Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.COC(=O)C(NS(C1C=CC2C(=CC=CC=2)C=1)(=O)=O)CC1C=C2C(=CC=1)C(N)=NC=C2.Cl.Cl.[CH3:35][O:36][C:37](=[O:52])[CH:38]([NH2:51])[CH2:39][C:40]1[CH:49]=[C:48]2[C:43]([CH:44]=[CH:45][N:46]=[C:47]2[NH2:50])=[CH:42][CH:41]=1.[CH3:53][O:54][C:55]1[CH:64]=[C:63]2[C:58]([CH:59]=[CH:60][C:61]([S:65](Cl)(=[O:67])=[O:66])=[CH:62]2)=[CH:57][CH:56]=1>>[CH3:35][O:36][C:37](=[O:52])[CH:38]([NH:51][S:65]([C:61]1[CH:60]=[CH:59][C:58]2[C:63](=[CH:64][C:55]([O:54][CH3:53])=[CH:56][CH:57]=2)[CH:62]=1)(=[O:67])=[O:66])[CH2:39][C:40]1[CH:49]=[C:48]2[C:43]([CH:44]=[CH:45][N:46]=[C:47]2[NH2:50])=[CH:42][CH:41]=1
Reactant: COc1ccc2ccc(S(=O)(=O)Cl)cc2c1
Reactant: COC(=O)C(N)Cc1ccc2ccnc(N)c2c1
Agent: COC(=O)C(Cc1ccc2c(N)nccc2c1)NS(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Product: COC(=O)C(Cc1ccc2ccnc(N)c2c1)NS(=O)(=O)c1ccc2ccc(OC)cc2c1

Procedure:
Using the procedure described for 11a, methyl ester 37i and compound 12a gave 3-(1-amino-7-isoquinolinyl)-2-[[(7-methoxy-2-naphthalenyl)sulfonyl)amino]propionic acid methyl ester. This ester was saponified and subsequently coupled with 4-methylpiperidine using the procedure described for 4 to give 37. 1H-NMR 200 MHz (CD3OD) δ: −0.20-0.77 (5H, m), 1.22-1.58 (3H, m), 1.73-3.20 (4H, m), 3.65-4.19 (2H, m), 3.93 (3H, s), 4.53-4.68 (1H, m), 7.00-7.06 (1H, m), 7.23-7.31 (2H, m), 7.43-7.51 (2H, m), 7.56-8.15 (6H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1B(O)O>>[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]1[C:2]1[CH:3]=[C:4]([O:8][S:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[N:6][CH:7]=1
Reactant: Cn1c(B(O)O)cc2ccccc21
Reactant: O=S(=O)(Oc1cncc(Br)c1)N1CCOCC1
Product: Cn1c(-c2cncc(OS(=O)(=O)N3CCOCC3)c2)cc2ccccc21

Procedure:
Morpholine-4-sulfonic acid 5-bromo-pyridin-3-yl ester and N-methyl-indoleboronic acid are processed according to the method described in Example 100 to give morpholine-4-sulfonic acid 5-(1-methyl-1H-indol-2-yl)-pyridin-3-yl ester. MS (ESI) m/z 374.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.B(Br)(Br)Br>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[CH:19][N:20]=[CH:21][C:13]2=3)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(C(=O)N2CCOc3ccncc32)cc1Br
Agent: BrB(Br)Br
Product: O=C(c1ccc(O)c(Br)c1)N1CCOc2ccncc21
Yield: 89.9 %

