Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH2:4][CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][CH2:2][C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH2:4][CH3:5]
Reactant: CC[C@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: CC[C@H](CO)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.3 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-hydroxymethyl-propyl)-amide (34 mg, 0.064 mmol) and TFA (0.6 ml, 7.8 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (2 mL) and ethylenediamine (420 μl, 6.3 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (1:1 dichloromethane/heptane) to afford 8 mg (30%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-hydroxymethyl-propyl)-amide as a yellow solid. MS: [M+H]+=399; 1H NMR (DMSO-d6) δ: 12.74 (br. s., 1H), 9.13 (s, 1H), 8.64 (d, J=8.7 Hz, 1H), 8.43 (s, 1H), 8.18 (d, J=9.1 Hz, 1H), 7.98 (d, J=1.1 Hz, 1H), 7.20-7.38 (m, 1H), 5.04 (t, J=5.1 Hz, 1H), 4.17 (s, 3H), 3.98-4.13 (m, 1H), 3.50-3.70 (m, 2H), 1.55-1.85 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH:1]([NH:5][CH2:6][CH:7]1[O:11][CH2:10][CH2:9][O:8]1)([CH2:3][CH3:4])[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>O>[CH:1]([N:5]([CH2:6][CH:7]1[O:8][CH2:9][CH2:10][O:11]1)[C:26](=[O:27])[CH2:25][Cl:24])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCC(C)N(CC1OCCO1)C(=O)CCl

Procedure:
N-Sec-Butyl-N-(1,3-dioxolan-2-ylmethyl)amine (12.0 grams, benzene (100 ml), water (100 ml) and sodium carbonate (10 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The mixture was cooled to about 5° to 10° C. and chloroacetyl chloride (6.0 ml) was added dropwise with stirring. After the addition was completed stirring was continued until the reaction mixture reached room temperature. After this time the organic phase was separated from the aqueous phase and was washed with water. The washed solution was then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-sec-butyl-N-(1,3-dioxolan-2-ylmethyl)-α-chloroacetamide as an oil.
Reaction SMILES: [O:1]([CH2:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][CH2:18][Cl:19].C(N(CC)CC)C>O1CCCC1>[O:1]([CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][Cl:19])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCC2CCNCC2)cc1
Reactant: ClCCCBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: ClCCCN1CCC(COc2ccccc2)CC1
Yield: 83.6 %

Procedure:
A mixture of 28.6 g (0.15 mole) of 4-phenoxymethylpiperidine, 23.5 g (0.15 mole) of 1-bromo-3-chloropropane, 40.4 g (0.4 mole) of triethylamine and 150 ml of tetrahydrofuran is heated under reflux for 5 hours. After cooling, the reaction mixture is filtered, the filtrate is evaporated in a vacuum, the residue is extracted with diethyl ether and the extract is evaporated. There are obtained 33.6 g (84% of theory) of crude 3-(4-phenoxymethylpiperidino)-propyl chloride in the form of an oil which can be further used in this form. The pure compound is obtained by distillation and boils at 180° - 183° C/0.4 mm Hg.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[N:40][CH:39]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:37]([C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)=[O:44])[CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[NH:20][C:21]([C:23]2[NH:24][CH:25]=[C:26]([C:28]#[N:29])[CH:27]=2)=[O:22])[CH2:4][CH2:3]1
Reactant: CC1CCN(c2cc(C3CCNCC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Reactant: O=C(Cl)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1CCN(c2cc(C3CCN(C(=O)c4cccnc4)CC3)ccc2NC(=O)c2cc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
A mixture of 4-cyano-1H-pyrrole-2-carboxylic acid [2-(4-methyl-piperidin-1-yl)-4-piperidin-4-yl-phenyl]-amide bis(trifluoroacetic acid salt) (as prepared in Example 35, 25.0 mg, 0.0400 mmol), nicotinoyl chloride (10.8 mg, 0.0600 mmol) and anh Na2CO3 (21.0 mg, 0.200 mmol) in 1 mL of DMF was stirred at RT for 2 days. Treated with 30 mL of EtOAc, the mixture was washed with H2O (3×10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3% MeOH/DCM) gave 19.6 mg (98%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 10.67, (s, 1H), 9.17 (s, 1H), 8.74 (d, 1H, J=1.6 Hz), 8.69 (dd, 1H, J=4.5, 1.6 Hz), 8.32 (d, 1H, J=8.4 Hz), 7.82 (ddd, 1H, J=7.7, 1.9, 1.9 Hz), 7.47 (dd, 1H, J=3.3, 1.2 Hz), 7.40 (dd, 1H, J=8.0, 4.9 Hz), 7.07 (d, 1H, J=1.9 Hz), 7.04 (dd, 1H, J=8.4, 1.9 Hz), 6.87 (s, 1H), 4.90 (s, 1H), 3.87 (s, 1H), 3.22 (s, 1H), 2.69-3.00 (m, 6H), 1.53-2.06 (m, 7H), 1.35-1.46 (m, 2H), 1.00 (d, 3H, J=6.5 Hz). Mass spectrum (ESI, m/z): Calcd. for C29H32N6O2, 497.3 (M+H), found 497.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[CH2:23][CH2:22]1)=[O:20]>C(#N)C>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[S:27]([N:24]1[CH2:23][CH2:22][N:21]([C:19](=[O:20])[CH2:18][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25]1)(=[O:29])=[O:28]
Reactant: Nc1ccccc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CNc1ccccc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Reaction time: 3 h
Yield: 86.2 %

