Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:27]1([C:25]#[C:26][C:2]2[C:3]([F:17])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:29][CH2:28]1
Reactant: C#CC1CC1
Reactant: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Fc1c(C#CC2CC2)ccc2c1cnn2C1CCCCO1
Temperature: 120 °C
Yield: 56.4 %

Procedure:
In a high pressure tube, a mixture of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.0 g, 26.8 mmol; Intermediate 21), PdCl2(PPh3)2 (3.7 g, 5.35 mmol), CuI (1.0 g, 5.35 mmol), and triethylamine (30 mL) was deoxygenated with three cycles of vacuum/nitrogen. Ethynylcyclopropane (8.9 g, 134 mmol) was added under N2 atmosphere. The tube was sealed and the reaction mixture was heated at 120° C. for 63 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0˜10% ethyl acetate in petroleum ether) affording the title compound (4.3 g). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 5.88 (dd, 1H), 3.88-3.85 (m, 1H), 3.76-3.73 (m, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m, 2H), 1.76-1.72 (m, 1H), 1.62-1.56 (m, 3H), 0.93-0.89 (m, 2H), 0.79-0.74 (m, 2H); LCMS: 285 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:31][CH:30]=[CH2:29])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.6 g of approximately 55 % sodium hydride and the solution was stirred for 30 minutes at room temperature. To this was further added 3.6 g of allyl bromide, and the mixture was reacted for 2 hours at room temperature. Then, the solvent was distilled off from the resulting mixture under reduced pressure to leave a residue, to which was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.9 g of 1(m-nitrophenyl)-3 -allylquinazoline- 2,4(1H, 3H)-dione as light brown needles, melting at 165°-166° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#[N:13])=[CH:7][CH:6]=1.Br[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Br>CN1C(=O)CCC1.CCOCC>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:12]#[N:13])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: BrCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 0 °C
Yield: 77.2 %

Procedure:
A mixture of NaH (3.1 g, 76 mmol) in 100 mL NMP stirred at 0° C., was treated dropwise with the mixture of 2-(4-methoxyphenyl)acetonitrile (4.5 g, 31 mmol) and 1-bromo-2-(2-bromoethoxy)ethane (7.1 g, 31 mmol) in 30 mL ether. The mixture was allowed to warm to room temperature and stirred for 5 hours, M+Na=240. The mixture was carefully quenched with 100 mL H2O, and the pH was adjusted to 5. The mixture was extracted with ether (3×100 mL). The combined organic layers were washed with H2O (3×50 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-20% EtOAc/hexane to give 5.2 g of the product as a pale yellow oil. MS (m/z)=240 (M+H)+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]([CH3:40])(/[C:10](=[N:17]\[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27]N2C=C(C)OC2C2C=CC=CC=2)=[CH:22][CH:21]=1)/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6].O.Cl.[O:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>CO>[CH3:40][C:4]([CH3:3])(/[C:10](=[N:17]\[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:10]2[N:17]=[C:47]([C:46]3[CH:16]=[CH:11][CH:12]=[CH:44][CH:45]=3)[O:43][C:4]=2[CH3:3])=[CH:22][CH:21]=1)/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(C)(C)/C(=N\OCc1ccc(OCN2C=C(C)OC2c2ccccc2)cc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/c2ccccc2)C(C)(C)C(=O)O)cc1
Temperature: 25 °C
Yield: 52 %

Procedure:
Potassium hydroxide (1.83 g) was added to a solution of ethyl Z-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-3-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate (265 mg) in tetrahydrofuran (3 ml)-water (3 ml)-methanol (6 ml), the mixture was heated to reflux for 3 days and cooled to room temperature. Dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain Z-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionic acid (130 mg, yield 52%) as pale-yellow crystals. m.p. 142-143° C. (decomposition).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]3[NH:18][C:17](=[O:19])[C:16]3([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[CH2:26]([O:33][C:34]([CH2:36][CH2:37][N:38]=[C:39]=[O:40])=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:25]=[CH:24][C:13]([O:14][CH:15]3[N:18]([C:39]([NH:38][CH2:37][CH2:36][C:34]([O:33][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:35])=[O:40])[C:17](=[O:19])[C:16]3([CH2:20][CH3:21])[CH2:22][CH3:23])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CCC1(CC)C(=O)NC1Oc1ccc(C(=O)N2CCN(C)CC2)cc1
Reactant: O=C=NCCC(=O)OCc1ccccc1
Product: CCC1(CC)C(=O)N(C(=O)NCCC(=O)OCc2ccccc2)C1Oc1ccc(C(=O)N2CCN(C)CC2)cc1

