Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>Br.O>[N:9]1([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[N:10]1
Reactant: COc1cccc(-n2ncc3ccccc32)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1cccc(-n2ncc3ccccc32)c1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of 1-(3-methoxyphenyl)-1H-indazole 1 (6.50 g, 28.98 mmol) in hydrogen bromide acid (45 mL, 48%) was refluxed (110-120° C.) for 23 hours at an atmosphere of nitrogen. Then the mixture was cooled down to ambient temperature and neutralized with a solution of K2CO3 in water until there was no gas to generate. Then the precipitate was filtered off and washed with water several times. The collected solid was dried in air to afford the product as a brown solid 5.70 g in 94% yield. 1H NMR (DMSO-d6, 400 MHz): δ 6.63 (dd, J=8.4, 2.0 Hz, 1H), 7.00-7.03 (m, 2H), 7.08 (t, J=7.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 8.17 (s, 1H), 9.67 (bs, 1H). 13C NMR (DMSO-d6, 100 MHz): δ 109.08, 110.54, 112.45, 113.63, 121.48, 121.61, 125.05, 127.42, 130.41, 135.48, 138.02, 140.72, 158.35.
Reaction SMILES: [CH2:1]([N:6]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:12]([O:14]C)=O)[CH3:7])[CH2:2][CH:3]([CH3:5])[CH3:4].CC[C@@H]([C@H](NC([C@H]1N(C([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](NC([C@@H](N)C(C)C)=O)CO)=O)CCC(N)=O)=O)CC(N)=O)=O)CC2C=CC(O)=CC=2)=O)CCC1)=O)C(N[C@H](C(N[C@H](C(N)=O)CCC(N)=O)=O)C(C)C)=O)C.O.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:130].Cl.[NH2:132][C@@:133](C)([CH2:149][C:150]1[CH:155]=[C:154]([F:156])[CH:153]=[C:152]([F:157])[CH:151]=1)[C@H:134]([OH:148])[CH2:135][NH:136][C:137]1([C:140]2[CH:145]=[CH:144][CH:143]=[C:142]([CH2:146][CH3:147])[CH:141]=2)[CH2:139][CH2:138]1>O1CCCC1.CO.O.C(OCC)(=O)C>[ClH:130].[ClH:130].[F:156][C:154]1[CH:155]=[C:150]([CH:151]=[C:152]([F:157])[CH:153]=1)[CH2:149][C@H:133]([NH:132][C:12](=[O:14])[C:11]1[CH:16]=[C:17]([CH3:19])[CH:18]=[C:9]([CH2:8][N:6]([CH2:1][CH2:2][CH:3]([CH3:4])[CH3:5])[CH3:7])[CH:10]=1)[C@H:134]([OH:148])[CH2:135][NH:136][C:137]1([C:140]2[CH:145]=[CH:144][CH:143]=[C:142]([CH2:146][CH3:147])[CH:141]=2)[CH2:139][CH2:138]1
Reactant: CCc1cccc(C2(NC[C@@H](O)[C@@](C)(N)Cc3cc(F)cc(F)c3)CC2)c1
Reactant: COC(=O)c1cc(C)cc(CN(C)CCC(C)C)c1
Agent: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)C(C)C)C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(N)=O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cccc(C2(NC[C@@H](O)[C@H](Cc3cc(F)cc(F)c3)NC(=O)c3cc(C)cc(CN(C)CCC(C)C)c3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To methyl 3-{[isopentyl(methyl)amino]methyl}-5-methylbenzoate prepared by the method in Example SP-211, Step 1 (160 mg, 0.61 mmol) in tetrahydrofuran/methanol/water (2:1:1, 8 mL) is added lithium hydroxide monohydrate (51 mg, 1.2 mmol), and the reaction is stirred at room temperature 16 h. The solution is concentrated under reduced pressure, redissolved in DMF (5 mL), and diisopropylethylamine (424 μL, 2.4 mmol), HATU (290 mg, 0.8 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-{[1-(3-ethylphenyl)cyclopropyl]amino}-3-methylbutan-2-ol dihydrochloride prepared by the method in Example SP-272 (291 mg, 0.7 mmol) are added. The reaction stirred at room temperature 2 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (2 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 592.3 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:10]O.B(F)(F)F>O>[CH2:3]([C:2](=[CH2:10])[C:1]([OH:9])=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC(=O)O
Reactant: CO
Agent: FB(F)F
Solvent: O
Product: C=C(CCCCC)C(=O)O
Reaction time: 1 h

Procedure:
