Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([C:12]([NH:14][CH2:15][CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[NH:19][CH:18]=2)=[O:13])[CH2:11][CH2:10]1.[OH-].[Na+]>C(O)(=O)C>[Br:1][C:18]1[NH:19][C:20]2[C:25](=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:17]=1[CH2:16][CH2:15][NH:14][C:12]([CH:9]1[CH2:11][CH2:10]1)=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2[nH]cc(CCNC(=O)C3CC3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(Br)c(CCNC(=O)C3CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29 %

Procedure:
N-bromo succinimide (0.89 g, 5 mmol) was added to a solution of N-cyclopropanoyl-5-methoxytryptamine, 4j (1.29 g, 5 mmol) in acetic acid (20 mL). The reaction mixture was stirred under N2 at room temperature for 4 h, then cooled at 0° C., neutralized with a 50% solution of NaOH and extracted with ethyl acetate. The combined organic layers were washed with NaCl solution, dried (Na2SO4) and concentrated. Purification by flash chromatography (silica gel; ethyl acetate/cyclohexane 6:4) and crystallization gave 0.490 g (29% yield) of 4h as white solid, mp 82°-83° C. IR νmax : 3460, 3300, 1650. 1H NMR: 0.72(m, 2H, CH2cyclopropyl), 0.99(m, 2H, CH2cyclopropyl), 1.27(m, 1H, cyclopropyl-CH), 2.93(t, 2H, β -CH2), 3.56(q, 2H, α-CH2), 3.85(s, 3H, OCH3), 5.72(br s, 1H, NH), 6.80-7.25(m, 3Harom), 8.21(br s, 1H, NHindole).
Reaction SMILES: [NH2:1][N:2]1[C:13](=[O:14])[C:12]2[C:15]3[N:4]([CH:5]([CH3:18])[CH2:6][O:7][C:8]=3[C:9](F)=[C:10]([F:16])[CH:11]=2)[C:3]1=[O:19].[C:20]([O:24][C:25](=[O:34])[NH:26][C@@H:27]([C@H:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:28])([CH3:23])([CH3:22])[CH3:21].C(N(CC)CC)C>C(#N)C>[C:20]([O:24][C:25](=[O:34])[NH:26][C@H:27]([C@@H:29]1[CH2:33][CH2:32][N:31]([C:9]2[C:8]3=[C:15]4[C:12]([C:13](=[O:14])[N:2]([NH2:1])[C:3](=[O:19])[N:4]4[CH:5]([CH3:18])[CH2:6][O:7]3)=[CH:11][C:10]=2[F:16])[CH2:30]1)[CH3:28])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC1COc2c(F)c(F)cc3c(=O)n(N)c(=O)n1c23
Reactant: C[C@@H](NC(=O)OC(C)(C)C)[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1COc2c(N3CC[C@@H]([C@H](C)NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)n(N)c(=O)n1c23
Yield: 73.7 %

