Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23]([C:39]([CH3:41])=[CH2:40])[N:22]=3)[C@@H:15]([CH3:42])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H][H]>CCO.[Pd]>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[C:26]([C:27]4[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[C:30]([F:36])=[CH:29][C:28]=4[O:37][CH3:38])=[CH:25][CH:24]=[C:23]([CH:39]([CH3:41])[CH3:40])[N:22]=3)[C@@H:15]([CH3:42])[CH2:14]2)[CH:4]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:8]=1
Reactant: [H][H]
Reactant: C=C(C)c1ccc(-c2cc(C(C)C)c(F)cc2OC)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@@H]2C)n1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(C)C)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropenylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one (Example 5, 8.0 mg, 0.011 mmol) in EtOH (2 mL) was charged with hydrogen at 1 atm with catalytic amount of Pd/C. The mixture was stirred at room temperature for 1 h. The mixture was filtered through Celite and concentrated. The title compound was obtained after flash chromatography on silica gel using EtOAc:hexane 10:90 as the elute to afford 4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-(4-fluoro-5-isopropyl-2-methoxyphenyl)-6-isopropylpyridin-2-yl]methyl}-4-methyl-1,3-oxazinan-2-one. LCMS=627.2 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 7.86 (s, 3H), 7.68 (brs, 1H), 7.18 (brs, 1H), 7.14 (br m, 1H), 6.71 (d, J=11.9 Hz, 1H), 5.31-5.27 (m, 2H), 4.31-4.24 (m, 2H), 3.80 (s, 3H), 2.21 (m, 1H), 1.82 (m, 1H), 1.26 (br s, 3H), 1.21 (br m, 12H).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:18])[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[NH:7][CH:8]=1)[CH3:2].I[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:1]([C:3]1[C:4](=[O:18])[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[N:7]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:8]=1)[CH3:2]
Reactant: CCc1c[nH]c(CCc2ccc(F)cc2)nc1=O
Reactant: CC(C)(C)OC(=O)CI
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cn(CC(=O)OC(C)(C)C)c(CCc2ccc(F)cc2)nc1=O
Yield: 78.8 %

Procedure:
5-Ethyl-2-[2-(4-fluorophenyl)ethyl]-1H-pyrimidin-4-one (B40) (955 mgs) in dichloromethane (20was treated with t-butyl iodoacetate, (2.82 g) and diisopropylethylamine (2.03 mls) at room temperature for 3 days. The solution was washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulphate. The solution was concentrated to give a semi-solid which was triturated with ether:dichloromethane, 5:1, giving the title compound as a white solid, (1.101 g, 79%), 1H-NMR (CDCl3) δ 1.16 (3H, t), 1.47 (9H, s), 2.47 (2H, q), 2.74 (2H, t), 3.14 (2H, t), 4.27 (2H, s), 6.90 (1H, s), 6.98 (2H, m) and 7.17 (2H, m). (APCI+) Found (M+1)=361, C20H25FN3 requires 360.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20](=[O:25])C(F)(F)F)=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].[OH2:28]>CN(C=O)C.COC(C)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([OH:25])=[O:28])=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: O
Reactant: O=C(c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2cc(F)cc(F)c2)c2cc(Cl)ccc12
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
To a solution of 2.2 g (6.5 mmol) 1-[6-chloro-1-(3,5-difluoro-benzyl)-1H-indol-3-yl]-2,2,2-trifluoro-ethanone in 65 ml DMF were added 1.7 g (36 mmol) sodium hydride (50% in oil) at room temperature. After stirring for 5 min. 0.59 ml (33 mmol) water were added dropwise. Stirring was continued at room temperature for 45 min. The reaction mixture was diluted with 150 ml of tert-butyl methyl ether and extracted with two 150-ml portions of a 1 M aqueous solution of sodium hydroxide. The combined aqueous layers were acidified to pH 1 with concentrated hydrochloric acid solution and extracted with three 150-ml portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dried in high vacuo at 80° C. to give 2.0 g (95%) of the crude title compound as a brown solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[F:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>CCCCCC.C(OCC)(=O)C>[F:30][C:31]1[N:36]=[CH:35][C:34]([C:2]2[C:10]3[O:9][CH2:8][CH:7]([C:11]4[CH:16]=[CH:15][C:14]([CH:17]([CH3:18])[CH3:19])=[CH:13][CH:12]=4)[C:6]=3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=2[CH3:29])=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccc(F)nc1)OCC2c1ccc(C(C)C)cc1
Yield: 58 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (6-fluoropyridin-3-yl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 58%. Melting point: 135-137° C. (hexane-ethyl acetate).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:4].C(O)C.O.C(=O)=O.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]([NH:5][C:6]1[C:11]([N+:21]([O-:23])=[O:22])=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[CH3:13])=[O:4]
Reactant: Cc1c(F)cccc1NC(=O)CCl
Reactant: O=[N+]([O-])O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: Cc1c(F)ccc([N+](=O)[O-])c1NC(=O)CCl
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A solution of 2-chloro-N-(3-fluoro-2-methylphenyl)acetamide (47.2 g, 234 mmol) in conc. sulphuric acid (220 ml) was treated at ca. −20° C. (ethanol/water/CO2(s) bath) with conc. nitric acid (69%, 15.25 ml, 19 g, 235 mmol) over 30 minutes, keeping internal temperature ≦9° C. The reaction was complete at the end of the addition. The mixture was added to ice with vigorous stirring then left to stand overnight. Filtration, washing of the solid with water and drying afforded the product (54.6 g, 95%) containing ˜9% impurity.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])[CH:15]=2)[CH:11]=[CH:12]1)[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.1 %