The distilled acid, 20 g, containing 14% of unreacted heptanoic acid, was treated at room temperature (22° C.) with 100 g absolute methanol and 0.4 ml of the methanol complex solution of boron trifluoride. After standing for 1 hr., 100 ml of water was added and the layers were separated. The water was extracted twice with 100 ml portions of hexane. The combined layer was freed from hexane by evaporation, and the residue was fractionally distilled. The forerun 2.7 g, boiling range 77°-120° C. vapor temperature at 20mm Hg contained mostly the methyl ester of the saturated acid. The residue, 15.4 g contained 98% acid by titration and consisted of 99% α-pentylacrylic acid according to the gas chromatographic analysis.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=[C:16]([NH2:23])[C:15]=2[N:14]=[C:13]1[CH3:24].[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>C(Cl)(Cl)Cl>[NH2:23][C:16]1[C:15]2[N:14]=[C:13]([CH3:24])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:20]=2[C:19]([CH3:21])=[C:18]([CH3:22])[N:17]=1
Reactant: CC(C)C(=O)Cl
Reactant: Cc1nc(N)c2nc(C)n(CCCN)c2c1C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(N)c2nc(C)n(CCCNC(=O)C(C)C)c2c1C
Reaction time: 0.25 h
Yield: 25.3 %

Procedure:
Triethylamine (0.78 mL, 5.6 mmol) was added to a solution of 1-(3-aminopropyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine (1.00 g, 4.3 mmol) in chloroform (50 mL). The solution was cooled in an ice bath and then isobutyryl chloride (0.49 mL, 4.7 mmol) was added. The reaction mixture was stirred for 15 minutes then the ice bath was removed and the reaction mixture was stirred for an additional 15 minutes. The reaction mixture was diluted with chloroform to a volume of 150 mL. Water (50 mL) was added then the pH was adjusted to 11 with solid potassium carbonate and then to pH 14 with 50% sodium hydroxide. The resulting precipitate was isolated by filtration and dried to provide 0.33 g of N-[3-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)propyl]-2-methylpropanamide as a white solid, m.p. 178.1-178.8° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:8][O:9][C:10]=2[C:11]([F:14])([F:13])[F:12])[N:3]=[CH:2]1.B(O)(O)[C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1>>[C:15]1([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[CH:5]=3)=[C:10]([C:11]([F:14])([F:12])[F:13])[O:9][N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1onc(-c2ccccc2)c1-c1c[nH]cn1
Product: Cc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)cc1
Yield: 42 %

Procedure:
As described for Example 1j, 4-(1H-imidazol-4-yl)-3-phenyl-5-trifluoromethyl-isoxazole (100 mg, 0.36 mmol) was converted, using p-tolylboronic acid instead of phenylboronic acid, to the title compound (55 mg, 42%) which was obtained as a white solid. MS (ESI): m/e=370.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH2:18]Cl)=[N:16][C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:14]1)=O.C1N2CN3CN(C2)C[N:30]1C3>C(O)C>[Cl:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]1[C:6]2[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=2[N:13]2[N:14]=[C:15]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:16]=[C:17]2[CH2:18][N:30]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CCOC(=O)c1nc(CCl)n(-c2sc(CC)cc2C(=O)c2ccccc2Cl)n1
Solvent: CCO
Product: CCOC(=O)c1nc2n(n1)-c1sc(CC)cc1C(c1ccccc1Cl)=NC2

Procedure:
A mixture of 3.50 g. of ethyl 1-[3-(2-chlorobenzoyl)-5-ethyl-2-thienyl]-5-chloromethyl-1H-1,2,4-triazole-3-carboxylate, 3.36 g. of hexamethylenetetramine and 80 ml. of ethanol is refluxed for 15 hours, followed by concentration. Then, addition of water to the residue gives ethyl 6-(2-chlorophenyl)-8-ethyl-4 H-thieno[3,2-f]-s-triazolo[1,5-a][1,4]-diazepine-2-carboxylate as crystals. Recrystallization from ethanol yields pale yellow prisms melting at 147.5° to 148.5° C.