Procedure:
A solution of 0.11 g (0.41 mmol) of 5-amino-8,9-difluoro-3-methyl-2,3-dihydro-1-oxa-3a,5-diazaphenalene-4,6-dione (Example 24h), 0.26 g (1.3 mmol) of ((R)-(S)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.25 g (2.5 mmol) of triethylamine and 10 mL of acetonitrile is heated at reflux for 18 hours. The solvent is removed in vacuo and the residue is partitioned between ethyl acetate/water. The organic layer is washed with water, dried (MgSO4) and concentrated in vacuo. The residue is chromatographed over flash grade silica gel (230–400 mesh) eluting with dichloromethane/ethanol (95:5) to give 0.14 g of the title compound. 1H NMR (400 MHz, CDCl3): 7.43 (d, 1H), 5.24 (bs, 2H), 4.82 (m, 1H), 4.56 (m, 1H), 4.33 (d, 1H), 3.99 (m, 1H), 3.86 (m, 1H), 3.73 (m, 1H), 3.59 (m, 2H), 2.18 (m, 1H), 3.01 (m, 1H), 1.67 (m, 1H), 1.44 (s, 9H), 1.40 (m, 3H), 1.25 (m, 1H), 1.20 (d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)=[CH:22][C:21]=2[Cl:34])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH2:45]Br.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([S:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[C:42]([Cl:41])[CH:43]=4)[CH:28]=3)=[CH:22][C:21]=2[Cl:34])[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(CCCc2ccc(Sc3cccc(O)c3)cc2Cl)COC(C)(C)OC1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(CCCc2ccc(Sc3cccc(OCc4cccc(Cl)c4)c3)cc2Cl)COC(C)(C)OC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Example 34 (500 mg) in DMF (10 mL), potassium carbonate (500 mg) and m-chlorobenzyl bromide (0.16 mL) were added and the mixture was stirred at 70° C. for 1 hour. The reaction mixture was then poured into water and was extracted with ethyl acetate. The organic phase was sequentially washed with water and a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the desired product (520 mg) as a colorless powder.
Reaction SMILES: [CH2:1]([N:8]1[C:24](=[O:25])[C:23]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15](CC4C=CC=CC=4)[C:14]=3[C:13]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:12][C:11]=2[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH2:1]([N:8]1[C:24](=[O:25])[C:23]2[C:22]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][C:14]=3[C:13]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:12][C:11]=2[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cc(-c3ccccc3)c3c(c2C(=O)N1Cc1ccccc1)c1ccccc1n3Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C1c2cc(-c3ccccc3)c3[nH]c4ccccc4c3c2C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
220 mg of N-benzyl-9-benzyl-1-phenylcarbazole-3,4-dicarboximide was dissolved in 30 ml of benzene. Thereto was added 240 mg of anhydrous aluminum chloride. The mixture was stirred at room temperature for 3 hours, washed with water and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 140 mg (yield: 78%) of N-benzyl-1-phenylcarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: S(Cl)([Cl:3])=O.C(O)(=O)C(O)=O.O[CH2:12][C@@H:13]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14]1.O>C(Cl)(Cl)Cl>[Cl:3][CH2:12][C@@H:13]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14]1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CO)c2c1
Agent: O=C(O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CCl)c2c1
Temperature: 60 °C

Procedure:
3.6 cm3 of thionyl chloride were added dropwise, at a temperature in the region of 20° C., to a stirred solution of 2.9 g of (3R,4R)-3-hydroxymethyl4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine oxalate in 20 cm3 of chloroform. The mixture was heated for 2 hours at a temperature in the region of 60° C. and then, after cooling, was poured onto 50 cm3 of water to which 250 g of ice had been added. After separating by settling from the chloroform phase, the mixture was extracted with 100 cm3 of dichloromethane. 5 g of sodium hydrogencarbonate were added to the aqueous phase, which was then extracted with 2 times 200 cm3 of dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40°. 1.3 g of (3R,4R)-3-chloromethyl-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine were obtained in the form of an oil with a brown color.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.[CH3:18][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:9]([OH:10])[CH3:18])[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 93.9 %

Procedure:
In THF, dissolved was 3-(cyclopropylmethoxy)-4-(difluoromethoxy)benzaldehyde (24 g, 99 mmol), and 3M CH3MgBr (49 ml, 148 mmol) was added thereto at −78° C. The reaction mixture was neutralized with NH4Cl, and extracted with EA. The extract was washed twice with brine, dried over MgSO4, filtered and evaporated under reduced pressure to remove solvent. The mixture was purified via column chromatography (n-hexane/EA=1/1) to obtain 1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]ethanol (24 g, 94%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:32](OC(=O)C)=[O:33]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:30])[CH3:29])[C:18]2=[O:31])[CH2:13][CH2:14][N:15]([CH:32]=[O:33])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc([C@@H](CCNO)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reactant: CC(=O)OC=O
Solvent: ClCCl
Product: CCOc1cc([C@@H](CCN(O)C=O)N2C(=O)c3cccc(NC(C)=O)c3C2=O)ccc1OC
Reaction time: 1 h
Yield: 24.1 %

