Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26]C(OC(C)(C)C)=O)=[CH:21][CH:20]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:15][CH2:16][CH3:17])[CH2:12][CH2:13][CH3:14])[CH3:2].Cl.O1CCOCC1>C(O)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][NH2:26])=[CH:23][CH:24]=1)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH3:17])[CH3:2]
Reactant: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
The compound (21.265 g) obtained in Example 72-1 was dissolved in ethanol (100 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (140 ml) and the whole was stirred at room temperature for 1 hour. Subsequently, the solution was stirred at 40° C. for 1 hour. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution to make the pH thereof to 12. The solution was subjected to extraction with chloroform and dried with magnesium sulfate. The solvent was distilled off, thereby obtaining the subject compound (16.46 g) as a colorless oily substance.
Reaction SMILES: C[O:2][C:3]([C:5]1([OH:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[O:8][CH2:7][CH2:6]1)=[O:4].O[Li].O>>[OH:17][C:5]1([C:3]([OH:4])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(O)CCOc2ccc(OC)cc21
Agent: [Li]O
Solvent: O
Product: COc1ccc2c(c1)C(O)(C(=O)O)CCO2

Procedure:
The sub-title compound was prepared according to the method described in Example 1(ii) above from 4-hydroxy-6-methoxychroman-4-yl-carboxylic acid, methyl ester (1.09 g; 4.58 mmol; from step (i) above) and LiOH.H2O (0.39 g; 9.2 mmol). Yield 0.71 g (69%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14].[CH3:22][C:23]([C:25]1[CH:26]=[CH:27][C:28](O)=[CH:29][CH:30]=1)=[O:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=2[C:13]([F:15])([F:16])[F:14])=[CH:29][CH:30]=1)(=[O:24])[CH3:22]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)c(C(F)(F)F)c1
Product: CC(=O)c1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)cc2C(F)(F)F)cc1

Procedure:
Synthesized as described in Example 1C from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-3-(trifluoromethyl)benzonitrile and 4-hydroxyacetophenone: MS (APCI) m/z 431 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC>C1COCC1>[C:14]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:13])=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(=O)oc2cc(OC(=O)c3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-hydroxy-4-methyl-chromen-2-one (0.5210 g, 3.0 mmol) and benzoyl chloride (0.4844 g, 0.4 mL, d=1.211 g/mL, 3.4 mmol) in THF (40 mL) was added Et3N (1 mL) at room temperature. The reaction mixture was stirred at room temperature overnight and filtered. The filtrate was concentrated to give the crude product 7-benzoyloxy-4-methyl-coumarin.
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:4]([CH2:16][CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[C:4]([CH2:16][CH3:17])[CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: CCc1cc(I)ccc1OCCN1CCCC1
Product: CCc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 1-[2-(4-iodo-2-ethylphenoxy)ethyl]pyrrolidine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 44 mg (12% of theoretical); C27H27ClN2O (M=430.969); calc.: molpeak (M+H)+: 431/433 (Cl); found: molpeak (M+H)+: 431/433 (Cl); HPLC-MS: 5.74 minutes (method A).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:8]=1[CH2:9][CH3:10])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11]2)[CH3:2]
Reactant: CCc1ccc(CCCC(=O)O)cc1CC
Agent: O=S(=O)(O)O
Product: CCc1cc2c(cc1CC)C(=O)CCC2

Procedure:
Alternatively 4-(3',4'-diethylphenyl) butanoic acid (23.3 g; 0.106 mole) may be cyclised by stirring at 100° C. with 80% sulphuric acid (115 ml) for 11/2 hours. After dilution, extraction into ether, and distillation 15.83 g (74%) of the tetralone was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH2:14](O)[CH3:15]>C(O)(=O)C>[CH3:14][C:15]1[NH:1][C:2]2[C:3](=[O:13])[NH:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: CCO
