Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:10](O)=O>C(OC(OCC)OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=CO
Solvent: CCOC(OCC)OCC
Product: Brc1cnc2[nH]cnc2c1
Yield: 86.7 %

Procedure:
A solution of 5-bromo-pyridine-2,3-diamine (3.0 g, 15.96 mmol) and HCOOH (1.1 mL) in triethoxymethane (48 mL) was stirred at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 40:1 DCM/MeOH to give 6-bromo-3H-imidazo[4,5-b]pyridine as a light brown solid (2.74 g, 86.7%). 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.44 (s, 1H), 8.30 (br s, 1H). LCMS (ESI) m/z 198 (M+H)+.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:20]([NH:19][CH2:18][C@@H:16]1[O:15][C:14](=[O:23])[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]34[CH2:6][CH:5]3[CH2:4][N:3]([C:32]([O:34][CH3:35])=[O:33])[CH2:2]4)=[CH:12][CH:11]=2)[CH2:17]1)(=[O:22])[CH3:21]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC2CC2(c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)C1
Temperature: 0 °C
Yield: 75.2 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (200 mg, 0.57 mmol) in DCM (25 mL), was added triethyl amine (0.3 mL, 2.27 mmol). The resulting solution was cooled to 0° C. and methyl chloroformate (0.07 mL, 0.86 mmol) was added dropwise. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was diluted with DCM (100 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.2:9.8 MeOH:CHCl3) to provide the title compound (160 mg, 74%) as white solid.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.P(CCCC)(CCCC)CCCC>CC#N>[F:14][C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[NH:7][CH:6]=[C:5]2[CH:4]=[CH:21][C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)Cc1c[nH]c2ccc(F)cc12
Reactant: O=Cc1cccnc1
Agent: CCCCP(CCCC)CCCC
Solvent: CC#N
Product: Fc1ccc2[nH]cc(C=Cc3cccnc3)c2c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution of 5-fluorogramine (576 mg, 3 mmol) and pyridine-3-carboxaldehyde (531 mg, 3 mmol) in MeCN (6 mL) is treated with Bu3P (1.12 mL, 4.5 mmol) and stirred at 90° C. for 24 h. The mixture is concentrated, filtered through a pad of silica gel eluting with 30% EtOAc in heptane to afford 5-fluoro-3-(2-pyridin-3-yl-vinyl)-1H-indole as a mixture of olefin isomers, which is used in the next step without further purification.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]([CH2:7][C:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23])([OH:15])[CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[N:4]1([C:5]([CH2:7][C:8]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])([OH:15])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)N1CC1

Procedure:
1(N-[2-Hydroxyethyl]carbamoyl)-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g), triphenylphosphine (1.09 g) and diethyl azodicarboxylate (0.72 g) were stirred at room temperature for 20 hours in dry tetrahydrofuran (20 ml). The reaction mixture was then diluted with water (70 ml) and extracted with ethyl acetate (3×5 ml). The combined organic extracts were washed with saturated sodium chloride solution (2×20 ml), dried (MgSO4), and evaporated to a brown gum. This material was chromatographed on Merck "Kieselgel 60" silica, eluting with 5% by volume ethanol in ether increasing to 10% ethanol in ether. The eluted material, which was one compound as judged by thin-layer chromatography, was crystallized from ethyl acetate/n-pentane to give colorless crystals of the title compound, 441 mg, m.p. 151°-153° C.
Reaction SMILES: Cl.C1C2C(COC([N:19]3[CH2:24][C@@H:23]([C:25](=[O:44])[N:26]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43])[CH:32]=4)[CH:27]4[CH2:29][CH2:28]4)[CH2:22][C@@H:21]([NH2:45])[CH2:20]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[C:46](Cl)(=[O:50])[CH:47]([CH3:49])[CH3:48]>CC#N>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:26]([CH:27]2[CH2:29][CH2:28]2)[C:25]([C@H:23]2[CH2:22][C@@H:21]([NH:45][C:46](=[O:50])[CH:47]([CH3:49])[CH3:48])[CH2:20][NH:19][CH2:24]2)=[O:44])=[CH:32][C:33]=1[O:38][CH2:39][CH2:40][CH2:41][O:42][CH3:43]
Reactant: COCCCOc1cc(CN(C(=O)[C@H]2C[C@@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)ccc1Cl
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CC#N
Product: COCCCOc1cc(CN(C(=O)[C@@H]2CNC[C@H](NC(=O)C(C)C)C2)C2CC2)ccc1Cl