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:24])[C@H:12]([C@@H:21]([CH3:23])[OH:22])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH2:25]([O:32][C:33]([N:35]([CH3:49])[C@H:36]([C:46](O)=[O:47])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:10][C:11](=[O:24])[C@H:12]([C@@H:21]([CH3:23])[O:22][C:46](=[O:47])[C@H:36]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)[N:35]([C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34])[CH3:49])[NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COc1ccc(C[C@@H](C(=O)O)N(C)C(=O)OCc2ccccc2)cc1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C[C@@H](C(=O)O[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)c2ccccc2)N(C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.8 %

Procedure:
To a solution of D3 (33.72 g, 100 mmol) in DCM at 0° C., DMAP (3.66 g, 30 mmol), and E1 (34.33 g, 100 mmol) were added. After stirring 10 min at 0° C., DCC (22.7 g, 110 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. Then the mixture was filtered and the filtrate concentrated to dryness. The residue was chased with ACN (100 ml), filtered again and the filtrate was concentrated. The residue was dissolved in EtOAc (200 ml) and partitioned successively between aq KHSO4 (100 ml, 10%), aq NaHCO3 (100 ml, sat.) and brine (100 ml). The organic phase was dried (Na2SO4), filtered and concentrated. The residue was purified by flash LC (silica gel, grad EtOAc-Hex 1:4 to 1:2) to yield D2 (65.5 g, 98%). [α]D22−39.56 (c 1.06 CHCl3); Rf=0.55 (EtOAc:Hex 1:1).
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:13][CH3:14])=[CH:6][C:7]([CH3:12])=[C:8]([CH:11]=1)[CH:9]=O)([CH3:3])[CH3:2].[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[CH2:19]2>>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[CH:9][C:8]1[CH:11]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]([O:13][CH3:14])=[CH:6][C:7]=1[CH3:12]
Reactant: COc1cc(C)c(C=O)cc1C(C)C
Reactant: O=C1Cc2cc(F)ccc2N1
Product: COc1cc(C)c(C=C2C(=O)Nc3ccc(F)cc32)cc1C(C)C

Procedure:
5-Isopropyl-4-methoxy-2-methylbenzaldehyde was condensed with 5-fluoro-2-oxindole to give 0.25 g of 5-fluoro-3-(5-isopropyl-4-methoxy-2-methylbenzylidene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:25])[C@H:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])[CH3:16])C1C=CC=CC=1.[BH4-].[Na+]>C1COCC1.O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:15]([CH3:16])[CH2:14][OH:25])=[C:18]([F:24])[CH:19]=1
Reactant: C[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CO)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of ((S)-4-benzyl-3-((S)-2-(4-bromo-2-fluorophenyl)propanoyl)oxazolidin-2-one) (1.7 g, 4.2 mmol) in THF (12 mL) was added a solution of sodium borohydride (700 mg, 21 mmol) in water (2 mL). The reaction mixture was stirred for 3 h at room temperature. The excess hydride was quenched by slow addition of aqueous hydrochloric acid (1 N, ca. 2.9 mL). The mixture was further diluted with water (10 mL) and extracted with ethyl acetate (1×30 mL). The combined organics were washed with brine (2×10 mL), dried over sodium sulfate, and evaporated under vacuum. The residue was purified by flash chromatography of the residue afforded the desired product (0.8 g, 82%) as light yellow oil: ESI MS m/z 234 [C9H10BrFO+H]+
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:26]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:27](=[O:35])[C:28]2[C:33]([CH3:34])=[N:32][O:31][C:29]=2[N:30]=1)[CH:22]([CH3:24])[CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.[ClH:44]>O1CCOCC1>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:26]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27](=[O:35])[C:28]2[C:33]([CH3:34])=[N:32][O:31][C:29]=2[N:30]=1)[CH:22]([CH3:23])[CH3:24])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[ClH:44].[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:26]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27](=[O:35])[C:28]2[C:33]([CH3:34])=[N:32][O:31][C:29]=2[N:30]=1)[CH:22]([CH3:23])[CH3:24])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3onc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)N(CCCN)C(c2nc3onc(C)c3c(=O)n2Cc2ccccc2)C(C)C)cc1

Procedure:
