Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1.C(O)=O.C(=O)(O)[O-].[Na+]>CO.C(O)C.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1
Reactant: Cc1cccc(N)n1
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCO
Solvent: O=CO
Product: Cc1cccc(NCc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.4 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.170 g, 0.56 mmol) and 2-amino-6-picoline (0.050 g, 0.46 mmol), in methanol (10 mL) was refluxed overnight. The reaction was concentrated and the residue was flash chromatographed on silica gel (25 g). Elution proceeded as follows: 10% ethyl acetate/hexane (500 mL), nil; 20% ethyl acetate t hexane (300 mL), nil; (100 mL), 0.082 g of intermediate imine; (300 mL), 0.192 g of a mixture of starting material and imine. The pure imine (0.082 g 0.21 mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon (0.082 g) and formic acid (0.357 mL, 9.45 mmol) were added. The reaction was stirred at ambient temperature for 24 hours. The reaction was carefully neutralized with sodium bicarbonate and then filtered through celite. The pad was well washed with ethyl acetate. The filtrate was concentrated to afford 0.068 g (82%) of 3-(2-chloro-phenyl)-6-fluoro-2-[(6-methyl-pyridin-2-ylamino)-methyl]-3H-quinazolin-4-one as a colorless oil which had: 1H NMR δ 7.92 (dd, J=3, 8 Hz, 1H), 7.80 (dd, J=5, 9 Hz, 1H), 7.65-7.64 (m, 1H), 7.53-7.48 (m, 4H), 7.43-7.40 (m, 1H), 7.37-7.31 (m, 1H), 6.47 (d, J=7 Hz, 1H), 6.25 (d, J=8 Hz, 1H), 4.18 (dd, J=5, 18 Hz, 1H), 4.00 (dd, J=5, 18 Hz, 1H), 2.37 (s, 3H); APCI MS m/z=395 (P+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33]Br)[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:21])[CH3:19])=[O:16].[F-].[K+].[F:44][C:45]1[C:50]([F:51])=[CH:49][C:48]([F:52])=[C:47]([F:53])[C:46]=1[OH:54].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:35])[CH2:33][O:54][C:46]1[C:47]([F:53])=[C:48]([F:52])[CH:49]=[C:50]([F:51])[C:45]=1[F:44])[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:21])[CH3:19])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)CBr)n(C)c2ccccc12
Reactant: Oc1c(F)c(F)cc(F)c1F
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2c(F)c(F)cc(F)c2F)n(C)c2ccccc12

Procedure:
The titled product was prepared as described in Example 82 using N-[(1-methyl-3-isobutyl-indole-2-carbonyl)cyclohexylalaninyl]-3-amino-5-bromo-4-oxo-pentanoic acid, tert-butyl ester (50.8 mg, 0.08 mmol), potassium fluoride (12.0 mg, 0.21 mmol), and 2,3,5,6-tetrafluorophenol (13.3 mg, 0.08 mmol) in DMF (2.0 ml). TLC (hexane/EtOAc, 3/1): Rf=0.25.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1C=O.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[NH2:20].[CH3:21]O>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2/[CH:21]=[N:20]/[CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]2[CH3:13])[CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCc2ccccc2N1
Reactant: CC1CCCCC1N
Reactant: CO
Product: CC1CCCCC1/N=C/c1cccc2c1NCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
1.06 g of tetrahydroquinolino aldehyde was dissolved in 17 mL of methanol, and 1.3 mL of 2-methylcyclohexyl amine was slowly added. After agitated overnight at the room temperature, the resultant solution was removed of the solvent under reduced pressure and then dissolved in hexane again to prepare a thick solution, which was stored in a freezer. This solution contained two stereoscopic isomer products at a ratio of about 1.5:1. After about 2 days, a white crystalline solid appeared in the solution. The same procedures were performed on the remaining store solution to collect a solid, which was washed with cold methanol and hexane and dried to yield pure stereoscopic isomer products (yield: 50%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:20])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.I[CH2:22][C:23]([CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:22]=[C:23]([CH:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[N:20]=[C:9]2[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])([CH3:12])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)CI
Reactant: CC(C)(C(=N)Nc1ccc(Br)cc1)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCC1c1cn(-c2ccc(Br)cc2)c(C(C)(C)c2ccccc2Cl)n1
Reaction time: 48 h
Yield: 5.5 %

