Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([O:16][C@H:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl>>[ClH:1].[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([O:16][C@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCNC1
Yield: 93 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline was reacted with hydrogen chloride (4.0M in 1,4-dioxane) to give 4-(3-chloro-2-fluoroanilino)-6-[(3S)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride (1.94 g, 93%); 1H NMR Spectrum: (DMSO d) 2.18-2.28 (m, 1H); 135-145 (m, 1H); 3.27-3.46 (m, 3H); 3.73-3.82 (m, 1H); 3.99 (s, 3H); 5.41-5.47 (m, 1H); 7.31-7.37 (m, 1H); 7.44 (s, 1H); 7.47-7.54 (m, 1H); 7.58-7.64 (m, 1H); 8.66 (s, 1H); 8.80 (s, 1H); 9.42 (bs, 1H); 9.61 (bs, 1H); 12.24 (bs, 1H); Mass Spectrum: (M−H)+389.
Reaction SMILES: [Cl-].[CH2:2]([N+:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:25]([O:28][C:29]1[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:31]([OH:33])=[O:32])(=[O:27])[CH3:26].[OH-].[Na+]>O>[C:25]([O:28][C:29]1[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=1[C:31]([O-:33])=[O:32])(=[O:27])[CH3:26].[CH2:15]([N+:12]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH3:14])[CH3:13])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: CCCCCCCCCC[N+](C)(C)CCCCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1ccccc1C(=O)[O-]
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A stoichiometric mixture of didecyldimethylammonium chloride, acetylsalicyclic acid, and NaOH in distilled water was stirred at 60° C. for 2 h and then cooled to room temperature. The aqueous solution was extracted by chloroform. Chloroform was removed and prepared didecyldimethylammonium 2-acetoxybenzoate with 90% yield was dried in vacuum.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[O:28])[C:26](I)=[C:25]([O:30][CH3:31])[C:24](=[O:32])[NH:23][C:22]=2[CH:33]=1.C([Sn](CCCC)(CCCC)[C:39]1[CH:43]=[CH:42][S:41][CH:40]=1)CCC>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[S:41]1[CH:42]=[CH:43][C:39]([C:26]2[C:27](=[O:28])[C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:33][C:22]=3[NH:23][C:24](=[O:32])[C:25]=2[O:30][CH3:31])=[CH:40]1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: Cc1ccccc1
Product: COc1c(-c2ccsc2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
A solution of tri(2-furyl)phosphine (0.046 g) and tris(dibenzylideneacetone)dipalladium (O) (0.046 g) in toluene (75 mL) was allowed to stir for 10 minutes. To this solution was added 8-chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]-azepine (1.82 g), followed by 3-tributylstannylthiophene (2.2 g). The reaction was heated to reflux for 3 hours. After allowing the reaction mixture to cool to room temperature and stir for 16 hours, a solid precipitated. The filtered solid was recrystallized from ethyl acetate/methanol (2:1) to afford the title compound (0.54 g); NMR: 11.49 (bs, 1), 7.78 (m, 1), 7.63 (d, 1, J=8.4), 7.52 (m, 1), 7.38 (d, 1, J=1.9), 7.30 (dd, 1, J=8.6, 2.1), 7.20 (m, 1), 3.75 (s, 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[N:8]=[CH:7][C:6]([OH:15])=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][CH:24]1[CH2:26][CH2:25]1.O>CS(C)=O>[CH:24]1([CH2:23][O:15][C:6]2[CH:7]=[N:8][C:9]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:11][C:10]=3[N+:12]([O-:14])=[O:13])[CH2:26][CH2:25]1
Reactant: O=[N+]([O-])c1cc(F)cc2cc(O)cnc12
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(F)cc2cc(OCC3CC3)cnc12

Procedure:
A solution of 6-fluoro-8-nitro-quinolin-3-ol (1.285 g, 6.21 mmol) and cesium carbonate (4.046 g, 12.42 mmol) in dimethylsulfoxide (5 ml) was treated with bromomethyl-cyclopropane (1.09 g, 8.1 mmol). After stirring at room temperature overnight water (250 ml) was added and the mixture was extracted with ethyl acetate (2×20 ml) and dichloromethane (2×20 ml). The organic layers were collected, dried and evaporated. The crude product was purified by chromatography on silica gel using a 9:1-mixture of cyclohexane/ethyl acetate as the eluent. 3-Cyclopropylmethoxy-6-fluoro-8-nitro-quinoline was obtained as a yellow solid (600 mg, 45%); (calculated) C13H11FN2O3 [262.2]; (found) [M+H]+=263.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([NH:20][C:21]([NH2:23])=[NH:22])=[O:19])[C:15]2[C:10](=[CH:11][C:12]([O:24]COC)=[CH:13][CH:14]=2)[N:9]=1.Cl.[OH-].[Na+]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]([NH:20][C:21]([NH2:23])=[NH:22])=[O:19])[C:15]2[C:10](=[CH:11][C:12]([OH:24])=[CH:13][CH:14]=2)[N:9]=1
Reactant: COCOc1ccc2c(C(=O)NC(=N)N)cc(-c3ccccc3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1ccccc1-c1cc(C(=O)NC(=N)N)c2ccc(O)cc2n1
Yield: 50.6 %