Procedure:
A stirred solution of aniline (15.3 g, 0.16 mol) and di-isopropyl ethylamine (DIEA, 56 mL, 0.33 mol) in acetonitrile (120 mL) is heated to 60° C. and 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 5, 0.3 g, 0.85 mmol) is added dropwise. The reaction mixture is kept stirring at this temperature for another 3 h and is then evaporated to dryness. Water is added to the residue, and extracted with ethyl acetate (2×30 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resultant crude product was purified by column chromatography on silica gel (hexane:ethyl acetate:3:7) to obtain the title compound (300 mg, 76.53%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:13])[CH:12]=1)[O:5][CH2:6][C:7](=O)[CH3:8].Cl.[NH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[C:28]([O:29][CH3:30])=[N:27][N:26]([CH3:31])[C:25]1=[O:32]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:13])[CH:12]=1)[O:5][CH2:6][C:7](=[N:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[C:28]([O:29][CH3:30])=[N:27][N:26]([CH3:31])[C:25]1=[O:32])[CH3:8]
Reactant: CC(=O)COc1cc(Cl)cc(Cl)c1
Reactant: COc1nn(C)c(=O)n1-c1ccccc1CON
Agent: Cl
Solvent: c1ccncc1
Product: COc1nn(C)c(=O)n1-c1ccccc1CON=C(C)COc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Yield: 20.7 %

Procedure:
To a stirred solution of the title compound of Step A (0.33 g, 1.5 mmol) in pyridine (30 mL) under a nitrogen atmosphere was added the title compound of Step C (0.43 g, 1.5 mmol) and the resulting mixture was heated at 90 ° C. for 2 h. The reaction mixture was allowed to cool to room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with 1 N aqueous HCl and was extracted three times with ethyl acetate. After drying (MgSO4), the combined organic extracts were concentrated under reduced pressure. Chromatography of the residue on silica gel (200 g) with 1:1 hexane: ethyl acetate afforded 0.14 g of the title compound of Step D, a compound of the invention, as an oil. 300 MHz 1H NMR CDCl3): δ 7.44 (m,3H), 7.23 (m,1H), 6.96 (m,1H), 6.81 (m,2H), 5.12 (q,2H), 4.44 (s,2H), 3.9 (s,3H), 3.43 (s,3H), 1.89 (s,3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:3]=1[F:22].Cl[CH2:24][CH:25]([OH:28])[CH2:26]Cl>N1C=CC=CC=1>[CH:13]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:22])=[C:2]([N:1]4[CH2:26][CH:25]([OH:28])[CH2:24]4)[C:11]=3[F:12])[C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8]2)[CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N)c(F)cc2c1=O
Reactant: OC(CCl)CCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(O)C3)c(F)cc2c1=O
Yield: 54.9 %