Procedure:
According to the method of Shrenik et al (J. Med. Chem., 35, 3745-3754 (1992)), 4-[4-[[(4-methyl)piperazin-1-yl]carbonyl]phenoxy]-3,3-diethyl-2-azetidinone, prepared as in Example 5, step F, (0.68 g, 1.97 mmol) and 2-(benzyloxycarbonyl)ethylisocyanate (0.705 g, 3.94 mmol) gave, following purification by flash column chromatography (gradient from petrol/EtOAc, 1:1 to MeOH/EtOAc, 1:9 to MeOH/EtOAc, 1:1), the title compound (840 mg, 78%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1.[CH3:14][O:15][C:16]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:17]=1[NH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:22]=[C:21]([N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([C:10]([F:13])([F:12])[F:11])=[CH:4][N:3]=1
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(-n2cncn2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CNc1nc(Nc2ccc(-n3cncn3)cc2OC)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 24.9 %

Procedure:
A mixture of 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (80 mg, 0.38 mmol), 2-methoxy-4-(1H-1,2,4-triazol-1-yl)aniline (72 mg, 0.38 mmol) and p-toluene sulphonic acid (72 mg, 0.38 mmol) in dioxane (2 mL) was heated at 100° C. for 1 h. The mixture was cooled and filtered. The solid was partitioned between dichloromethane (10 mL) and saturated aqueous NaHCO3 (10 mL) and the product was extracted into dichloromethane (3×10 mL). The combined organics were passed through a phase separation cartridge and the solvent removed under reduced pressure. Purification of the residue via silica gel column chromatography (0-100% ethyl acetate/isohexane) afforded a residue that was triturated with methanol/diethyl ether yielding N2-(2-methoxy-4-(1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine as a white solid (34.5 mg, 25%). LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=366 at 3.13 min. 1H NMR (400 MHz, DMSO): δ 9.29 (s, 1H); 8.33 (d, J=8.7, 1H); 8.24-8.15 (m, 3H); 7.53 (d, J=2.4, 1H); 7.45 (dd, J=8.7, 2.4, 1H); 7.23 (d, J=5.2, 1H); 3.97 (s, 3H); 2.92 (d, J=4.4, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:22])([F:21])[C:5]1[CH:6]=[C:7]([CH:15]2[O:19][C:18](=[O:20])[NH:17][CH2:16]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.Br[CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:26]=1[I:35]>C1COCC1>[F:22][C:4]([F:3])([F:21])[C:5]1[CH:6]=[C:7]([CH:15]2[O:19][C:18](=[O:20])[N:17]([CH2:24][C:25]3[CH:30]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:28]=[CH:27][C:26]=3[I:35])[CH2:16]2)[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Reactant: O=C1NCC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1OC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1cc(C(F)(F)F)ccc1I
Reaction time: 0.33 h

Procedure:
A stirred suspension of sodium hydride (60% in oil, 167 mg, 4.18 mmol) in THF (5 mL) was treated at 0° C. with 5-[3,5-bis(trifluoromethyl)phenyl]-1,3-oxazolidin-2-one (500 mg, 1.67 mmol) dissolved in THF (1 mL), under an atmosphere of N2. The reaction was stirred for 20 min and a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (610 mg, 1.67 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at room temperature for 18 h. The reaction was quenched with H2O (1 mL) and partitioned between EtOAc (80 mL) and H2O (25 mL). The aqueous phase was re-extracted with EtOAc (2×20 mL) and the combined organic extracts were washed with brine (30 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash silica-gel chromatography (0-30% EtOAc in hexanes gradient) to afford 5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]1,3-oxazolidin-2-one. Rf=0.55 (515% EtOAc/hexanes). LCMS 584 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.05 (d, J=8.2 Hz, 1H), 7.95 (br s, 1H), 7.85 (br s, 2H), 7.51 (br s, 1H), 7.32 (m, 1H), 5.72 (t, J=8.0 Hz, 1 H), 4.74 (d, J=15.5 Hz, 1H), 4.64 (d, J=15.3 Hz), 4.14 (t, J=7.1 Hz, 1H), 3.47 (dd, J=7.1, 1.6 Hz).
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][C:11]1[CH:16]=[C:15]([NH:17]C(OC(C)(C)C)=O)[CH:14]=[CH:13][C:12]=1[C:25]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]1)C)=O)(C)(C)C.[ClH:33]>CCOC(C)=O.ClCCl>[ClH:33].[NH2:17][C:15]1[CH:14]=[CH:13][C:12]([C:25]2([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]2)=[C:11]([CH2:10][NH:8][CH3:6])[CH:16]=1
Reactant: CCOC(=O)C1(c2ccc(NC(=O)OC(C)(C)C)cc2CN(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1(c2ccc(N)cc2CNC)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 111.9 %