A solution of {3-[[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (method 48) (0.058 g, 0.1 mmol) in 3 ml of 4 M HCl in dioxane was stirred at room temperature for 2 hr. The solvent was distilled off by vacuo, the residue was dried at 40˜50° C. for overnight under vacuum. N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide was obtained as the HCl salt. Yield was 0.046 g (88%). m/z 488 (MH+), 1H NMR (500 MHz, 100° C., DMSO-d6): 0.48 (d, 3H), 0.94 (d, 3H), 1.30 (m, 1H), 1.60 (m, 1H), 2.35 (m, 2H), 2.38 (s, 3H), 2.58 (s, 3H), 2.70 (m, 1H), 3.37 (m, 2H), 5.11 (d, 1H), 5.64 (d, 1H), 5.90 (d, 1H), 7.23-7.39 (m, 9H), 7.63 (br, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:27]([O:29][CH3:30])=[O:28]>C(O)C.[Pd].O>[CH3:30][O:29][C:27]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)=[O:28]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1CCN(C(=O)OC)CC1=O
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate (Iselin, B. M. and Hoffmann, K., Helv. Chim. Acta, 1954, 37, 178) (14.0 g; 47 mmol) in aqueous ethanol (300 ml; 50%) was hydrogenated (ca. 300 kPa) in a PARR hydrogenation apparatus by using a 10% Pd-C catalyst (1.4 g). The reaction mixture was filtered and evaporated to dryness in vacuo. To an ice cooled solution of the residue in water (50 ml) was added with stirring an iced solution of potassium carbonate (19.4 g; 140 mmol) in water (20 ml) followed by addition of methyl chloroformate (11.3 g; 120 mmol). Stirring was continued at 0° C. for 30 minutes and at 25° C. for 30 minutes. The mixture was extracted with three 100 ml portions of ether. The combined and dried (Na2SO4) ether phases were evaporated in vacuo to give 10.0 g of crude product. Ball-tube distillation at 40-130 Pa (oven temperature 170° C.) gave IVa (9.0 g; 84%) as a colourless oil, which slowly crystallized, m.p. 36°-38° C. IR (film): 2980-2850 (several bands, m-s), 1700 (s), 1655 (s), 1620 (m) cm-1. 1H NMR (CCl4): δ12.3 (1H, s), 4.13 (q, J 7 Hz) and 4.0-3.9 (m) (a total of 4H), 3,62 (3H, s), 3,43 (2H, t, J 6 Hz), 2.4-2.1 (2H, m), 1.30 (3H, t, J 7 Hz).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH:14]=O)[CH:7]=[CH:6]1.C(O)(=O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO.O>[NH:4]1[C:14]2[C:3](=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][NH:5][CH2:6][CH2:7][CH3:8])[CH:2]=[CH:1]1
Reactant: CCCN
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCNCc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Add propyl amine (3.66 g, 62.07 mmol) to a solution of indole-7-carboxaldehyde (3.0 g, 20.68 mmol) and acetic acid (2.65 ml, 41.3 mmol) in toluene (100 ml). Heat at reflux constantly removing water with a Dean Stark apparatus. Concentrate the reaction under reduced pressure and re-dissolve in methanol. Gently add sodium borohydride (0.39 g, 10.34 mmol). Stir for 1 hour at room temperature, concentrate, and partition between ethyl acetate and saturated aqueous sodium bicarbonate. Concentrate the organic layers under reduced pressure. Compound carried onto next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:22](O)=[O:23])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:4]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])[CH2:12][CH:11]([C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:10]2)=[CH:2][CH:1]=1)[CH3:5]
Reactant: Nc1ccccc1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(C(=O)Nc3ccccc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
33 mg (0.10 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-carboxylic acid (Example 11A) and 10 mg (0.11 mmol, 1.1 eq.) of aniline were reacted according to General Method 1. Yield: 26 mg (64% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.C([Li])(C)(C)C.[CH:19]([B:21](O)O)=[CH2:20].Cl>C1COCC1.CCCCC.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[B:21]([CH:19]=[CH2:20])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: COCOCc1cc(F)ccc1Br
Reactant: C=CB(O)O
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Solvent: O
Product: C=CB1OCc2cc(F)ccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Compound 5b (2.0 g, 8.0 mmol) in THF (30 mL) was cooled to −78° C. and tert-butyllithium (9.9 mL, 16.8 mmol) as 1.7 M solution in pentane was added slowly. After stirring at −78° C. for 30 min, dibutyl ester of vinyl boronic acid was added dropwise. The mixture was stirred at −78° C. for 1 h, then was warmed up to room temperature and stirred overnight. Concentrated HCl (4 mL) was added and was stirred at room temperature for 4 h. Water (10 mL) was added and THF was removed under reduced pressure. The residue was extracted with ethyl ether, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (9:1 hexane/ethyl acetate) to give 11 (383 mg, 30%) as a yellowish oil; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 5.27 (s, 2H), 6.25 (t, J=8.5 Hz, 1H), 6.50 (d, J=9.4 Hz, 2H), 7.06-7.15 (m, 2H), 7.89 (dd, J=5.6, 7.9 Hz, 1H); ESI-MS m/z (M+H)+; HPLC purity: 98.7%; Anal. (C9H8BFO 0.1H2O)C, H.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:7]=1[C:8]([O:10]CC=C)=[O:9])[CH3:2].N1CCCC1>C(#N)C>[CH2:1]([NH:3][C:4](=[O:22])[NH:5][C:6]1[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:7]=1[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: C=CCOC(=O)c1cc(C(F)(F)F)ccc1NC(=O)NCC