Procedure:
To an ice cold solution of 6-(tert-butyl-dimethyl-silanyloxy)-1H-indole (1 g, 4.04 mmol) and cesium carbonate (1.45 g, 4.45 mmol) in DMF (10 ml) under an argon atmosphere was added bromo-acetic acid ethyl ester (490 μl, 4.45 mmol). The mixture was naturally warmed to room temperature, stirred for 14 h, poured onto 1 N HCl/ice water 1/1 and extracted two times with ethyl acetate. The combined organic layers were washed with water and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography (silica gel, heptane/AcOEt) to give 1.2 g (3.6 mmol, 89%) of the title compound as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-])=O)=[CH:15][C:14]=2[CH3:23])=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:14]([CH3:23])=[CH:15][C:16]([NH2:20])=[CH:17][C:18]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(N)cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Yield: 99.5 %

Procedure:
A 1 L rocking Parr hydrogenator was charged with a solution containing 19.11 g of 4-(4-chloro-5,6,7,8-tetrahydro-1-naphthoxy)-3,5-dimethyl-1-nitrobenzene in 600 mL of toluene. To this was then added 1.0 g of 5% platinum on carbon. This was then placed under an atmosphere of hydrogen at 100 psi. The internal pressure was maintained between 80 and 100 psi while hydrogen uptake continued. When the hydrogen uptake ceased, the contents of the hydrogenator were removed and the vessel washed with toluene. The washings were combined with the reaction mixture. This was then filtered through celite. Removal of the solvents afforded 17.30 g of pale yellow solid. mp 126°-135° C. NMR(CDCl3): δ1.6-1.8 (m, 4H), 2.0 (S, 6H), 2.6-2.9 (m, 4H), 3.45 (S, 2H), 6.13 (d, J=9 Hz, 1H), 6.37 (S, 2H), 6.93 (d, J= 9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:17]1([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[N:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N=Cc2ccc(-c3ccccc3)cc2)cc1

Procedure:
p-Toluidine (0.20 mole), 4-biphenylcarboxaldehyde (0.20 mole), and IRC-50 (weakly acidic) ion exchange resin (0.5 g.) were azeotropically refluxed in toluene (150 cc). The required amount of water had been removed after 3 hours. The solvent was removed on the rotary evaporator and the residue was recrystallized with 95% ethanol to yield N-(p-phenylbenzylidene)-p-methylaniline; m.p. 137°-139° C.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[F:9][C:10]([F:24])([F:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=O)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:7][O:8][CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:10]([F:9])([F:23])[F:24])=[CH:16][CH:15]=2)[O:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=CCCCCc1ccc(C(F)(F)F)cc1
Reactant: CCCC(CO)CO
Solvent: Cc1ccccc1
Product: CCCC1COC(CCCCc2ccc(C(F)(F)F)cc2)OC1
Yield: 51.2 %