Procedure:
15F (0.173 g, 0.386 mmol) was dissolved in EtOAc (3 mL) and dichloromethane (2 mL), then HCl (4M in dioxane) (2 mL, 8.00 mmol) was added. The reaction mixture was stirred for 6 h at rt. The solvent was removed under reduced pressure, and the residue was dried under high vacuum to give 15G (0.123 g, 99% yield) as an off-white solid. MS (ESI) m/z: 249.1[M+1]+. 1H NMR: (400 MHz, CD3OD) δ ppm 7.69 (1H, d, J=2.27 Hz), 7.59 (1H, d, J=8.34 Hz), 7.42 (1H, dd, J=8.34, 2.27 Hz), 4.38 (2H, s), 4.14 (2H, q, J=7.07 Hz), 2.84 (3H, s), 1.83 (2H, d, J=3.03 Hz), 1.31-1.39 (2H, m), 1.20 (3H, t, J=7.20 Hz).
Reaction SMILES: S(N)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=O)=O.C[C:13]([OH:15])=[O:14]>[Zn]>[C:4]12([C:13]([OH:15])=[O:14])[CH2:8][CH:7]([CH2:9][CH2:10]1)[CH:6]=[CH:5]2
Reactant: CC(=O)O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [Zn]
Product: O=C(O)C12C=CC(CC1)C2
Yield: 96.8 %

Procedure:
Compound 4 (27.0 g; 0,062 mole) and Zn° (16.2 g; 0.249mol) were combined in HOAc (100 ml) and heated to reflux for one half hour. The reaction mixture was cooled and filtered through Celite®. The filtrate was concentrated and the residue suspended in H2O, whereupon the oil crystallized. The solid was filtered, washed with H2O and suction dried to yield 18.4 g (96.8%) of Compound 5 as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]([F:37])([F:36])[CH2:34]I.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][CH2:16][C:17]([C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][N:20]=3)=[O:18])[N:14]=2)=[CH:3][C:2]=1[O:1][CH2:34][C:33]([F:37])([F:36])[F:32]
Reactant: FC(F)(F)CI
Reactant: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OCC(F)(F)F
Temperature: 80 °C

Procedure:
A 0.23 g quantity of 3-[2-(3-hydroxy-4-methoxyphenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one obtained in Example 136 and 0.28 g of potassium carbonate were dissolved in 5 ml of dimethylformamide. A 0.29 g quantity of 1,1,1-trifluoro-2-iodoethane was added thereto, and the mixture was stirred with heating at 80° C. overnight. The reaction mixture was allowed to cool, water was then added thereto, and extraction was performed with ethyl acetate. After washing with water twice, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:ethyl acetate=1:1) to give 0.14 g of white powdery 3-{2-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]oxazol-4-yl}-1-(3-methylpyridin-2-yl)propan-1-one.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[Cl:8].[N+:11](=[CH2:13])=[N-:12].[CH3:14]COCC>>[Cl:1][C:2]1[C:3](=[O:10])[C:4]2[CH:13]=[N:11][N:12]([CH3:14])[C:5]=2[C:6](=[O:9])[C:7]=1[Cl:8]
Reactant: O=C1C=CC(=O)C(Cl)=C1Cl
Reactant: C=[N+]=[N-]
Reactant: CCOCC
Product: Cn1ncc2c1C(=O)C(Cl)=C(Cl)C2=O

Procedure:
2,3-Dichlorobenzoquinone (22 grams) was added portionwise to a stirred solution of diazomethane (14 grams) in ether (500 milliliters) maintained at a temperature below 15° C. A pale yellow solid separated out from the solution, and this was filtered off and dried to yield the desired product having a melting point of 176°-177° C.
Reaction SMILES: [Na].[C:2]([O:6]CC)(=O)[CH:3]=[CH2:4].[NH2:9][C:10]1[CH:14]=[CH:13][NH:12][N:11]=1.CC[OH:17]>>[N:12]1[N:11]2[C:4]([OH:17])=[CH:3][C:2]([OH:6])=[N:9][C:10]2=[CH:14][CH:13]=1
Reactant: CCO
Reactant: C=CC(=O)OCC
Reactant: Nc1cc[nH]n1
Agent: [Na]
Product: Oc1cc(O)n2nccc2n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 62 %