Solvent: CC#N
Solvent: C1CCNC1
Product: CCNC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.5 %

Procedure:
Preparation B1, Step 3: The allyl 2-(3-ethylureido)-5-(trifluoromethyl)benzoate (1.8 g, ca. 5.7 mmol) was dissolved in acetonitrile (50 mL) The solution was charged with pyrrolidine (1.0 mL, 12 mmol) and Ph(PPh3)4 (140 mg, 0.17 mmol) and then stirred for 2 h at RT before being concentrated in vacuo. The residue was diluted with EtOAc and this was washed successively with 1N HCl (2×) and brine (1×) before being dried (Na2SO4), filtered, and concentrated in vacuo. The residue was triturated with methylene chloride to afford pure 2-(3-ethylureido)-5-(trifluoromethyl)benzoic acid (0.89 g). 1H-NMR (300 MHz, d4-MeOH): δ 8.59 (d, 1H, J=9.6 Hz), 8.26 (d, 1H, J=1.5 Hz), 7.72 (dd, 1H, J=9.2, 1.8 Hz), 3.23 (q, 2H, J=7.3 Hz), 1.17 (t, 3H, J=7.2 Hz).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][N:4]=1.[Na+].[I-].C[Si](Cl)(C)C>CO.[Pd]>[CH2:9]([C:6]1[CH:7]=[CH:8][C:3](=[O:2])[NH:4][CH:5]=1)[CH3:10]
Reactant: C=Cc1ccc(OC)nc1
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: [I-]
Solvent: CO
Product: CCc1ccc(=O)[nH]c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To a solution of 2-methoxy-5-vinyl-pyridine (2 g) in anhydrous MeOH was added Pd/C (10 wt %, 100 mg). The mixture was stirred under H2 atmosphere for 5 hours before it was filtered through a pad of celite. The solvent was removed in vacuo and the residue was taken directly into next step without further purification. The crude product from previous step was dissolved in anhydrous MeCN. To this solution was added NaI (3.3 g, 21.9 mmol) and TMSCl (2.8 mL, 21.9 mmol). The resulting mixture was heated to 65° C. for 5 hours before it was filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography to afford the desired product (1.5 g, 83% yield). 1H NMR (300 MHz, CDCl3): δ 1.17 (t, J=7.5 Hz, 3 H), 2.39-2.49 (m, 2 H), 6.50-6.58 (m, 1 H), 7.15 (s, 1 H), 7.35-7.45 (m, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[BH4-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=Cc1ccc(Br)c2cccnc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1ccc(Br)c2cccnc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of 5-bromoquinoline-8-carbaldehyde ([CAS 885267-41-7] 423 mg, 1.79 mmol) in MeOH (5 mL) and THF (10 mL) was added sodium borohydride (68 mg, 1.79 mmol) at 0° C. After stirring at 0° C. for 30 min, the reaction mixture was quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried with magnesium sulfate and concentrated under reduced pressure to give rise to 430 mg of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:25]([F:28])([F:27])[F:26])[O:16][N:15]=[C:14]([C:17]3[S:21][C:20]([CH:22]=[O:23])=[C:19]([CH3:24])[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1>O1CCCC1>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([C:25]([F:27])([F:26])[F:28])[O:16][N:15]=[C:14]([C:17]3[S:21][C:20]([CH:22]([OH:23])[CH3:1])=[C:19]([CH3:24])[CH:18]=3)[CH2:13]2)[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: C[Mg]Br
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C=O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methylmagnesium bromid (1.80 ml, 3M in diethyl ether) is added to a solution of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carbaldehyde (Example 1, (ii) step B, 2 g) in tetrahydrofuran (39 ml) under nitrogen at 0° C. The mixture is slowly warmed to room temperature and stirred overnight. After 21 hours, the reaction is quenched with a saturated aqueous solution of NH4Cl in water. The mixture is extracted two times with ethyl acetate. The organic phases are combined, dried over MgSO4 and concentrated in vacuo to yield 1-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-ethanol (2.1 g) as a yellowish foam. The crude product obtained is used without further purification. MS (HPLC/MS): 424 (MH+). Retention time: 2.03 min.