Procedure:
2-(2'-Methylphenyl)-7-methoxymethyloxyquinoline-4-carbonylguanidine (0.9 g) formed in Example 45 was heat-stirred in 20 ml (0.5M) of an isopropyl alcohol solution of hydrochloric acid at approximately 60° C. for 3.5 hours. The reaction mixture was allowed to cool, then neutralized with a 5% sodium hydroxide aqueous solution, and concentrated. The residue was filtered, and the crystals obtained were washed with water, and dried to obtain 0.40 g of the above-mentioned compound as a brown crystal. m.p. 202°-208° C.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH:3]=[CH2:4].N1C=CC=CC=1.[F:12][CH:13]([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].O>ClCCl>[F:12][CH:13]([C:17]([F:20])([F:19])[F:18])[C:14]([O:5][CH:2]([CH:3]=[CH2:4])[CH3:1])=[O:15]
Reactant: C=C[C@H](C)O
Reactant: O=C(Cl)C(F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C=CC(C)OC(=O)C(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
In 20 ml of dichloromethane were dissolved 0.72 g of (S)-(-)-3-buten-2-ol (98%ee) and 0.95 g of pyridine, and then 1.65 g of 2,3,3,3-tetrafluoropropionyl chloride was dropwise added to the above-obtained solution while the solution was being cooled with ice. The resulting mixture was stirred at room temperature for 30 minutes, subsequently water was added thereto, and then the reaction mixture was subjected to extraction with ether. The resulting extract was washed with 1N hydrochloric acid, a 5% aqueous solution of sodium hydrogencarbonate, and brine, and then dried with magnesium sulfate. Subsequently, the solvent was removed under reduced pressure, and the residual product was distilled, thereby obtaining 1.50 g of 3-buten-2-yl 2,3,3,3-tetrafluoropropionate having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[O:54]1C2C=CC(C(O)=O)=CC=2[O:56][CH2:55]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][C:31]4[O:54][CH2:55][O:56][C:2]=4[CH:3]=3)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4c(c3)OCO4)nn2)cc(OC)c1OC
Yield: 100 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (87 mg, 0.28 mmol), 1,3-benzodioxole-5-carboxylic acid (60 mg, 0.37 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) in dimethylformamide (2 mL) gave N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1,3-benzodioxole-5-carboxamide (127 mg, 100%) as a yellow oil. MS m/z 453 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[N:5]=[C:4]1[C:11]([O:13]CC)=O)[CH3:2].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[N:5]=[C:4]1[C:11]([N:25]1[CH2:26][CH2:27][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:23][CH2:24]1)=[O:13])[CH3:2]
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1CC
Reactant: c1ccc(N2CCNCC2)nc1
Product: CCn1cc([N+](=O)[O-])nc1C(=O)N1CCN(c2ccccn2)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 1.23 g (5.06 mmol) of ethyl 1-ethyl-4-nitro-1H-imidazole-2-carboxylate (prepared in analogy to Example 10A) and 2.48 g (15.2 mmol) of N-(pyridin-2-yl)piperazine is stirred at 100° C. overnight. For the work-up, the crude mixture obtained is purified by preparative HPLC. 0.724 g (43% of theory) of product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[C:4]([N:6]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20](=[O:39])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]2[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][O:2][C:3]([C:4]1[N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:13]2[C:14]([C:20](=[O:39])[C:21]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([N:32]3[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]3)(=[O:30])=[O:31])=[CH:25][CH:24]=1)=[CH:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)=[O:40]
Reactant: COC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1c(Cc2ccc(S(=O)(=O)N3CCC(O)CC3)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 80 °C