Procedure:
Intermediates J1 and J2 were prepared essentially according to the procedure described in US Patent Publication No.: US 2006/0041131 A1. Sodium metal (6.64 g, 289 mmol) was added to EtOH (450 mL) and stirred for 40 min until all was dissolved. Next, ethyl acrylate (24.12 ml, 159 mmol) and 3-aminopyrazole (12.00 g, 144 mmol) were added, and the reaction mixture was heated to reflux for 3 h. The reaction mixture was cooled to room temperature, filtered, and the collected solids rinsed with excess EtOH. The isolated solids were dissolved in water (˜300 mL), which was cooled with and ice water bath. The aqueous mixture was acidified to pH=1-2 with concentrated HCl. The resulting precipitate was filtered and rinsed with excess water. The isolated solid was dried in a vacuum oven at 30° C. over the weekend to afford the title compound (J1) as an off-white solid (13.5 g, 62%). LRMS m/z (M+H+H2O) 170.1 found, 152.0 required.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[CH3:22][C:23]1[C:24]([NH2:32])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[CH:26]2.C1(C)C(C)=CC=CC=1.[Cl-].[Na+]>C(OCC)(=O)C>[F:16][C:13]([F:14])([F:15])[C:10]([CH:11]=[N:32][C:24]1[C:23]([CH3:22])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[N:27][NH:28]2)([OH:17])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1c(F)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cc1ccc2[nH]ncc2c1N
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COc1c(F)cccc1C(C)(C)CC(O)(C=Nc1c(C)ccc2[nH]ncc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
4-(3-Fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal (308 mg, 1.0 mmol) and 5-methyl-1H-indazol-4-ylamine (148 mg, 1.0 mmol) are introduced into 15.0 ml of xylene and mixed with titanium(IV)ethylate (0.42 ml, 2.0 mmol). After 3 hours under reflux, the reaction mixture is allowed to cool to room temperature. After ethyl acetate and saturated sodium chloride solution are added, it is stirred vigorously for 30 minutes at room temperature. The deposited precipitate is suctioned off, the aqueous phase is separated, and the organic phase is dried on sodium sulfate. The purification is carried out by means of chromatography on silica gel with hexane/ethyl acetate (30-40% ethyl acetate). 345 mg (79% of theory) of 1,1,1-trifluoro-4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-[(5-methyl-1H-indazol-4-ylimino)methyl]-pentan-2-ol is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][C:20]1[N:25]=[CH:24][C:23]([O:26][C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([O:18][CH2:19][C:20]2[N:25]=[CH:24][C:23]([O:26][C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CN(C)C(=O)Oc1ccc(CO)nc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CN(C)C(=O)Oc1ccc(COc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, dimethyl-carbamic acid 6-hydroxymethyl-pyridin-3-yl ester and DBU in DME. ES-MS m/e (%): 403 (M+Na+, 45), 381 (M+H+, 100).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:10][CH3:11])=[CH:4][CH:3]=1.[CH3:25][NH:26][CH2:27][CH2:28][NH:29][CH3:30]>>[CH3:25][N:26]([CH2:27][CH2:28][NH:29][CH3:30])[C:2]1[N:7]=[CH:6][C:5](/[C:8](/[C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[C:9](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CC/C(=C(/c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Reactant: CNCCNC
Product: CC/C(=C(/c1ccc(O)cc1)c1ccc(N(C)CCNC)nc1)c1ccccc1