Procedure:
To a solution of N-(4-bromophenyl)-2-(2-chlorophenyl)-2-methylpropanimidamide (3.51 g, 10 mmol) in 60 mL dioxane was added tert-butyl 2-(2-iodoacetyl)pyrrolidine-1-carboxylate (3.38 g, 10 mmol) and NaHCO3 (2.5 g, 30 mmol). The mixture was heated to reflux with stirring for 2 days. The reaction was monitored by LC/MS. The reaction mixture was cooled and filtered over celite. The crude mixture was initially purified by silica gel column chromatography. The fraction containing the desired product was further purified by prep HPLC, affording 300 mg (5.5%) of tert-butyl 2-(1-(4-bromophenyl)-2-(2-(2-chlorophenyl)propan-2-yl)-1H-imidazol-4-yl)pyrrolidine-1-carboxylate. 1H NMR (CD3OD): δ 1.4 (m, 10H), 1.6 (m, 3H,), 1.8 (m, 1H), 1.9-2.3 (m, 5H), 3.4 (m, 1H), 3.6 (m, 1H) 4.6 (m, 1H), 6.9 (m, 3H), 7.05 (m, 1H), 7.2 (m, 2H), 7.25 (m, 1H), 7.50 (m, 2H); LC/MS M+H 544 (observed).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21](=[S:23])[NH2:22])[O:20][C:16]=2[C:15]([F:24])=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]=1[CH3:31])#[N:11].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O.C1(C)C=CC=CC=1>[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]3[S:23][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:22]=3)[O:20][C:16]=2[C:15]([F:24])=[C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:13]=1[CH3:31])#[N:11]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(N)=S)nc2c1C#N
Reactant: CCOC(=O)C(=O)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)n1
Temperature: 125 °C
Yield: 91.3 %

Procedure:
Ethyl 3-bromopyruvate (72.2 μl, 0.518 mmol) was added to a toluene (10 ml) solution of 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carbothioamide (I-196-1) (124 mg, 0.398 mmol), followed by heating under reflux in an oil bath at 125° C. for 2 hours. After cooling to room temperature, p-toluenesulfonic acid monohydrate (15.2 mg, 0.080 mmol) was added to the reaction liquid, followed by heating under reflux in an oil bath at 125° C. for 15 hours. After cooling to room temperature, an aqueous saturated sodium hydrogencarbonate solution (50 ml) and water (50 ml) were added, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution (50 ml) and saturated brine (50 ml), and dried over anhydrous sodium sulfate. After concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=100:1→25:1) to obtain the entitled compound (148 mg, 91.2%) as a pale yellow solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Br:37][C:38]1[CH:39]=[CH:40][C:41](F)=[N:42][CH:43]=1.[C:45]([CH2:47][C:48]([OH:50])=O)#[N:46]>CN(C=O)C.C(OCC)(=O)C>[Br:37][C:38]1[CH:39]=[CH:40][C:41]([NH:8][C:48](=[O:50])[CH2:47][C:45]#[N:46])=[N:42][CH:43]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Fc1ccc(Br)cn1
Reactant: N#CCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#CCC(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
BOP (3.07 g, 6.94 mmol) and DIEA (606 μl, 3.47 mmol) were added to a mixture of 5-bromo-2-fluoropyridine (400 mg, 2.312 mmol) and cyanoacetic acid (201 mg, 2.358 mmol) in DMF (11.6 mL). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate and washed with water (2×). The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (ethyl Acetate/hexanes) to afford N-(5-bromopyridin-2-yl)-2-cyanoacetamide. MS ESI calc'd for C8H7BrN3O [M+H]+ 240 and 242. found 240.
Reaction SMILES: C[O:2][P:3]([O:6][CH3:7])[O:4][CH3:5].[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14]>>[Cl:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([P:3](=[O:2])([O:6][CH3:7])[O:4][CH3:5])=[O:14]
Reactant: COP(OC)OC
Reactant: O=C(Cl)CCCCCl
Product: COP(=O)(OC)C(=O)CCCCCl
Reaction time: 8 h
Yield: 94.8 %