Procedure:
By the same method as in Example 3, (3-bromo-4-methoxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (296 mg, 0.85 mmol) and 1M solution of boron tribromide (4.25 ml, 4.25 mmol) were reacted to obtain the target compound 38, i.e., (3-bromo-4-hydroxy-phenyl)-(2,3-dihydro-pyrido[4,3-b][1,4]oxazin-4-yl)-methanone (256 mg, 89%).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH:19]1([CH2:22]Br)[CH2:21][CH2:20]1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CN(C)C=O.ClCCl.O>[CH:19]1([CH2:22][N:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)[CH2:21][CH2:20]1
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Reactant: BrCC1CC1
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C1Cc2ccccc2-c2ccccc2N1CC1CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a solution of 0.5 g (2.4 mmol) of 5H,7H-dibenzo[b,d]azepin-6-one in 6 ml of dimethylformamide at room temperature 0.143 g (3.58 mmol) of sodium hydride was added. After stirring for 1 hour at 60° C. 0.97 g (7.2 mmol) of cyclopropylmethyl bromide were added and stirring was continued at 60° C. overnight. After cooling to room temperature the mixture was was distributed between water and dichloromethane. The combined organic layers were reextracted with sodium sulphate solution and dried (MgSO4). After concentration in vacuo the residue was purified by column chromatography (hexane/ethyl acetate=1:1) to yield 0.6 g (95%) of 5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one as a white crystalline compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][C:9]([OH:11])=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:12][C:13]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1)=[N:18]2>>[Cl:23][C:22]1[C:13]([NH:12][C:9](=[O:11])[CH2:8][C:2]2([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:29]1)[CH:16]=[CH:15]2
Reactant: CCOC(=O)C1CCN(c2ccc3c(N)c(Cl)ccc3n2)CC1
Reactant: CC1(CC(=O)O)CCCCC1
Product: CCOC(=O)C1CCN(c2ccc3c(NC(=O)CC4(C)CCCCC4)c(Cl)ccc3n2)CC1
Yield: 70.7 %

Procedure:
Prepared according to the method of example 62(a), using 1-methyl-cyclohexaneacetic acid (280 mg) and 1-(5-amino-6-chloro-2-quinolinyl)-4-piperidinecarboxylic acid, ethyl ester (Example 77(a)) (200 mg), to afford the sub-titled compound (200 mg).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg+].[Br-]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:29])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[S:14]2)[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2C[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36.7 %

Procedure:
To a solution of tert-butyl ((3aR,5S,6S,7aR)-6-(benzyloxy)-5-formyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.920 g, 2.26 mmol) in anhydrous THF (20 mL) at 15° C. was added a solution of MeMgBr (1.4 M in THF/toluene, 4.1 mL, 5.7 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 h, and then quenched with saturated aqueous NaHCO3 solution (30 mL). The mixture was extracted with EtOAc (2×30 mL), and the combined extracts were dried over anhydrous Na2SO4. After filtration the solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (MeOH/DCM, 0:4 to 1:4), affording tert-butyl ((3aR,5R,6S,7aR)-6-(benzyloxy)-5-(1-hydroxyethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)(methyl)carbamate (0.350 g, 37%) as a white foam; 1H NMR (400 MHz, CDCl3) for this material indicated that it contained two diastereomers with a ratio of 1:2. Also isolated was the deprotected side product 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(methylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.300 g, 41%) as a white solid; 1H NMR (400 MHz, CDCl3) for this material indicated that it contained two diastereomers with a ratio of 1:1.4.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[N:9]([O-])=[O:10].[Na+].Cl>O>[N:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4])=[O:10]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=NN1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of L-proline (2.50 kg, 21.6 moles) and sodium nitrite (2.10 kg, 30.4 moles) in water (5.0 L) maintained at 0-10° C. is added concentrated hydrochloric acid (2.53 L) and the resulting slurry is stirred for 16 hours at ambient temperature. The reaction mixture is extracted with t-butyl methyl ether (1×6 L+2×3 L) and the organic solution is concentrated using a rotary evaporator with a bath temperature below 35° C. Residual water is removed by evaporation with 2.0 L of toluene. The resulting (2S)-1-nitrosoproline (3.25 kg, 105%) is isolated as a yellow solid and dried under vacuum at 25° C., m.p. 100-102° C., HPLC purity, 96.3% (area % HPLC conditions described in Example 7) and residual toluene, 4%. The product of the example is used directly, without further purification, in the next step (see example 2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:35][C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])(=[O:34])=[O:33])=[CH:27][C:26]=3[F:42])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:43][CH3:44].C([O-])([O-])=O.[K+].[K+].[Br:51][CH2:52][CH2:53][CH2:54]Br>CC#N>[Br:51][CH2:52][CH2:53][CH2:54][N:35]([C@H:36]([CH3:41])[C:37]([O:39][CH3:40])=[O:38])[S:32]([C:28]1[CH:27]=[C:26]([F:42])[C:25]([CH2:24][S:23][C:14]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:11]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:43][CH3:44])[CH:4]=3)([CH3:9])[CH3:10])=[CH:12][N:13]=2)=[C:30]([F:31])[CH:29]=1)(=[O:33])=[O:34]
Reactant: COC(=O)[C@@H](C)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@@H](C)N(CCCBr)S(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Temperature: 60 °C
Yield: 0 %