Procedure:
The title compound is prepared analogously as described in Example 61 using (3R*,5S*)-3-amino-5-{[4-chloro-3-(3-methoxy-propoxy)-benzyl]-cyclopropyl-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester, hydrochloride (Example 92A.) and isobutyryl chloride. MS: 466.4 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.04 min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[C:16]1([CH2:15][CH2:14][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(CCCc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.32 g (25.0 mmol) of 4-picoline in 40 mL of THF at −78° C. was slowly added 17.5 mL of a 1.6 M solution of n-butyllithium in hexanes (28.0 mmol). The reaction mixture was allowed to warm to rt and stirred for 1 h at rt. This reaction mixture was added via cannula to a solution of 6.8 mL (50.0 mmol) of (2-bromoethyl)benzene in 30 mL of THF at −50° C. The mixture was warmed to rt, quenched by the addition of 50 mL of H2O and extracted with ether. The combined organic fractions were extracted with 2N HCl. The combined aqueous fractions were brought to pH=12 with 5N NaOH and again extracted with ether. The combined ether layers were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate=3:1) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:20]#[N:21])[N:11]=2)=[CH:5][CH:4]=1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH3:22])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([C:20]3[NH:25][N:24]=[N:23][N:21]=3)[N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N(C)c2nc(C#N)nc3ccccc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)c2nc(-c3nnn[nH]3)nc3ccccc23)cc1
Temperature: 130 °C
Yield: 13.2 %

Procedure:
To 4-[(4-methoxy-phenyl)-methyl-amino]-quinazoline-2-carbonitrile (100 mg, 0.34 mmol) in DMF (3.4 mL) was added sodium azide (269 mg, 4.1 mmol) and ammonium chloride (220 mg, 4.1 mmol). The reaction was heated to 130° C. for 15 min in a microwave. The reaction was quenched with aqueous NaHCO3 and diluted with EtOAc. The aqueous phase was acidified with HCl (12 M) to pH 1 and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated. Purification via gradient MPLC gave 15 mg (13%) of the title compound as a solid. 1H NMR (MeOH-d4) δ 7.91 (d, 1H), 7.74-7.70 (t, 1H), 7.30 (d, 2H), 7.16 (t, 1H), 7.06 (d, 2H), 7.0 (d, 1H), 3.86 (s, 3H), 3.82 (s, 3H); LC-MS (ESI+; 334 ([M+H]+)).
Reaction SMILES: C1(CCC[CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)=[CH:30][CH:29]=3)[CH3:27])=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])C=CC=CC=1.[OH-:40].[Na+]>>[O:40]([CH:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][O:24][N:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:30][CH:29]=2)[CH3:27])=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=NOCCOc1ccc(CC(CCCc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CC(=NOCCOc1ccc(CC(Oc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1

Procedure:
Reaction and post-treatment were carried out according to Example 18 using 1.28 g of ethyl 2-phenoxy-3-[4-[2-[[1-[4-(2-pyridyl)phenyl]ethylidene]aminoxy]ethoxy]phenyl]propionate obtained in Example 20 and 7.00 ml of a 1N aqueous sodium hydroxide solution to obtain 1.13 g of the desired compound as a crystalline powder.
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1>CO.C(OCC)(=O)C.[Pd]>[OH:1][CH2:2][C@:3]12[CH2:37][CH2:36][C@@H:35]([CH:38]([CH3:40])[CH3:39])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:34])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 24 h

Procedure:
A mixture of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a, 8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid (50 mg, 0.092 mmol) and a catalytic amount of Pd/C (9.77 mg, 0.092 mmol) was dissolved in a mixture of methanol (1 mL) and ethyl acetate (1 mL) and stirred under 1 ATM of H2 for 24 hours. LCMS indicated the completion of the reaction. The reaction mixture was filtered to remove the catalyst. The solution was concentrated in vacuo and the residue was purified using reverse phase prep HPLC to afford the title compound as a white solid. LCMS: m/e 529.29 (M+H−H2O)+, 0.15 min (method 1). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.80 (d, 3H), 0.88 (d, J=6.71 Hz, 3H), 0.97 (s, 6H), 1.02 (s, 6H), 1.12 (s, 3H), 1.18-2.23 (m, 24H), 3.36 (d, J=10.99 Hz, 1H), 3.84 (d, J=10.68 Hz, 1H), 5.27-5.42 (m, 1H), 7.26 (d, J=7.93 Hz, 2H), 8.01 (d, J=8.24 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Si]([O:33][NH2:34])(C(C)(C)C)(C)C.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([S:14]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:34][OH:33])=[O:22])(=[O:16])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)ON
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCN(c3ccc(Cl)cc3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(NO)c1cccc(S(=O)(=O)N2CCN(c3ccc(Cl)cc3)CC2)c1
Yield: 50.6 %