Procedure:
Chlorovaleric acid (5.0 g, 0.037 moles) is dissolved in 40ml of dry methylene chloride in a round bottom flask under a nitrogen atmosphere. Freshly distilled oxalyl chloride (9.58 ml, 0.110 moles) is added and the mixture is stirred overnight. The solution is concentrated under vacuum to dryness to yield 5.15 g of chlorovaleryl chloride. Trimethylphosphite (3.9 ml, 0.033 mole) is slowly added to chlorovaleryl chloride (5.15 g, 0.033 mole) under a continuous flow of nitrogen. The mixture is allowed to stir overnight to yield 7.15 g of dimethyl chlorovalerylphosphonate.
Reaction SMILES: [F:1][C:2]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)([F:4])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=2)[O:30][N:29]=1.CC#N>CCOC(C)=O>[F:4][C:2]([C:5]1[N:6]([CH2:27][C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=3)[O:30][N:29]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:15])([F:17])[F:16])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)([F:1])[CH3:3]
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: CC(F)(F)c1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(F)(F)c1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1
Temperature: 70 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
A mixture of the indole (0.050 g, 0.18 mmol) from step A, Cs2CO3 (0.065 g, 0.20 mmol), 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole (0.046 g, 0.20 mmol) and CH3CN (4 mL) was stirred at 70° C. for 24 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), brine (15 mL), dried over (MgSO4) and concentrated. Added 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.065 g, 76%) as a light tan solid: 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J=8.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.74-7.64 (m, 3H), 7.23 (s, 1H), 5.99 (s, 2H), 2.24 (t, 3H); MS m/z 467 (M−H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18]>C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.[Cu](I)I.N1CCCCC1>[CH2:14]([O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:2]2[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#Cc1ccc(OCCCCC)cc1
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CCCCCOc1ccc(C#Cc2ccc(S(F)(F)(F)(F)F)cc2)cc1

Procedure:
8.5 g of p-bromophenyl-sulfur pentafluoride and 20 ml of piperidine are added to a mixture of 8.5 g of 4-pentoxyphenylacetylene, 20 ml of piperidine, 420 mg of triphenylphosphine-palladium(II) chloride and 30 mg of copper iodide, and the combined mixture is heated for 20 hours. Concentration and working up in the customary manner gives 4-(2-(4-pentoxyphenyl)-ethynyl)-phenyl-sulfur pentafluoride.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([NH2:19])=[O:18])[CH2:12]1)=O)(C)(C)C.S(=O)(=O)(O)O>CO.O1CCOCC1>[NH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]([NH2:19])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCC1CCCN(C(N)=O)C1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CO
Product: NCCC1CCCN(C(N)=O)C1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 93.8 %