Procedure:
2-Propyl-1,3-propanediol 5.90 g (49.9 mmol) and the above 5-(4-trifluoromethylphenyl)pentanal 7.50 g (32.6 mmol) were dissolved in toluene 70 ml, and PTS 1 g was added, and the mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with a saturated sodium bicarbonate aqueous solution, and then with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene), and recrystallized twice from ethanol to obtain 5-propyl-2-(4-(4-trifluoromethylphenyl)butyl)-1,3-dioxane 5.55 g (16.7 mmol). The yield was 51.2% from 5-(4-trifluoromethylphenyl) pentanal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]1([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]1.[N+:21]([O-])([O-:23])=[O:22].[K+].C([O-])([O-])=O.[K+].[K+]>OS(O)(=O)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:21]([O-:23])=[O:22])=[CH:4][C:3]=1[C@:8]1([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:15])([F:16])[F:17])[C:10]([NH2:19])=[N:9]1
Reactant: C[C@@]1(c2ccccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: C[C@@]1(c2cc([N+](=O)[O-])ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R,5R)-5-(2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (1.035 g, 3.57 mmol) in H2SO4 (6 ml) was added in portions KNO3 (0.379 g, 3.74 mmol) under ice-water cooling. The reaction mixture was stirred for 2 h at 25° C., diluted with water and basified with K2CO3 under cooling. The product was extracted with EtOAc. Combined extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. Purification via chromatography on silica gel (hexane-EtOAc 4:1 to 1:1 containing 0.05% NEt3) gave the title compound as a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.50; UPLC RtH5=0.749 min; ESIMS: 336 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 8.48 (dd, 1H), 8.14 (m, 1H), 7.15 (dd, 1H), 4.20 (br s, 2H), 4.04 (dd, 1H), 3.91 (dd, 1H), 1.54 (s, 3H), 1.49 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:17])[N:11]=[C:12](SC)[NH:13][CH:14]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:38])([F:37])[F:36]>C(O)C>[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:12]3[NH:13][CH:14]=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:10](=[O:17])[N:11]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:35]([F:36])([F:37])[F:38]
Reactant: CSc1nc(=O)c(Cc2ccc(C)nc2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCO
Product: Cc1ccc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Yield: 49 %

Procedure:
5-(6-methyl-pyridin-3-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (50 mg, 0.202 mmol, 1 eq) and 2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamine (100 mg, 0.317 mmol, 1.57 eq) were heated in a sealed vial at 130° C. in 300 μl of absolute ethanol for 20 hours. Solvent was then evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 10 g normal phase silica SNAP column and DCM/20% MEOH in DCM solvent system (gradient 5-40% of 20% MeOH in DCM in 25 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and the resulting crude was purified once more under the same conditions. Solvent from the gathered fractions of appropriate composition was evaporated the resulting oil was triturated with cyclohexane and diethyl ether to afford 2-{2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethylamino}-5-(6-methyl-pyridin-3-ylmethyl)-1H-pyrimidin-4-one (51 mg, yield=46.54%, purity=95%). MS: [M+H]=515.34. 1H NMR (300 MHz; CDCl3) δ/ppm 2.48 (s, 3H), 2.87 (t, J=7.23 Hz, 2H), 3.57 (s, 2H), 3.52-3.62 (m, 4H), 5.55 (br.s., 1H), 6.93 (d, J=8.23 Hz, 2H), 6.98-7.06 (m, 2H), 7.21 (d, J=8.23 Hz, 1H), 7.28 (d, J=2.84 Hz, 1H), 7.36-7.43 (m, 2H), 7.60 (br.s., 1H), 8.39 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([O:19][CH:20]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]([CH3:38])=[N:36][N:37]=2)=[CH:29][CH:28]=1)[C:21](N(OC)C)=[O:22])[CH3:18]>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:21](=[O:22])[CH:20]([O:19][CH2:17][CH3:18])[C:27]3[CH:28]=[CH:29][C:30]([C:33]4[O:34][C:35]([CH3:38])=[N:36][N:37]=4)=[CH:31][CH:32]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCOC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Cl
Product: CCOC(C(=O)c1ccc(-c2cc(OC)c(Cl)c(OC)c2)o1)c1ccc(-c2nnc(C)o2)cc1