Procedure:
To N-(5-chloro-2-{3-[4-(4-hydroxypiperidine-1-sulfonyl)-phenyl]-propionyl}-phenyl)-N-phenyl-oxalamic acid methyl ester (0.40 g) in MeOH (15 mL) was added K2CO3 (0.096 g), and the mixture heated at 80° C. for 1.5 h, then concentrated. The residue was taken up in EtOAc/H2O, and the aqueous layer washed with EtOAc (2×25 mL). The combined organic layers were dried over Na2SO4, and the solvent removed under reduced pressure. The residue was chromatographed on anhydrous silica (20% EtOAc/hexanes 0-5 min; 60% EtOAc/hexanes 6-10 min; 100% EtOAc 11-40 min) to provide 7-chloro-3-[4-(4-hydroxypiperidine-1-sulfonyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester (compound 69). M+H 567; mp=170.0-171.0° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.C(N(CC)CC)C.C1C=CN=CC=1.O=S(=O)=O>CS(C)=O>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Agent: O=S(=O)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCCC(C=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-(hydroxymethyl)cyclohexylcarbamate (1.4 g, 6.11 mmol) in dimethylsulfoxide (10 mL) was added triethylamine (1.853 g, 18.32 mmol) followed by the pyridine-sulfur trioxide (2.92 g, 18.32 mmol) in 5 mL of dimethylsulfoxide, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with ice water and extracted into ethyl acetate (30 mL×2). The organic layer was washed with water and brine solution (25 mL each), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[S:8])=[CH:5][C:4]=1[CH3:12].C(O)(=O)C.Br.C([O-])([O-])=O.[Na+].[Na+]>O>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[S:8])=[CH:5][C:4]=1[CH3:12]
Reactant: COc1ccc(C(O)=S)cc1C
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(O)=S)ccc1O
Temperature: 25 °C

Procedure:
4-Methoxy-3-methylthiobenzoic acid (0.5 g, 2.5 mmol) is suspended in 7 ml of a mixture of glacial acetic acid and 48% strength HBr (1+1). The reaction mixture is stirred under reflux for 6 h. The reaction mixture is cooled to RT and added to 20 ml of H2O. The aqueous solution is adjusted to pH=2 using 10% strength Na2CO3 solution and extracted 4× using 20 ml of diethyl ether each time. The organic extracts are combined, washed 2× with saturated NaCl solution, dried over Na2SO4 and concentrated: dirty-brown oil, which crystallizes on allowing to stand at RT. The crystallizate is dried, washed with H2O with stirring, filtered off and dried. Yield: 240 mg (52%).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:24])[C:4]([OH:23])([CH3:22])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].C(O)(C)C>C(O)C>[OH:1][NH:2][C:3](=[O:24])[C@@:4]([OH:23])([CH3:22])[CH2:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: CC(O)(CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Solvent: CC(C)O
Solvent: CCO
Product: C[C@@](O)(CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Yield: 41.8 %

Procedure:
A solution of N,2-dihydroxy-2-methyl-3-[(4-phenoxyphenyl)sulfonyl]propanamide (20 g) in ethanol (1500 mL) was sequentially injected in 12 mL portions onto a Prochrom® column (50 mm I.D., 36 mm bed length) packed with Chiralpak® AD. The mobile phase used was 30% isopropyl alcohol/70% heptane. Fractions were collected automatically and pooled. The first eluting peak was collected and the appropriate fractions were combined to provide the title compound (8.351 g). HPLC purity: 100%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:20][C:21]2[S:25][C:24]([Cl:26])=[N:23][C:22]=2[Cl:27])[CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[OH:19][C:16]([CH3:18])([CH3:17])[CH2:15][N:14]([CH2:20][C:21]1[S:25][C:24]([Cl:26])=[N:23][C:22]=1[Cl:27])[CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(O)CN(Cc1sc(Cl)nc1Cl)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)(O)CN(Cc1sc(Cl)nc1Cl)C1CCNCC1
Reaction time: 2 h
Yield: 99.9 %

Procedure:
Add 4-{[(2,4-dichloro-thiazol-5-yl)methyl]-(2-hydroxy-2-methyl-propyl)-amino}-piperidine-1-carboxylic acid tert-butyl ester (0.4487 g, 1.02 mmol) to a stirred solution of dichloromethane (60 mL) and anisole (9.0 mL, 82.8 mmol). Cool the reaction to 0° C. Add the trifluoroacetic acid (6.0 mL, 72.9 mmol). Stir the reaction for 10 minutes at 0° C. and then for 2 hours at room temperature. The reaction is loaded directly onto a 10 g prepacked SCX-2 cartridge and washed with methanol (200 mL). The product is then eluted off with 2M ammonia in methanol (100 mL) and concentrated on a rotary evaporator to yield 0.3448 g (99%) of N-(2-hydroxy-2-methylpropyl)-N-[(2,4-dichloro-1,3-thiazol-5-yl)methyl]piperidin-4-amine: mass spectrum (ion spray): m/z=338.1 (M+1); 1H NMR (CDCl3): δ=3.97 (s, 2H), 3.18-3.15 (m, 2H), 2.59-2.53 (m, 5H), 1.80-1.70 (m, 4H), 1.49-1.39 (m, 2H), 1.22 (s, 6H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])C1C=CC=CC=1>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[CH2:23]([O:22][C:20]([C:14]1[C:13]2[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=2)[N:17]=[C:16]([CH3:19])[CH:15]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)c1cc(C)nc2c(OCc3ccccc3)cccc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C)nc2c(O)cccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 8-benzyloxy-4-ethoxycarbonyl-2-methylquinoline (663 mg) and palladium(II) hydroxide (60 mg) in a mixture of ethanol (6 ml) and dioxane (6 ml) was stirred for 3 hours at ambient temperature under hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated. The residue was pulverized with n-hexane to give 4-ethoxycarbonyl-8-hydroxy-2-methylquinoline (370 mg) as pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:23]([O-:25])=[O:24])=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)=[O:6]
Reactant: Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1