Procedure:
3-(2-tert-Butoxycarbonylaminoethyl)piperidine-1-carboxamide (392.7 mg, 1.45 mmoles) (prepared as described in Preparative Example 242, Step A above) was dissolved in methanol (7.5 mL) and 10% conc. sulfuric acid in 1,4-dioxane (19.5 mL) was added. The mixture was stirred at 25° C. for 1.25 h. The mixture was diluted with methanol and BioRad AG1-X8 resin (OH− form) was added until the pH was basic. The resin was filtered off, washed with methanol, evaporated to dryness and chromatographed on a silica gel column (30×2.5 cm) using 15% (10% conc, ammonium hydroxide in methanol)-dichloromethane as the eluant to give 3-(2-aminoethyl)piperidine-1-carboxamide (233 mg, 94%): FABMS: m/z 172.1 (MH+); HRFABMS: m/z 172.1444 (MH+). Calcd for C8H18N3O requires: m/z 172.1450; δH (CDCl3+3% CD3OD) 1.14 (1H, m, CH2), 1.40 (2H, m, CH2), 1.49 (1H, m, CH), 1.58 (1H, m, CH2), 1.69 (1H, m, CH2), 1.85 (1H, m, CH2), 2.55 (1H, m, CH2), 2.67 (5H, m, CH2/NH2), 2.76 (1H, bm, CH2), 2.84 (1H, m, CH2) and 3.82 ppm (2H, m, CONH2); δC (CDCl3+3% CD3OD) CH2, 24.8, 30.9, 36.6, 38.9, 44.9, 50.0; CH, 33.4.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.CC(C)([O-])C.[K+].[O:15]1[CH:19]=[CH:18][C:17]2[CH:20]=[C:21]([CH:24]3[CH2:26][O:25]3)[CH:22]=[CH:23][C:16]1=2.Cl>C(OCC)(=O)C.CS(C)=O>[O:15]1[CH:19]=[CH:18][C:17]2[CH:20]=[C:21]([CH:24]([OH:25])[CH2:26][O:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:22]=[CH:23][C:16]1=2
Reactant: OCc1cccnc1
Reactant: c1cc2cc(C3CO3)ccc2o1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: OC(COCc1cccnc1)c1ccc2occc2c1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 14.2 %

Procedure:
A mixture of 1.6 g of 3-pyridinemethanol, 1.7 g of potassium tert-butoxide and 23 ml of dimethyl sulfoxide was heated to 80° C. Thereto was added 2.4 g of 2-(benzo[b]furan-5-yl)oxirane. The resulting mixture was stirred at 85°-90° C. for 15 minutes. The reaction mixture was added to a mixture of 50 ml of ice water and 50 ml of ethyl acetate. The resulting mixture was adjusted to pH 1 with 6N hydrochloric acid. The aqueous layer was separated and 30 ml of ethyl acetate was added thereto. The resulting mixture was adjusted to pH 9.5 with potassium carbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=50/1) to obtain 0.56 g of 1-(benzo[b]furan-5-yl)-2-(pyridin-3-ylmethoxy)ethanol (compound No. 339).
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:32]=[CH:31][CH:30]=[CH:29][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:34]([C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[C:39]([OH:46])[CH:38]=1)(=[O:36])=[O:35]>>[CH2:1]([C:8]1[O:9][C:10]2[CH:32]=[CH:31][CH:30]=[CH:29][C:11]=2[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:34]([C:37]3[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[C:39]([OH:46])[CH:38]=3)(=[O:36])=[O:35])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[CH:17][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: O=[N+]([O-])c1cc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)ccc1O
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)oc5ccccc45)cc3)cc2[N+](=O)[O-])cc1O

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzofuran-3-yl)-3-nitro-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a yellow solid, mp 200° C.; MS m/e 620 (M−H)+;
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])OCC[O:43]2)[C@:22]([CH2:31][CH2:32][F:33])([OH:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].O.S(=O)(=O)(O)O.C(OCC)(=O)C>C(#N)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:43])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[C@:22]([CH2:31][CH2:32][F:33])([OH:30])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCF)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCF)C(=O)O)C(=O)OC)cc1
Reaction time: 26 h
Yield: 12.6 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-(2-fluoro-ethyl)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate (21.0 mg, 0.0282 mmol) was dissolved in acetonitrile (1.0 mL), and water (0.01 mL, 0.556 mmol) and sulfuric acid (0.005 mL, 0.0938 mmol) were then added at room temperature. After stirring for 26 hours, ethyl acetate (10 mL) and water (10 mL) were added and the mixture was separated. The ethyl acetate layer was washed with a saturated aqueous solution (10 mL) of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure. The obtained residue was purified by preparative TLC (diol, n-hexane/acetone=4/1) to obtain 2.3 mg of the title compound (0.00356 mmol, yield 13%) as a minor component.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C@H:25]([OH:46])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:30]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:29]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:69][C:70]1[CH:77]=[CH:76][C:73]([CH2:74][NH2:75])=[CH:72][CH:71]=1>ClCCl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:8]([CH2:24][C@H:25]([OH:46])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[C:30]([S:42]([CH3:45])(=[O:43])=[O:44])[CH:29]=1)[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:75][CH2:74][C:73]3[CH:76]=[CH:77][C:70]([F:69])=[CH:71][CH:72]=3)=[O:20])=[CH:22][CH:23]=2)[CH2:13][CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)O)cc3)CC2)ccc1OCc1ccccc1
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)c1cc(OC[C@@H](O)CN(Cc2ccccc2)[C@H]2CC[C@H](c3ccc(C(=O)NCc4ccc(F)cc4)cc3)CC2)ccc1OCc1ccccc1
Reaction time: 48 h