Procedure:
To a solution of (R)-methyl 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate (200 mg, 0.30 mol) in MeCN (4 mL) were added K2CO3 (124 mg, 0.90 mol) and 1,3-dibromopropane (121 mg, 0.60 mol). The reaction flask was heated at 60° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting product was purified by column chromatography (silica, Hex/EtOAc, 1:1) to afford (R)-methyl 2-(N-(3-bromopropyl)-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenylsulfonamido)propanoate (113 mg, 47%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, 2H), 7.19 (s, 1H), 7.16-7.18 (d, 1H), 6.80-6.84 (t, 2H), 6.50-6.53 (m, 2H), 6.43-6.46 (m, 2H), 4.63-4.65 (q, 1H), 4.13 (s, 2H), 3.72 (s, 3H), 3.55 (s, 3H), 3.27-3.45 (m, 4H), 2.10-2.31 (m, 2H), 1.47 (s, 6H), 1.45 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][C:7]=1[CH3:8].[NH2:15][NH2:16]>>[CH3:8][C:7]1[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]=[N:3][C:2]=1[NH:15][NH2:16]
Reactant: Cc1cc(-c2ccccc2)nnc1Cl
Reactant: NN
Product: Cc1cc(-c2ccccc2)nnc1NN
Temperature: 100 °C

Procedure:
3-Chloro-4-methyl-6-phenylpyridazine (0.510 g, 2.49 mmol) was dissolved in hydrazine (1.56 ml, 49.8 mmol) then the reaction mixture was heated at 100° C. for 1.5 hours. The precipitate that had formed in the mixture was collected and washed with iPrOH. The solid was dried under high vacuum to afford 1-(4-methyl-6-phenylpyridazin-3-yl)hydrazine as a pale yellow solid.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(Cl)Cl.[C:15]1([CH3:34])[CH:20]=[CH:19][C:18]([S:21]([O:24][C:25]2[C@@H:26]([OH:33])[C@@H:27]3[O:32][CH2:31][C@H:29]([CH:30]=2)[O:28]3)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(OCC)C>[C:15]1([CH3:34])[CH:16]=[CH:17][C:18]([S:21]([O:24][C:25]2[C:26](=[O:33])[C@@H:27]3[O:32][CH2:31][C@H:29]([CH:30]=2)[O:28]3)(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OC2=C[C@H]3CO[C@H](O3)[C@@H]2O)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC2=C[C@H]3CO[C@H](O3)C2=O)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
360 mg of pyridinium chlorochromate was added to 20 ml of a dry methylene chloride solution containing 50 mg of 1,6-anhydro-3-O-p-toluenesulfonyl-4-deoxy-β-D-erythro-hex-3-enopyranose, and the mixture was stirred at room temperature for 48 hours. Disappearance of the starting material was confirmed by thin layer chromatography, and then 60 ml of diethyl ether was added thereto. The mixture was further stirred at room temperature for 15 minutes. Then, the reaction mixture was filtered by silica gel and washed with 200 ml of diethyl ether. The washing solution was concentrated under reduced pressure together with the filtrate. The obtained syrup crude product was purified by silica gel column chromatography (ethyl acetate: hexane=1:2) to obtain 34 mg of the desired product (Intermediate No. 3) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]1)[CH3:2].N.[H][H]>[Ni].CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][NH2:24])[CH2:20][CH2:21]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOCCn1c(CC2CCN(CC#N)CC2)nc2cccnc21
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOCCn1c(CC2CCN(CCN)CC2)nc2cccnc21
Yield: 100 %