Reactant: CCCn1c(N)c(N)c(=O)[nH]c1=O
Solvent: CC(=O)O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(C)nc21

Procedure:
A solution of 22.6 g of 5,6-diamino-1-propyl-2,4-(1H,3H)-pyrimidinedione in 50 ml of acetic acid was refluxed for 2 hours. 30 ml of ethanol was added. The received crystals were filtered off. Yield 19.8 g. The amide was refluxed in 80 ml of 2N NaOH for 2 hours and then neutralized with 5N HCl. The crystals were filtered off and recrystallized from 2.1 l ethanol. Yield 9.8 g (38%) (XXXXVI) NMR (see Table I).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15](O)=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4].[NH4+].[Cl-].C1C=CC2N(O)N=[N:36]C=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([NH2:36])=[O:16])=[O:12])[CH2:7][CH2:8][CH2:9][CH3:10])=[O:4]
Reactant: On1nnc2ccccc21
Reactant: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Boc-Gly-Nleu-Pro-OH (1.1 g, 2.85 mmol.), NH4Cl (0.5 g, 8.6 mmol.) and HOBt (0.5 g, 3.7 mmol.) were dissolved in DMF and the solution was chilled to 0° C. on a water-ice bath. Triethylamine (1.4 ml) was added slowly while stirring the solution. After 10 minutes, EDC (0.73 g, 3.7 mmol.) was added to the solution and the stirring continued overnight. The DMF was removed under reduced pressure and the resulting mixture was poured into 300 ml ethyl acetate. The ethyl acetate solution was washed by H2O 2×10 ml, saturated NaHCO3 2×10 ml, brine 2×10 ml, saturated NaHSO4 2×10 ml and brine again until the pH of the brine layer was approximate 7. The organic layer was dried using Na2SO4 and the ethyl acetate was distilled under reduced pressure to obtain the product Boc-Gly-Nleu-Pro-NH2. The Boc group of this product was removed in 30 ml solution of 30% TFA in DCM. The deprotection reaction was allowed to proceed for 40 minutes. The DCM and TFA was removed under reduced pressure and benzene 3×20 ml was added and distilled to remove trace TFA. The product TFA salt of Gly-Nleu-Pro-NH2 was dissolved in 100 ml ethyl ether and the solution was chilled to 0° C. HCl/dioxane (4N) was added to the solution until no more precipitation was seen. The ether was removed by filtration to obtain the product (white solid, 0.65 g, 69%). Analytical HPLC profile, single peak, RT=10.5 min. (8-40% B in 30 min.). FAB-MS, observed (M+H)+ =285. 1H-NMR (500 MHz, DMSO-d6, 27° C., assignment by TOCSY) δ 8.15 (s, 3H, NH3+), 7.70 (s, C-terminal NH2), 7.58 (s, C-terminal NH2), 7.38 (s, C-terminal NH2), 7.26 (s, C-terminal NH2), 7.23 (s, C-terminal NH2), 6.92 (m, C-terminal NH2), 4.38 (m, Pro-α), 4.30 (s, Nleu-α), 4.26 (s, Nleu-α), 4.22-4.13 (m, Nleu-α, Pro-α), 4.10 (s, Nleu-α), 4.07 (s, Nleu-α), 3.81 (m, Gly-α), 3.73-3.63 (m, Nleu-α, Gly-α), 3.61-3.55 (m, Gly-α, Pro-δ), 3.43 (m, Pro-δ), 3.17-2.97 (m, 2H, Nleu-β), 2.23-1.62 (m, 5H, Nleu-γ, Pro-β, Pro-γ), 0.83 (m, 6H, methyl of Nleu-δ).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]C)=O)[C:5](=[CH:10][C:11]=1[F:12])[C:6]([O:8]C)=O.[H-].[Na+].[CH3:19]CCCCC.CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][C:11]=1[F:12])[C:6](=[O:8])[CH2:19][C:13]2=[O:15]
Reactant: COC(=O)c1cc(C)c(F)cc1C(=O)OC
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cc2c(cc1F)C(=O)CC2=O
Temperature: 100 °C
Yield: 62 %

Procedure:
Dimethyl 4-methyl-5-fluorophthalate 9e (1.65 g, 7.29 mmol) was dissolved in anhydrous ethyl acetate (4 mL). Sodium hydride (348 mg, 14.5 mmol) was added and the mixture was heated at 100° C. for 4 hours. The reaction mixture was cooled to room temperature and a mixture containing 10 mL of hexane and 6 mL of ethyl ether/ethanol (1/1) was added. The yellow precepitate was triturated for 5 min, filtered and dried under vacuum. The yellow solid (1.07 g) was then suspended in a solution containing water (22 mL) and concentrated hydrochloric acid (2.2 mL) and the suspension was heated for 17 min at 80° C. The mixture was then lyophilized to give 810 mg (62%) of 5-methyl-6-fluoro-1,3-indandione 9f as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.[CH2:16]([NH2:19])[CH:17]=[CH2:18]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:19][CH2:16][CH:17]=[CH2:18])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2cccc(Br)c2)C1