Procedure:
A solution of 0.8 g (2.60 mmoles) of ethyl 7-amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 0.33 g (2.60 mmoles) of 1,3-dichloro-2-propanol and 25 ml of pyridine is agitated for 3 days, protected from light at ambient temperature; then left refluxing for 3 days and more. The solution is concentrated almost to dryness, poured onto water giving a precipitate which is filtered and washed with water. The solid is dried under vacuum, yielding 0.52 g (55%) of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-hydroxy-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylate. Its melting point and spectroscopic data are identical to those of the derivative obtained according to method A.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[OH-].[K+].[CH2:10](I)[CH3:11]>CCO>[C:1]([O:7][CH2:10][CH3:11])(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCC(=O)O
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCC(=O)OCC
Temperature: 25 °C
Yield: 65 %

Procedure:
4-Pentenoic acid (12.0 g, 0.120 mol) was dissolved in 200 ml of dry EtOH and KOH pellets (7.1 g, 0.126 mol) were added. The mixture was stirred at room temperature until homogeneous. Ethyl iodide (24.3 g, 0.156 mol) was added and the solution was refluxed for 48 hrs. The cooled solution was poured onto H2O (600 ml) and extracted with pentane (200 ml). The organic extract was washed with H2O (2×500 ml) and dried (MgSO4). Solvent removal afforded 10.0 g (65%) of ethyl 4-pentenoate. From the ethyl 4-pentenoate the corresponding epoxy ester, ethyl 4,5-epoxy-pentanoate, is prepared as follows: ethyl 4-pentenoate (9.90 g, 77.3 mmol), and m-chloroperbenzoic acid (18.5 g, 92.8 mmol, 85% assay) were dissolved in 300 ml of CH2Cl2 and stirred for 18 hr in an oil bath at 50° C. The mixture was then filtered, washed with 10% NaHSO3, saturated aqueous NaHCO3 (2X), and H2O (2X) before drying (MgSO4). Concentration under slight vacuum at room temperature followed by distillation (32° C., 0.07 mm) afforded 6.1 g (55%) of the ethyl 4,5-epoxy-pentanoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.[Cu]I>[CH3:12][C:4]1[CH:3]=[C:2]([NH:1][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9](=[O:11])[CH3:10]
Reactant: Ic1ccccc1
Reactant: CC(=O)c1c(C)cc(N)cc1C
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(Nc2ccccc2)cc1C
Temperature: 110 °C

Procedure:
To a solution of 1-(4-amino-2,6-dimethylphenyl)ethanone (3.26 g, 20.0 mmol), K3PO4 (9.2 g, 40 mmol), and 1-iodobenzene (4.08 g, 20.0 mmol) in DMF (35.0 mL) was added CuI (761.8 mg, 40 mmol). The reaction was heated at 110° C. overnight under N2. The solution was cooled to room temperature and filtered through a small pad of Celite. The cake was washed with ethyl acetate (50 mL) and the combined filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 1-(2,6-dimethyl-4-(phenylamino)phenyl)ethanone as red-brown syrup: 1H NMR (500 MHz, CDCl3) δ 7.30 (d, J=8.2 Hz, 2 H), 7.10 (d, J=7.7 Hz, 2 H), 6.99 (d, J=4.2 Hz, 1 H), 6.71 (s, 1 H), 2.47 (s, 3 H), 2.18 (s, 6 H); ESI-MS: m/z 239.5 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.Cl[CH2:32][C:33]1[O:37][N:36]=[C:35]([CH2:38][S:39][CH3:40])[N:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:40][S:39][CH2:38][C:35]1[N:34]=[C:33]([CH2:32][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])[O:37][N:36]=1
Reactant: CSCc1noc(CCl)n1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
According to GP1 tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (1 g; compound B50) is reacted with 5-(chloromethyl)-3-[(methylsulfanyl)methyl]-1,2,4-oxadiazole (410 mg; compound D11) in the presence of potassium carbonate (320 mg) in DMF (20 ml). The reaction mixture is stirred at 100° C. for 1 h. Ice cold water is added and the mixture is extracted with DCM 4 times. The combined organic layers are dried (sodium sulfate) and concentrated in vacuo. The residue is purified by flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 1/0 to 1/1 (v/v)] to afford the title compound as a solid.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]=12.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:3]=12
Reactant: CCOC(=O)c1cnc2c(c1O)CCCCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c1Cl)CCCCCC2