Procedure:
Following the same procedure as described in example 39, step D, (E)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1.0 eq, made from example 2) was reacted with N,N′-dimethylethane-1,2-diamine (262 mg, 10.0 eq) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=2.4 z, 1H), 7.06-7.14 (m, 6H), 6.69 (d, J=8.8 Hz, 2H), 6.49 (d, J=8.8 Hz, 1H), 6.43 (d, J=8.8 Hz, 2H), 3.71 (t, J=6.4 Hz, 2H), 3.08 (s, 3H), 2.88 (t, J=6.4 Hz, 2H), 2.53 (q, J=7.6 Hz, 2H), 2.48 (s, 3H), 0.95 (t, J=7.6 Hz, 3H); m/z=388[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34](Cl)(Cl)=[O:35].[NH2:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][CH:43]=[CH:42]2>C(Cl)Cl.CO.C(Cl)Cl>[CH3:14][CH:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:34]([NH:38][C:39]3[CH:40]=[C:41]4[C:46](=[CH:47][CH:48]=3)[N:45]=[CH:44][CH:43]=[CH:42]4)=[O:35])[CH:7]=[CH:6][CH:5]=2)([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)[CH2:9][CH2:10]1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(Cl)Cl
Reactant: CC1CCC(c2cccc(N)c2)(N2CCN(c3ccccc3)CC2)CC1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(c2cccc(NC(=O)Nc3ccc4ncccc4c3)c2)(N2CCN(c3ccccc3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-aminophenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane (cis isomer, 116 mg, 0.332 mmol) and triethylamine (116 μL, 0.83 mmol) in dry CH2Cl2 (7 mL) was brought to 0° C. using an ice bath. Phosgene (1.93 M in toluene, 181 μL) was added dropwise and the resulting mixture was stirred at 0° C., under a dry N2 atmosphere, for 30 minutes. 6-aminoquinoline (53 mg, 0.365 mmol) was added as a solid and the reaction was allowed to come to room temperature. The reaction was stirred overnight, diluted with an equal volume of CH2Cl2, washed with H2O, dried (Na2SO4) and concentrated to give the crude urea. Silica gel chromatography (eluent: 5% CH3OH/CH2Cl2) yielded pure N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)cyclohexyl]phenyl]-N'-6-quinolinyl-urea (cis isomer) as an off-white solid. The HCI salt was prepared by adding excess saturated EtOAc/HCI solution to the free base in dry MeOH. Concentration of the homogeneous solution yielded a white solid which was washed with EtOAc. m=185-187° C.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[CH2:13]([NH:20][C@H:21](C(O)=O)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH:21]([CH3:22])[CH2:3][CH:2]2[CH:11]1[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCN(CC=O)C(=O)OCC
Reactant: C[C@H](NCc1ccccc1)C(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC2CC(C)N(Cc3ccccc3)C2C1

Procedure:
42.8 (0.25 mol) of ethyl N-allyl-N-(2-oxo -ethyl)-carbamate are heated under reflux overnight with 44.8 g (0.25 mol) of N-benzylalanine in 750 ml of toluene. The mixture is concentrated and the residue is distilled twice.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:13]([CH:15]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[C:17]([CH3:26])([CH3:25])[C:16]2=O)=[O:14])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2.C(Cl)(=O)C([Cl:32])=O>ClCCl.CN(C)C=O>[F:1][CH:2]([F:28])[C:3]1[CH:4]=[CH:5][C:6]([C:13]([C:15]2[C:20](=[O:21])[C:19]([CH3:23])([CH3:22])[C:18](=[O:24])[C:17]([CH3:26])([CH3:25])[C:16]=2[Cl:32])=[O:14])=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[CH:8]2
Reactant: CC1(C)C(=O)C(C(=O)c2ccc(C(F)F)c3ncccc23)C(=O)C(C)(C)C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)C(C(=O)c2ccc(C(F)F)c3ncccc23)=C(Cl)C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.25 g (0.65 mmol) of 2-(8-difluoromethylquinolin-5-yl)carbonyl-4,4,6,6-tetramethyl-cyclohexane-1,3,5-trione was dissolved in 15 ml of dichloromethane and 0.25 g (1.95 mmol) of oxalyl chloride and 7 drops of dimethylformamide were added. The mixture was stirred at 25° C. for 17 hours, after which the solvent was removed. This gave 0.2 g of colorless crystals.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.COCCOCOCCCCCCCCCCCC(O)=O.[CH:47]1([N:53]=[C:54]=[N:55][CH:56]2[CH2:61][CH2:60][CH2:59]CC2)CCCCC1>O1CCCC1>[CH3:1][N:53]([C:54]1[CH:59]=[CH:60][CH:61]=[CH:56][N:55]=1)[CH3:47]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Agent: COCCOCOCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 400 mg of radicicol, 856 mg of 12-(methoxyethoxymethoxy)dodecanoic acid, 6 ml of dry tetrahydrofuran, 567 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 893 mg of the title compound were obtained.