Procedure:
A mixture of 23.75 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineacetonitrile and 400 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 6 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 22.7 parts (100%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineethanamine as a residue (compound 179).
Reaction SMILES: [F:1][C:2]([F:16])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3](OCC)=[O:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]([F:16])([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(F)(F)CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC(F)(F)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of Intermediate 1 (1.0 g, 4.45 mmol) in tetrahydrofuran (15 mL) was added lithium aluminum hydride (0.22 g, 5.78 mmol). The mixture was stirred at room temperature overnight. To the crude reaction was added water (0.3 mL), 4N sodium hydroxide (0.3 ml) and water (0.9 mL). The resulting solid was filtered through Celite and the solvent removed under reduced pressure. The residue was diluted with methylene chloride (20 mL) and washed with water (10 mL), 2N hydrochloric acid (2×10 mL) and water (10 mL), dried (Na2SO4), and concentrated. The title compound was obtained as brown oil (0.6 g, 72%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:12]#[N:13])=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[N+]([CH3:18])([O-])=O.N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1([C:12]#[N:13])[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:18]1)=[O:14])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C(C#N)=C1CCCCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(C#N)CC12CCCCC2
Reaction time: 2.5 h
Yield: 74.9 %

Procedure:
To a solution of cyano-cyclohexylidene-acetic acid ethyl ester (1.37 g, 7.09 mmol) in 30 mL acetonitrile was added nitromethane (1.92 mL, 35.5 mmol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (1.06 mL, 7.09 mmol) resulting in an orange solution. The reaction was stirred for 2.5 hours, then partitioned between ethyl ether (Et2O) and 1N hydrochloric acid (HCl) (aq). The phases were separated, and the organic phase washed with brine, dried over magnesium sulfate (MgSO4), and concentrated. Flash chromatography of the residue (5% ethyl acetate (EtOAc)/hexanes) afforded 1.1 g (75%) of 1-cyano-spiro[2.5]octane-1-carboxylic acid ethyl ester as a colorless oil. 1H NMR (CDCl3) δ 4.22 (m, 2H), 1.77 (d, J=5.1 Hz, 1H), 1.42–1.72 (m, 10H), 1.40 (d, J=5.1 Hz, 1H), 1.30 (t, J=7.1 Hz, 3H). 13C NMR δ 166.40, 118.60, 62.72, 40.20, 34.67, 29.01, 28.75, 25.69, 25.54, 25.28, 24.66, 14.38. LRMS: m/z 208.0 (M+1). IR: 2239, 1732 cm−1. Anal. Calcd for C12H17NO2: C, 69.54; H, 8.27; N, 6.76. Found: C, 69.41; H, 8.33; N, 6.75.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C@@H:27]1[CH2:31][C@@H:30]([OH:32])[CH2:29][N:28]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C(=O)C>[CH2:36]([O:35][C:33]([N:28]1[CH2:29][C@H:30]([OH:32])[CH2:31][C@H:27]1[CH2:26][CH2:25][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:34])[CH3:37]
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Reactant: COc1ccc(O)c(CCc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(OC)cc1CCc1ccccc1
Yield: 24 %

Procedure:
1130 mg of 4-methoxy-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 610 mg of potassium t-butoxide and 1000 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 448 mg (yield 24%) of the title compound as an oily substance.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[CH2:8]([O:20][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCO
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)/C=C\C(=O)O