Procedure:
To a suspension of Example 63 (190 mg) was added O-(tert-butyldimethylsilyl)-hydroxylamine (81 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg). After stirring overnight at room temperature ethyl acetate (100 mL) was added and the organic layer was washed with water (2×25 ml), saturated NaHCO3 (2×25 ml) and water (25 ml), dried over MgSO4, filtered and evaporated. The colourless oil was dissolved in dichloromethane (20 ml) and treated with 1.0 M HCl solution in ether (1.5 ml). Filtration afforded the title compound as a white solid (100 mg, 50%).
Reaction SMILES: Br[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.C([Li])CCC.CON(C)[C:20](=[O:23])[CH2:21][CH3:22]>O1CCCC1.CCOCC>[CH3:11][C:10]1[C:3]2[CH:2]=[C:6]([C:20](=[O:23])[CH2:21][CH3:22])[S:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(=O)N(C)OC
Reactant: Cc1cccc2scc(Br)c12
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(=O)c1cc2c(C)cccc2s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
A solution of 3-bromo-4-methylbenzo[b]thiophene (1.69 g) in tetrahydrofuran (10 ml) was added dropwise under nitrogen at −70° C. over 10 minutes to a stirred solution of n-butyllithium (2.5M solution in hexanes; 3.87 ml) in ether (30 ml), then the mixture was stirred at −70° C. for 30 minutes. A solution of N-methoxy-N-methylpropionamide (1.31 g) in tetrahydrofuran (10 ml) was added dropwise at −70° C. over 10 minutes, the mixture was stirred at −70° C. for 3 hours, then it was allowed to warm to ambient temperature and quenched by the addition of saturated aqueous ammonium chloride solution (30 ml). The organic layer was separated, washed with saturated aqueous sodium chloride solution (30 ml), and dried (MgSO4). The solvents were removed in vacuao to give 1-(4-methylbenzo[b]thiophen-2-yl)propan-1-one (0.53 g) as an orange solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1ccccc1Cl
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: Clc1ccccc1CN1CCCC1
Yield: 75.7 %