Procedure:
A solution of 5 g of ethyl 5,6,7,8,9,10-hexahydro-4-hydroxycycloocta[b]pyridine-3-carboxylate in 20 ml of phosphorus oxychloride is refluxed for one hour and evaporated to dryness under reduced pressure. A solution of the residue in methylene chloride is treated with ice and water, and basified with 10 N sodium hydroxide. The layers are separated, the aqueous phase reextracted with methylene chloride, and the combined organic layers dried with magnesium sulfate, filtered, and solvent removed at reduced pressure to obtain ethyl 5,6,7,8,9,10-hexahydro-4-chlorocycloocta[b]pyridine-3-carboxylate as an oil which solidifies on standing, m.p. 33°-36°.
Reaction SMILES: C(O)(=O)C.C(OC([NH:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)=[O:20])=[O:16])=O)(C)(C)C.[CH:38]([C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=1)([CH3:40])[CH3:39]>CO>[NH2:12][C:13]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][C:14]=1[C:15]([NH:17][CH2:18][C:19]([NH:21][CH2:22][CH:23]1[CH2:28][CH2:27][N:26]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([CH:38]([CH3:40])[CH3:39])=[CH:42][CH:43]=2)[CH2:25][CH2:24]1)=[O:20])=[O:16]
Reactant: CC(C)c1ccc(C=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)NCC(=O)NCC1CCNCC1
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1ccc(CN2CCC(CNC(=O)CNC(=O)c3cc(OC(F)(F)F)ccc3N)CC2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Acetic acid (10 mL) was added to a mixture of 4-[[N-(2-(tert-butoxycarbonylamino)-5-(trifluoromethoxy)benzoyl)glycyl]aminomethyl]piperidine (0.050 mmol) with 4-isopropylbenzaldehyde (0.060 mmol), NaH3CN (0.15 mmol) and methanol (1.3 mL), and the resulting mixture was stirred at 60° C. for 8 hours, cooled to room temperature, then loaded onto a Varian™ SCX column and washed with methanol (10 mL). The obtained crude product was eluted with a 2 M methanol solution of NH3 (5 mL) and concentrated. A 4 M dioxane solution of HCl (2 mL) was then added to the resulting residue, and the obtained solution was stirred at room temperature overnight, concentrated and then purified by preparative TLC to provide 4-[[N-(2-amino-5-trifluoromethoxybenzoyl)glycyl]aminomethyl]-1-(4-isopropylbenzyl)piperidine (Compd. No. 1903) (6.6 mg, 26%). The purity was determined by RPLC/MS (93%). ESI/MS m/e 507 (M++H, C26H33F3N4O3).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([CH3:3])[CH3:2].[F:11][C:12]1[C:17](F)=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22].[OH-].[K+].CS(C)=O>O>[F:11][C:12]1[C:17]([O:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:13]=1[F:22]
Reactant: CC(C)c1ccccc1O
Reactant: Fc1c(F)c(F)c(F)c(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1ccccc1Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
A mixture of 50.0 g (0.36 mol) of 2-isopropylphenol, 137 g (0.72 mol) of hexafluorobenzene, 50.4 g (0.90 mol) of KOH powder, and 1000 ml of DMSO was stirred for 48 h at 80° C. This mixture was cooled to room temperature and then poured in 3000 ml of water. The product was extracted with 4×500 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated on Rotavap. The residue was distilled in vacuum, 130-140° C./13 mm Hg.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH:10]1[CH2:15][CH2:14][CH:13]([C:16](OCC)=[O:17])[CH2:12][CH2:11]1.N1C=CN=C1.CC(C[Al]CC(C)C)C>C(Cl)Cl>[C:4]([Si:1]([CH3:3])([CH3:2])[O:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: CC(C)C[Al]CC(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(CO)CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
tert-Butyldimethylsilyl chloride (8.8 g, 58 mmol) was added to a solution of ethyl 4-hydroxycyclohexanecarboxylate (10 g, 58 mmol) and imidazole (4.3 g, 64 mmol) in DCM (300 ml), and the mixture was stirred overnight at 20° C. After washing with water (2×100 ml), the organic phase was dried (MgSO4) and evaporated to dryness. The residue was dissolved in dry THF (300 ml) and cooled to −10° C. Dibal-H (1.0 M in toluene, 174 ml, 174 mmol) was added dropwise over a period of 60 min, while the temperature was kept at −10° C. After stirring for 2 hrs the reaction was quenched by slow addition of a saturated ammonium chloride solution (30 ml). The resulting suspension was filtered, and the filtrate was concentrated in vacuo to give 13 g of the title compound as a mixture of two isomers. LC-MS (m/z): 245 (M+1).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:31][CH2:32][CH:33]=[CH2:34]>>[CH2:34]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:27][CH3:28])=[O:19])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH2:33][CH:32]=[CH2:31]
Reactant: C=CCCBr
Reactant: CCOc1ccccc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: C=CCCOc1ccc(-c2nc(CCC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 363 and 4-bromo-1-butene, white powdery 3-[2-(4-but-3-enyloxy-3-difluoromethoxy phenyl)oxazol-4-yl]-1-(2-ethoxyphenyl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([F:14])[CH:3]=1.[CH3:15]COCC.C[Mg+].[Br-]>C(Cl)Cl>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH3:15])=[C:4]([F:14])[CH:3]=1
Reactant: CCOCC
Reactant: CON(C)C(=O)c1ccc(Cl)cc1F
Agent: C[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: CC(=O)c1ccc(Cl)cc1F
Temperature: 25 °C

