42 mmol) and 1-bromobutan-2-one (2.05 g, 13.6 mmol) were successively added. The mixture was stirred for 1 hour and allowed to stand for 4 days at room temperature, and thereafter quenched with 5% aq. sulfuric acid. The organic layer was separated, washed with water (2×50 ml), brine (1×25 ml), dried over anhydrous sodium sulfate and the solvent evaporated off. The crude product was purified by column chromatography over silica gel (100-200 mesh) using chloroform as eluent to give 2.30 g (75.63%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.O[CH2:18][NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22]>O>[F:22][C:21]([F:24])([F:23])[C:20]([NH:19][CH2:18][C:8]1[C:7]([Cl:11])=[C:3]([C:2]([Cl:1])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])=[O:25]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C(NCO)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1c(Cl)ccc(CNC(=O)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step i): A mixture of 2,6-dichlorobenzoic acid (4 g; 20.94 mmol), conc. H2SO4 (50 mL) and N-(hydroxymethyl)trifluoroacetamide (2.996 g; 20.94 mmol) was stirred at rt overnight. The mixture was diluted with 500 mL crushed ice and 200 mL H2O, the precipitate was filtered and dried to give crude 3-(trifluoromethylcarbonylamino-methyl)-2,6-dichloro-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH2:21][CH2:22][N:23](C(OC(C)(C)C)=O)[CH2:24][CH:25]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1)[CH3:2]
Reactant: CCOc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCNCC3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 66B (220 mg, 0.502 mmol) in 5 mL dichloromethane was added 2,2,2-trifluoroacetic acid (0.387 ml, 5.02 mmol). The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was dried under high-vacuum for 2 hours. The residue was dissolved with 3 mL methanol, and the mixture was treated with excess 2 M hydrochloric acid/diethyl ether followed by stirring for 20 minutes. The mixture was then diluted with 50 mL diethyl ether, and the solid was collected by filtration. The collected solid was dried under high-vacuum to give the title compound as a hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 13.48 (s, 1H) 9.64 (s, 2H) 9.08 (s, 1H) 7.42-7.59 (m, 2H) 7.32 (dd, J=9.16, 4.27 Hz, 1H) 6.80 (d, J=35.71 Hz, 2H) 4.15 (q, J=6.92 Hz, 3H) 3.84 (s, 2H) 3.31 (s, 2H) 2.77 (s, 1H) 1.07-1.28 (m, 3H). MS (ESI+) m/z 339.1 (M+H)+.