Procedure:
2-Methoxy-benzoyl chloride was condensed with 5-Amino-2-nitrobenzotrifluoride in dichloromethane in presence of triethylamine as acid scavenger to yield 2-Methoxy-N-(4-nitro-3-trifluoromethyl-phenyl)-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:17][CH2:16][CH:15]([CH:18]=[CH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1>CO.[C].[Pd]>[NH2:11][CH:12]1[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)C=CC1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CCC1CCC(N)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85.3 %

Procedure:
t-Butyl β-[4-(benzyloxycarbonylamino)cyclohexyl]acrylate (7.00 g, 19.5 mmol) was dissolved in methanol (200 ml) and 10% palladium-carbon (700 mg) was added. The mixture was stirred at room temperature for 24 hours under a hydrogen atmosphere. The reaction mixture was filtrated and low boiling matters were distilled away from the filtrate under reduced pressure. The residue was washed with a mixed solution of n-hexane and ethyl acetate to give 3.78 g of t-butyl 3-(4-aminocyclohexyl)propionate as a colorless solid (85%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:21][C:22]([F:25])([F:24])[F:23])[S:10]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])(=[O:12])=[O:11])=[C:4]([F:26])[CH:3]=1.[H-].[Na+].I[CH3:30].O>CN(C)C(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:21][C:22]([F:23])([F:24])[F:25])[S:10]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:30])[CH3:14])(=[O:12])=[O:11])=[C:4]([F:26])[CH:3]=1
Reactant: CC(c1ccccc1)S(=O)(=O)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(c1ccccc1)S(=O)(=O)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)ethanesulfonamide (307 mg, 0.67 mmol) in N,N-dimethylacetamide (5 mL) was added sodium hydride (60% in mineral oil) (33 mg, 0.81 mmol) and the reaction was stirred at ambient temperature for 1 hour. Iodomethane (0.063 mL, 1.0 mmol) was then added and the reaction was stirred at 75° C. for 16 hours. LCMS analysis showed a 1:1 mixture of starting material and product. Water was added and the reaction was diluted with EtOAc, washed with brine (×2), dried with MgSO4, concentrated an purified by silica gel column chromatography (0-10% EtOAc in heptane) to give 249 mg of an inseparable mixture of starting material and product. The mixture was used for the next step. LCMS (m/z) ES+ 471 [M+18]+ (starting material); LCMS (m/z) ES+ 485 [M+18]+ (product).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1>ClCCl>[F:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:3]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 23 %

Procedure:
3-[(3-aminophenyl)[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (50 mg, 0.12 mmol) was dissolved in 1 mL of dichloromethane. Triethylamine (25 μL, 0.18 mmol) followed by 4-fluorobenzoyl chloride were added. The solution was stirred at room temperature for 5 hours, at which time HPLC analysis indicated that no starting material remained. The reaction was quenched with water and filtered through pre-wetted celite eluting with ethyl acetate. The solvent was evaporated, and the residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to afford 15 mg (23%) of the desired 4fluoro-N-[3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]-phenyl]benzamide product as a yellow oil, which was greater than 98% pure by reverse phase HPLC analysis. HRMS calcd. for C25H21F8N2O3: 549.1424 [M+H]+, found: 549.1436. 1H NMR (CDCl3) δ3.6 (dd, 1H), 3.8 (dd, 1H), 4.4 (m, 1H), 4.6 (s, 2H), 5.9 (tt, 1H), 6.6 (d, 1H), 6.8 (d, 1H), 7.0-7.4 (m, 7H), 7.8 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]#[N:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]#[N:16])[CH2:9][CH2:10][C:11]3([O:19][CH2:18][CH2:17][O:14]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccc(F)cc2)CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
25 g of 1-(4-Fluoro-phenyl)-4-oxo-cyclohexanecarbonitrile (73) were dissolved in 850 mL of toluene. 9 mL of ethylene glycol and 1.5 g of p-toluene sulfonic acid were added and the mixture was refluxed at a Dean-Stark apparatus for 6 h. The mixture was allowed to cool down to room temperature and extracted twice with saturated sodium bicarbonate solution and once with brine. The organic layer was dried over sodium sulfate and evaporated to dryness to give 30.15 g of crude product, that was sufficiently pure for further conversion. Rt=1.47 min (Method C). Detected mass: 262.2 (M+H+).