Procedure:
To a solution of the above benzamide (1 eq) in CH2Cl2 (0.5 M) at 0° C. was added 3M/Et2O MeMgBr (1.25 eq). The reaction mixture was slowly warmed to rt over a 2 hrs period, quenched with 0.5 M aqueous citric acid and extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on silica gel eluted with 20% EtOAc/hexane to give the title compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:27][CH3:28])[CH:4]([NH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[CH2:27]([CH:3]([CH2:1][CH3:2])[CH:4]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)[C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:8]=2[C:9]=1[CH3:10])[CH3:28]
Reactant: CCC(CC)C(Nc1ccc(C(=O)OC)cc1)c1oc2ccc(F)cc2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)C(Nc1ccc(C(=O)O)cc1)c1oc2ccc(F)cc2c1C
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a mixture of methyl 4-{[2-ethyl-1-(5-fluoro-3-methyl-1-benzofuran-2-yl)butyl]amino}benzoate (709 mg) synthesized above, tetrahydrofuran (6 mL) and ethanol (6 mL) was added 1N aqueous sodium hydroxide solution (3.7 mL), and the mixture was heated under reflux for 14 hr. 1N Aqueous sodium hydroxide solution (4.0 mL) was added, and the mixture was further stirred with heating under reflux for 2 hr. 8N Aqueous sodium hydroxide solution (2.0 mL) and ethanol (2 mL) were added to the mixture, and the mixture was further stirred with heating under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (4.0 mL), ethanol (4 mL) and tetrahydrofuran (4 mL) were added, and the mixture was further stirred with heating under reflux for 1 hr. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate 100:0-70:30, v/v) to give the title compound (412 mg, 61%) as a colorless amorphous form.