Reactant: C=CCN
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1CC(Oc2cccc(Br)c2)C1
Reaction time: 48 h
Yield: 64.3 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(3-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 2.85 g (0.05 mole) of 2-propenylamine. After stirring for 48 hr, the reaction mixture was diluted with 100 ml of water and the reddish oil which separated solidified upon standing. The solids were collected by filtration, 5.9 g. Upon repeated trituration with boiling isopropyl ether, the combined triturates upon cooling yielded 4 g (64.4%) of fine white crystals, m.p. 90°-92° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12]O)[CH:3]=1.P(Br)(Br)[Br:15].O>CCOCC>[Br:15][CH2:12][CH2:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[CH:3]1
Reactant: BrP(Br)Br
Reactant: Cc1cn(CCO)c2ccccc12
Solvent: CCOCC
Solvent: O
Product: Cc1cn(CCBr)c2ccccc12
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a stirred solution of 7.2 g of 3-methylindole-1-ethanol, described in Example 1, in 500 ml. of dry ether (ice bath) is slowly added 1.2 ml of phosphorus tribromide in 100 ml of dry ether. A dark red oily complex separates. The eaction reaction is stirred 36-48 hours at room temperature, then decomposed with ice and water. The separated ether-layer is quickly washed with a 10% solution of sodium bicarbonate and with water again, dried over calcium chloride for 2 min., decanted, and dried over magnesium sulfate for 30 min. The filtrate is evaporated yielding 1-(2-bromoethyl)-3-methylindole.
Reaction SMILES: Cl.NO.Cl.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([N:24]=CC4C=CC=CC=4)[CH2:20][CH2:19]3)=[O:17])[C:10]=2[CH:32]=1>C(#N)C>[ClH:5].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12](=[O:14])[N:11]([CH2:15][C:16]([N:18]3[CH2:19][CH2:20][N:21]([NH2:24])[CH2:22][CH2:23]3)=[O:17])[C:10]=2[CH:32]=1
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCN(N=Cc2ccccc2)CC1
Agent: Cl
Agent: NO
Solvent: CC#N
Product: NN1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131 %

Procedure:
To a solution of hydroxylamine hydrochloride (25.2 g) in a mixed solvent of acetonitrile (300 ml) and 6N-hydrochloric acid (150 ml), was added 5-chloro-3-[(4-benzylideneamino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone (15 g). The resulting solution was stirred overnight at room temperature. After stirring for five hours under ice cooling, the crystalline precipitates were filtered, and washed successively with water (30 ml) and methylene chloride (75 ml). This product was suspended in water (30 ml) and then filtered to give 5-chloro-3-[(4-amino-1-piperazinyl)carbonylmethyl]-2-benzothiazolinone hydrochloride (8.60 g).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[Na])(C)(C)C>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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([N:31]3[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: CN1CCNCC1
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(N3CCN(C)CC3)cc2)C(=O)O1
Temperature: 80 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (400 mg, 0.96 mmol), 1-methylpiperazine (100 mg, 1.0 mmol), t-BuONa (129 mg, 1.34 mmol), Pd2(dba)3 (9 mg, 0.01 mmol), BINAP (6 mg, 0.01 mmol) in toluene. was heated to 80° C. and stirred overnight. Then the reaction mixture was concentrated to afford the residue, which was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-1,3-oxazinan-2-one (162 mg, 0.4 mmol). LC-MS Method 2 tR=1.77, min, m/z=438; 1H NMR (CD3OD) 1.50 (m, 3H), 2.20 (m, 2H), 2.30 (m, 3H), 2.35 (m, 1H), 2.60 (m, 6H), 3.00 (m, 1H), 3.10 (m, 4H), 5.00 (m, 2H), 5.45 (m, 1H), 5.65 (m, 1H), 6.70 (m, 2H), 6.80 (m, 2H), 7.05 (m, 2H), 7.25 (m, 2H).