Procedure:
Into an autoclave, were charged 295 parts of maleic anhydride, 570 parts of lauryl alcohol and 85 parts of toluene. The mixture was reacted at 60° C. for 5 hours under sealed condition, to obtain maleic acid monolauryl ester, containing 0.2% unreacted maleic anhydride. After adding to the mixture, 5 parts of sodium hydroxide, 275 parts of allyl chloride and 375 parts of triethyl amine, an atmosphere was substituted with nitrogen. The mixture was reacted at 80° C. for 8 hours, and cooled to a room temperature. The mixture was rinsed with 90 parts of 10% hydrochloric acid aqueous solution, followed by distillation of toluene under vacuum, to obtain 965 parts of lauryl allyl maleate of 98.6% purity and of Gardner Color 3. A molar ratio of maleic anhydride:lauryl alcohol was 1:1.02, and maleic acid monolauryl ester:allyl chloride:triethyl amine:formed water was 1:1.19:1.23:0.04.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20][O:19][C:15]4=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:31]N1C(=O)CCC1=O.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)(Cl)Cl>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Cl:31][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]3[O:19][CH2:20][CH2:21][NH:22][CH2:23][C:14]3=2)[N:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl 8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 17, 15 mg, 0.035 mmol) was dissolved in CHCl3 (2 mL) and N-chlorosuccinimide (7.0 mg, 0.053 mmol) was added. The mixture was heated at 70° C. overnight. The mixture was cooled to room temperature, TFA (1 mL) was added and the mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a light yellow solid (4.1 mg) in the form of the trifluoroacetate salt. MS m/z 363 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[C:7](=[O:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[F:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][C:17]=1[F:18].[NH4+].[Cl-]>C1COCC1>[F:11][C:12]1[CH:13]=[C:14]([C@:7]2([OH:8])[O:6][CH2:5][C:4]([CH3:10])([CH3:9])[NH:3][C@H:2]2[CH3:1])[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: Fc1ccc([Mg]Br)cc1F
Reactant: C[C@@H]1NC(C)(C)COC1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 25.8 %

Procedure:
A solution of morpholin-2-one 15 (410 mg, 2.86 mmol) in anhydrous THF (2.9 mL, 1M) was cooled to −78° C. and treated with 3,4-difluorophenylmagnesium bromide (1.2 equiv., 3.43 mmol, 6.90 mL, 0.5 M solution in THF) under an N2 atmosphere. After stirring the reaction mixture at −78° C. under an inert atmosphere for 1.5 h, saturated aqueous solution of NH4Cl was added to the reaction vessel. The reaction mixture was allowed to warm to room temperature and extracted with ether (three times). The combined organic extracts were washed (water, brine), dried (Na2SO4) and concentrated. Purification of the residue by column chromatography on silica gel using CH2Cl2 to CH2Cl2-MeOH—NH4OH (90:9:1) as the eluent gave 190 mg (25%) of 4m as a yellow solid: [α]22D +18.2° (c 1.0, CHCl3); 1H NMR (CDCl3) δ 7.45-7.39 (m, 1H), 7.34-7.32 (m, 1H), 7.18-7.10 (m, 1H), 3.82 (d, 1H, J=11.3 Hz), 3.40 (d, 1H, J=11.3 Hz), 3.18 (q, 1H, J=6.5 Hz), 1.38 (s, 3H), 1.08 (s, 3H), 0.78 (d, 3H, J=6.5 Hz); 13C NMR (CDCl3) δ 122.40, 122.31 116.74, 116.51, 115.8, 115.6, 96.5, 69.6, 53.4, 49.8, 27.3, 22.8, 16.5; LCMS (ESI) m/z 258.6, [(M+H)+, M=C13H17F2NO2].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH:29]=[CH2:30]>C(#N)C>[CH2:30]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Yield: 94.2 %

Procedure:
Benzyl 3-hydroxy-4-nitro-benzoate 29a (4.50 g, 16.47 mmol) was dissolved in 75 mL of anhydrous acetonitrile. The resulting solution was added with potassium carbonate (6.83 g, 49.41 mmol) and 3-bromopropene (2.9 mL, 32.94 mmol) successively, heated to reflux for 3 hours, then filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound benzyl 3-allyloxy-4-nitro-benzoate 29b (4.86 g, yield: 94.2%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2([CH2:10][OH:11])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([C:7]2([CH:10]=[O:11])[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(C2(CO)CC2)OCCO1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C2(C=O)CC2)OCCO1
Reaction time: 3 h
Yield: 79 %

Procedure:
10 g of 6 is dissolved in 500 ml of dichloromethane, and 3.7 g of sodium acetate and 19.3 g of pyridinium chlorochromate are added at room temperature under nitrogen. After 3 hours at room temperature, it is filtered on silica gel, concentrated by evaporation, diluted with diethyl ether, filtered again, and the solvent is removed, whereby 7.8 g of title compound 7 is obtained as a colorless oil.