Procedure:
1-(5-(4-Chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-chloro-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc-hexanes) gave the product as a pale yellow solid (0.122 g, 25% yield). MS: m/z 483.1 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.O>CN(C)C=O>[C:15]1([CH2:14][CH2:13][N:12]([CH2:24][C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[C:9]2[S:10][CH:11]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(CCNc2nc(-c3ccccc3)cs2)cc1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(CCc2ccccc2)c2nc(-c3ccccc3)cs2)cc1
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
To a solution of 4-phenyl-N-(2-phenylethyl)-1,3-thiazole-2-amine (4.63 g, 16.5 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (60% in oil, 990 mg, 24.8 mmol) and the mixture was stirred for 30 min. Methyl 4-(bromomethyl)benzoate (4.54 g, 19.8 mmol) was added and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-50% ethyl acetate/hexane) to give the title compound (3.39 g, yield 48%) as a yellow oil.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:37][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[N:23]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CCl
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
29 mg (0.73 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 152 mg (0.70 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.70 mmol) 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine (WO 2005/049573) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 288 mg (88%) of the title compound as beige powder.
Reaction SMILES: OC1C=CC(O[CH2:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[O:9])=CC=1.C(C(O)=O)[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(COc1ccc(O)cc1)OCCc1ccc(O)cc1
Reactant: O=C(O)CCc1ccc(O)cc1
Product: O=C(CCc1ccc(O)cc1)OCCc1ccc(O)cc1

Procedure:
Using a similar procedure, 4-hydroxyphenethyl 2-(4-hydroxyphenoxy)acetate (compound of Formula (V) where L1=bond, L4=—O—, m=2, n=1, y1=y2=0) is prepared by substituting 2-(4-hydroxyphenoxy)acetic acid for desaminotyrosine. Similar results are obtained.
Reaction SMILES: [C:1]([O:6]C)(=O)[C@@H:2]([CH3:4])[OH:3].[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C[O-].[Na+].CO>>[N:8]1([C:1](=[O:6])[C@H:2]([OH:3])[CH3:4])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: COC(=O)[C@@H](C)O
Reactant: C1COCCN1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)C(=O)N1CCOCC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To (R)-methyl lactate (24.42 g, 0.23 mol) were added morphline (21.46 g, 0.25 mol) and sodium methoxide in methanol (14%, 9.04 g, 0.02 mol) and the mixture was stirred for 3 hours at 50° C. After removal of the solvent in vacuo, the residue was subjected to azeotropic distillation three times with toluene to give the subject compound (quant.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.Br[CH2:28][C:29]#[N:30]>C1(C)C=CC=CC=1>[C:29]([CH2:28][N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)#[N:30]
Reactant: N#CCBr
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2nn(CC#N)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 190 °C
Yield: 1.8 %

Procedure:
A mixture of 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, step 3) (0.10 g), 4.2 g of bromoacetonitrile and 3 mL of toluene was heated at reflux for 2 hours. Toluene was distilled off and the mixture was heated at 190 ° C. for 24 hours. The reaction mixture was diluted with methylene chloride and filtered through silica gel. The filtrate was concentrated in vacuo and the residue was purified by HPLC (30% ethyl acetate-hexane). The second fraction eluted with 40% ethyl acetate-hexane yielding 1-cyanomethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (1 2 mg, 11%): mp 192-194° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=C[CH:4]=1.CSC1C=CC(NC)=[N:27]C=1>>[CH3:1][S:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[N:27][CH:4]=1
Reactant: CNc1ccc(SC)cn1
Reactant: CSc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Product: CSc1ccc(CN2C(=O)c3ccccc3C2=O)nc1

Procedure:
The title compound is prepared in analogy to preparation 6a, substituting 4-(methylthio)-benzylamine with (5-methylsulfanyl-pyridin-2-yl)-methylamine (preparation 16a). ESI mass spectrum: [M+H]+=285; r.t. HPLC: 0.51 min (X012_S01).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:44])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[C:29]4[CH:37]=[C:36]([N:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[N:35]=[CH:34][C:30]=4[N:31]=[CH:32][N:33]=3)=[CH:23][C:22]=2[CH3:43])[CH:15]=1)(C)(C)C>C(Cl)Cl>[CH3:43][C:22]1[CH:23]=[C:24]([NH:27][C:28]2[C:29]3[CH:37]=[C:36]([N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[N:35]=[CH:34][C:30]=3[N:31]=[CH:32][N:33]=2)[CH:25]=[CH:26][C:21]=1[O:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([OH:44])=[O:12]
Reactant: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1Oc1cccc(C(=O)O)c1
Yield: 99.4 %

Procedure:
Trifluoro acetic acid (10 mL) was added to a solution of 3-[2-Methyl-4-(6-pyrrolidin-1-yl-pyrido[3,4-d]pyrimidin-4-ylamino)-phenoxy]-benzoic acid tert-butyl ester (0.40 g, 0.82 mmol) in CH2Cl2 (10 mL). After 12 h the reaction was concentrated to give a red solid (0.36 g, 100%). LRMS: 4.42 (MH+), HPLC Rf: 8.34 min.