Reaction SMILES: [NH2:1][C:2]([CH3:12])=[CH:3][C:4](=[O:11])[CH2:5][S:6]([NH:9][CH3:10])(=[O:8])=[O:7].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([N:9]([CH3:10])[S:6]([CH2:5][C:4](=[O:11])[CH:3]=[C:2]([NH2:1])[CH3:12])(=[O:8])=[O:7])[CH:14]=[CH2:15]
Reactant: C=CCBr
Reactant: CNS(=O)(=O)CC(=O)C=C(C)N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCN(C)S(=O)(=O)CC(=O)C=C(C)N
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In accordance with the procedure described in Example 7, a solution of 3.8 g of 4-amino-N-methyl-2-oxo-3-pentenesulfonamide and 2.5 ml of allyl bromide in 50 ml of dimethylformamide was treated with 6 g of potassium carbonate and the mixture was stirred intensively at room temperature for 7 hours. The product was firstly chromatographed on 300 g of silica gel with methylene chloride/ethyl acetate (4:1) as the elution agent and then recrystallized from methylene chloride/ether. There were obtained 3.3 g of N-allyl-N-methyl-4-amino-2-oxo-3-pentenesulfonamide in the form of colorless crystals, m.p. 86°-89°.
Reaction SMILES: C[Al](C)C.[CH3:5][NH:6][CH2:7][CH2:8][CH3:9].[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]([O:23]CC)=O)[O:20][C:16]=2[C:15]([F:26])=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:13]=1[CH3:33])#[N:11].Cl>ClCCl.C1(C)C=CC=CC=1>[C:10]([C:12]1[C:17]2[N:18]=[C:19]([C:21]([N:6]([CH3:5])[CH2:7][CH2:8][CH3:9])=[O:23])[O:20][C:16]=2[C:15]([F:26])=[C:14]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:13]=1[CH3:33])#[N:11]
Reactant: CCCNC
Reactant: CCOC(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCN(C)C(=O)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Reaction time: 0.67 h
Yield: 55.4 %

Procedure:
Under nitrogen atmosphere, trimethylaluminium (1.03 M n-hexane solution) (2.40 ml, 2.47 mmol) was dropwise added at room temperature to a toluene (6 ml) solution of N-methylpropylamine (127 μl, 1.23 mmol), followed by stirring for 40 minutes. Subsequently, a dichloromethane (2 ml) solution of ethyl 4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-2-carboxylate (I-111) (200 mg, 617 μmol) was dropwise added, followed by stirring for 48.5 hours. After the reaction, aqueous 1 N hydrochloric acid solution was added to the reaction liquid with cooling with ice, followed by stirring at room temperature, then the reaction liquid was extracted with chloroform. Next, the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (120 mg, 55%) as a pale yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClCc1ccccc1SCc1ccccc1
Reactant: O=C1CCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.35 g of potassium-tert-butoxide in 25 mL of dimethylformamide, cooled to 0° C., was added 0.92 mL of 2-pyrrolidinone. As a white precipitate formed, the mixture was stirred for 10 minutes, and 3.0 g of 2-phenylmethylthio chloromethyl benzene was added in one portion. The resulting solution was allowed to warm to room temperature, stirred for 1 hour, poured into water, and extracted with methylene chloride. The organic layer was washed well with water, dried over magnesium sulfate, filtered, and the filtrate evaporated to leave 3.0 g of a yellow oil.