Procedure:
A solution of 0.3 g (0.441 mmol) of trans-4-[4-(benzyl{(2S)-3-[4-(benzyloxy)-3-(methylsulfonyl)phenoxy]-2-hydroxypropyl}amino)cyclohexyl]benzoic acid (preparation 4), of 0.78 g (0.91 mmol) of 1-hydroxybenzotriazole, of 0.169 g (0.88 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, of 0.184 ml of triethylamine and of 0.11 g (0.88 mmol) of 4-fluorobenzylamine in a mixture of 4 ml of dichloromethane and 0.8 ml of acetonitrile is stirred for 48 h. The solvents are evaporated under reduced pressure. Dichloromethane and water are added and the organic phase is washed three times with water. The organic phases are dried over magnesium sulfate and concentrated under reduced pressure. The product is obtained in the form of a white solid (0.232 g, 70%) after purification on silica gel (eluent: heptane/ethyl acetate 60/40 for 10 min, 60/40 to 40/60 in 10 min and then 40/60 for 20 min gradient). [M+H+]=751.5
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C(N(CC)CC)C.C1(=O)O[CH2:17][CH2:16][O:15]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]([F:6])([F:5])[CH2:3][O:4][CH2:17][CH2:16][OH:15]
Reactant: O=C1OCCO1
Reactant: OCC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Product: OCCOCC(F)(F)F
Yield: 61 %

Procedure:
2,2,2-Trifluoroethanol (10.0 g, 0.10 mol), triethylamine (10.1g, 0.10 mol), ethylene carbonate (13.2 g, 0.15 mol) and tetrabutyl ammonium iodide (0.74 g) were heated in a flask fitted with a reflux condenser under nitrogen in an oil bath at 100° C. for 1 day. The triethylamine and unreacted alcohol were removed by distillation. The product 2-(2,2,2-trifluoroethoxy)ethanol, b.p. 138° C., was obtained in 61% yield (8.6 g) of 97% pure material.
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:13][C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[OH:1][C:2]1([C:9]2[S:13][C:12]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[N:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: C[Si](C)(C)c1ncc(C2(O)CCC(=O)CC2)s1
Product: C[Si](C)(C)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(2-trimethylsilanyl-thiazol-5-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:14]
Reactant: CCNc1ccccc1
Reactant: Oc1ccc(OCCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(CCCOc1ccc(O)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 30 %

Procedure:
Compound 10a (500 mg, 2.2 mmol) and N-ethylaniline (1 g, 5.5 mmol) were reacted in acetonitrile for 30 mins before diisopropylethylamine (284 mg, 2.2 mmol) was added dropwise. The reaction mixture was then heated and stirred at 70° C. for 12 hours. After cooling to room temperature, the solvent was evaporated and the residue was purified by silica gel column chromatography to provide the compound 10 (170 mg, 0.66 mmol, 24% yield) as a pale yellow solid. MS (ESI, positive) m/z calcd. for C17H21NO2 [M+H]+: 272.16, found: 272.00. 1H NMR (400 MHz, Chloroform-d) δ 7.25 (d, J=7.8 Hz, 2H), 6.88-6.66 (m, 7H), 3.99 (t, J=5.8 Hz, 2H), 3.53 (t, J=7.1 Hz, 2H), 3.41 (q, J=7.2 Hz, 2H), 2.08 (q, J=6.7 Hz, 2H), 1.19 (t, J=7.1 Hz, 3H).