Procedure:
A solution of 50 g of 2-chlorobenzyl chloride in 100 ml of toluene is added in portions under agitation to a solution of 55 g of pyrrolidine in 150 ml of toluene, maintaining the temperature below 40° C. When all has been added, the mixture is brought to boiling point and heated under reflux for three hours. After cooling, it is washed twice with water, the toluene solution is dried over K2CO3, and the solvent is removed under reduced pressure. The residue is distilled under vacuum. B.P.=102°-104° C. 46 grams of N-(2-chlorobenzyl)-pyrrolidine are obtained. The analytical and spectral (I.R., N.M.R.) data agree with the proposed formula. Treating a solution in ether with gaseous HC1 gives the hydrochloride, M.P. 170° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:22])C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]2[CH:12]([O:22]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred solution of 3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (19.1 mmol, 3.5 g), in DCM (50 mL) cooled at 0° C., was added m-CPBA (32.2 mmol, 5.95 g (70%)) portion wise. The reaction was stirred at room temperature for 4 h. The reaction was diluted with DCM (50 mL) and washed with sat. Na2S2O3, sat. NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge (5% EtOAc in hexane -25% EtOAc in hexane) to provide 7-oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[S:18]([C:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:20])=[O:19]>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([CH:21]1[C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][C:24]([CH3:27])([CH3:28])[CH2:25][CH2:26]1)(=[O:20])=[O:19]
Reactant: CCOC(=O)C1=C(S(=O)(=O)Cl)CCC(C)(C)C1
Reactant: Nc1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CC(C)(C)CCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
2,4-Difluoroaniline (1.51 g) was dissolved in ethyl acetate (33 ml) and the resultant solution was admixed with triethylamine (2.51 ml) with ice-cooling, and then treated dropwise with a solution of ethyl 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-carboxylate (2.53 g) obtained in Reference Example 18 in ethyl acetate (17 ml). The reaction mixture was stirred under nitrogen flow at 0° C. for 30 minutes then at room temperature for 64.5 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with water (120 ml), 0.5 N HCl (120 ml), water (120 ml×2) and saturated brine (120 ml). The ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/9→1/7). A desired fraction was concentrated under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-3,3-dimethyl-1-cyclohexene-1-carboxylate (Compound 83; 0.83 g) as white crystals.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][OH:3].[H-].[Na+].[CH2:12]([N:19]1[CH2:25][CH2:24][C:23]([C:26]#[N:27])=[C:22](Cl)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1>[NH2:27][C:26]1[C:23]2[CH2:24][CH2:25][N:19]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21][C:22]=2[O:3][C:2]=1[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4]
Reactant: CCCCOC(=O)CO
Reactant: N#CC1=C(Cl)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1oc2c(c1N)CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 gm (0.008 mol) of butyl glycolate in 8 ml of absolute dioxane was added dropwise to a suspension of 0.4 gm (0.008 mol) of 50% sodium hydride in 5 ml of absolute dioxane, and the mixture was stirred for one hour at room temperature. Then, while the mixture was cooled with ice, a solution of 1.0 gm (0.004 mol) of 1-benzyl-4-chloro-5-cyano-2,3,6,7-tetrahydro-1H-azepine in 15 ml of absolute dioxane was added, and the mixture was stirred for one hour. The reaction mixture was then poured into about 80 ml of ice-cold water, and the aqueous mixture was extracted three times with ethyl acetate. The combined organic phases were washed twice with water, dried over sodium sulfate and concentrated by evaporation. The residue was purified by column chromatography on silicagel, using toluene/ethyl acetate (7:3) as eluant.
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:20][CH2:21][CH3:22])[C:11]2[CH:17]=[C:16]([CH2:18]O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45]1(=[O:55])[NH:49][C:48](=[O:50])[C:47]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:46]12.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:23]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH2:20][CH2:21][CH3:22])[C:11]2[CH:17]=[C:16]([CH2:18][N:49]3[C:45](=[O:55])[C:46]4[C:47](=[CH:51][CH:52]=[CH:53][CH:54]=4)[C:48]3=[O:50])[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:24][CH3:25]
Reactant: CCCN(CCC)CCCCc1nc2ccc(CO)cc2n1CCC
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)CCCCc1nc2ccc(CN3C(=O)c4ccccc4C3=O)cc2n1CCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
The compound (302 mg) obtained in Example 3-4 was dissolved in toluene (6.0 ml) and added with triphenylphosphine (275 mg) and phthalimide (193 mg) and the whole was cooled to 0° C. In this solution, a 40% diethyl azodicarboxylate/toluene solution (452 mg) was dropped and the whole was stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform and washed with water. Then, the resultant was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (174 mg) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)([C:16]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[C:17]=2[O:25]C)O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.[OH-].[Na+]>C(O)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2([CH:14]([C:27]3[CH:28]=[CH:29][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[C:17]=3[O:25]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(C)c(C)cc(C)c1C(O)(c1ccc(C(C)C)cc1)C1CCN(Cc2ccccc2)CC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(c1C)OC1(CCN(Cc3ccccc3)CC1)C2c1ccc(C(C)C)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of (1-benzyl-4-piperidyl)(4-isopropylphenyl) (3,4,6-trimethyl-2-methoxyphenyl)methanol (5.61 g, 11.89 mmol) in acetic acid (40 ml) was added a 47% hydrobromic acid (50 ml) and the resulting mixture was refluxed with heating for 13 hours. The reaction mixture was cooled down to room temperature and then an 8 N aqueous solution of sodium hydroxide was added into the mixture until it became basic. The product was extracted with ethyl acetate. T he extracts were washed with an aqueous saturated solution of sodium chloride, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from hexane to obtain 4.44 g (76% yield) of the title compound. Melting point: 125-128° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15].C(N(CC)CC)C.[C:23](Cl)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][C:2]1[CH:6]([CH3:7])[CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: CC1=CC(C)C(C)=C1c1ccccc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC1=CC(C)C(C)=C1c1ccccc1NC(=O)C(C)(C)C
Yield: 88.7 %

Procedure:
0.534 g of (2.68 mmol) of 2-(2,3,5-trimethylcyclopenta-1,4-dienyl)phenylamine, 0.325 g (3.22 mmol) of triethylamine, and 0.388 g (3.22 mmol) of pivaloyl chloride were used in the same manner as in Example 11. The resultant reaction product was purified through a column chromatography using a hexane/ethyl acetate (v/v, 5:1) solvent, and then the solvent in the purified product was removed in vacuum, thereby obtaining white solid (0.674 g, 89%).