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1>C1COCC1.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[CH:7]1([O:3][CH2:4][CH2:5][OH:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: C1CCC2(CC1)OCCO2
Agent: [Zr+4]
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: OCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To the slurry of zirconium tetrachloride (10.65 g, 45.7 mmol) in THF (100 mL) was added sodium borohydride (4.3 g, 114.3 mmol) in small portions at room temperature. A solution of 1,4-dioxaspiro[4.5]decane (6.5 g, 45.7 mmol) in THF (20 mL) was added dropwise and the resulting mixture was stirred at room temperature overnight. The reaction was carefully quenched with 1N HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated to give a crude product, which was purified via silica gel chromatography eluting with petroleum ether/ethyl acetate (3:2) to give 2-(cyclohexyloxy)ethanol (3.9 g, 59.2% yield) as light yellow oil. 1H-NMR (CDCl3) δ 3.68-3.70 (t, 2H), 3.53-3.56 (m, 2H), 3.27-3.29 (m, 1H), 2.54 (br, 1H), 1.89-1.93 (m, 2H), 1.70-1.73 (m, 2H), 1.51-1.54 (m, 1H), 1.17-1.28 (m, 5H).
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][OH:8])[CH2:3][C:4]#[CH:5].I[C:10]1[CH:15]=[CH:14][C:13](/[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)=[CH:17]/[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:12][CH:11]=1>O1CCCC1.C(N(CC)CC)C.C1C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[OH:8][CH2:7][CH2:6][N:2]([CH2:3][C:4]#[C:5][C:10]1[CH:11]=[CH:12][C:13](/[C:16](/[C:33]2[CH:42]=[CH:41][C:36]3[O:37][C:38]([CH3:40])=[CH:39][C:35]=3[CH:34]=2)=[CH:17]\[CH2:18][O:19][C:20]2[CH:31]=[CH:30][C:23]([O:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH3:32])[CH:21]=2)=[CH:14][CH:15]=1)[CH3:1]
Reactant: C#CCN(C)CCO
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(I)cc2)c2ccc3oc(C)cc3c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN(C)CCO)cc2)c2ccc3oc(C)cc3c2)cc1C
Temperature: 0 °C
Reaction time: 72 h

Procedure:
2-(N-Methyl-N-propargylamino)ethanol (440 mg, 3.89 mmol) was added under nitrogen atmosphere to a degassed solution of methyl (Z)-[4-[3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate (400 mg, 0.68 mmol; prepared as described in example 25) in a mixture of tetrahydrofuran (6 mL) and triethylamine (6 mL). The solution was cooled to 0° C. and tetrakis(triphenylphosphine)palladium (71 mg, 0.061 mmol) and copper(I) iodide (21 mg, 0.11 mmol) were added. The reaction mixture was stirred at ambient temperature for 72 h, diluted with benzene (100 mL), decanted and evaporated in vacuo. The residue was purified by column chromatography (silica gel Fluka 60, benzene/ethyl acetate 1:0-0:1) yielding methyl (E)-[4-[3-[4-[3-[N-(2-hydroxyethyl)-N-methylamino]-propynyl]phenyl]-3-(2-methyl benzo[b]furan-5-yl)allyloxy]-2-methylphenoxy]acetate.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][CH:43]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:39][O:40][C:41](=[O:49])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])[NH:17]2)=[O:36])=[N:44][CH:43]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)nc1
Yield: 58 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.5 g, 0.86 mmol) was reacted with 6-amino-nicotinic acid methyl ester (Aldrich) (0.3 g, 2 mmol), HATU (0.38 g, 1 mmol) and iPr2NEt (0.6 g, 4.6 mmol) in CH2Cl2 at room temperature for 20 h to give rac-6-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-nicotinic acid methyl ester as a white solid (0.3 g, 58%).