Procedure:
To a solution of (1R)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide (350 mg, 0.82 mmol) in methylene chloride (3 mL) was added a solution of acetyl formate (84 mg) in methylene chloride (1 mL) at 0° C. After 1 h, the mixture was extracted with ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with brine (20 mL) and dried over MgSO4. The solvent was removed in vacuo. The residue was purified with prep HPLC to give (1R)—N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl}-acetamide as a white solid (90 mg, 24% yield): mp: 96-98° C.; 1H NMR (CDCl3) δ 1.46 (t, J=7 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 2.81-2.83 (m, 2H, CH2), 3.56 (t, J=6 Hz, 2H, CH2), 3.85 (s, 3H, CH3), 4.10 (q, J=7 Hz, 2H, CH2), 5.25 (t, J=8 Hz, 1H, NCH), 6.82 (d, J=8 Hz, 1H, Ar), 7.06-7.09 (m, 2H, Ar), 7.45 (d, J=8 Hz, 1H, Ar), 7.64 (t, J=8 Hz, 1H, Ar), 7.72 (s, 1H, CH), 8.75 (d, J=8 Hz, 1H, Ar), 9.49 (s, 1H, NH); 13C NMR (CDCl3) δ 14.73, 24.95, 28.35, 46.61, 51.92, 55.93, 64.46, 111.37, 112.79, 115.21, 118.05, 120.63, 124.90, 130.33, 131.09, 136.02, 137.47, 148.48, 149.40, 155.73, 167.72, 169.27, 170.07; Anal Calcd for C23H25N3O7+0.3 H2O: C, 59.95; H, 5.60; N, 9.12; H2O, 1.17. Found: C, 59.94; H, 5.59; N, 8.98; H2O, 1.22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:39])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:35])([CH3:34])[C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[O:42]=[S:43]1(=[O:55])[CH2:48][CH2:47][CH:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:45][CH2:44]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:39])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:52]3[CH2:53][CH2:54][N:49]([CH:46]4[CH2:45][CH2:44][S:43](=[O:42])(=[O:55])[CH2:48][CH2:47]4)[CH2:50][CH2:51]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:35])([CH3:34])[C:31](=[O:33])[CH3:32])=[CH:26][C:25]=3[O:36][CH2:37][CH3:38])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C(C)=O)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[4-(1,1-dimethyl-2-oxo-propyl)-2-ethoxy-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride (example 22) to give the title product as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C40H49N4O5SCl2 [(M+H)+] 767.2795, observed 767.2790.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:50][CH2:51][CH3:52])[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]>C(O)(=O)C>[OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH2:50][CH2:51][CH3:52])[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:18][CH:19]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(CO)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 110.2 %

Procedure:
A solution of 0.28 g of ethyl 4-hydroxymethyl-2-propyl-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (b) above] in 4 ml of 75% v/v aqueous acetic acid was stirred at 60° C. for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was dissolved in toluene. The resulting solution was again concentrated by evaporation under reduced pressure, to remove as much water and acetic acid as possible. The residue was then purified by column chromatography through silica gel, using 9:1 and 4:1 by volume mixtures of methylene chloride and methanol as the eluent, to give 0.20 g of the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:7]=12.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21].CN(C)C(=O)C>C(OCC)(=O)C>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([NH:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:7]=12)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COC(=O)c1cc2ccnc(N)c2[nH]1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc2ccnc(NS(=O)(=O)c3cccs3)c2[nH]1
Yield: 1.5 %

Procedure:
A mixed solution of methyl 7-amino-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.40 g), thiophene-2-sulfonyl chloride (0.48 g) and N,N-dimethylacetamide (20 ml) was stirred at 120° C. for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-1:1) to give the title compound (10.5 mg, yield 1.5%) as pale-yellow crystals. melting point 159-160° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.[O:11]1[C:15]2([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[O:14][CH2:13][CH2:12]1>>[F:10][C:4]1[CH:3]=[C:2]([C:18]2([OH:21])[CH2:19][CH2:20][C:15]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:16][CH2:17]2)[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(Br)cc1F
Reactant: O=C1CCC2(CC1)OCCO2
Product: COc1ccc(C2(O)CCC3(CC2)OCCO3)cc1F

Procedure:
The title compound was prepared as a white solid from 4-bromo-2-fluoro-anisole (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:4]=2[N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]=[C:31]([OH:34])[CH:30]=[CH:29]2>>[CH2:7]([N:6]1[C:5]2[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:4]=2[N:3]=[C:2]1[NH:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]=[C:31]([OH:34])[CH:30]=[CH:29]2)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc2ccc(O)cc12
Reactant: FC(F)(F)c1ccc2c(c1)nc(Cl)n2CCc1ccccc1
Product: Oc1ccc2cccc(Nc3nc4cc(C(F)(F)F)ccc4n3CCc3ccccc3)c2c1

Procedure:
The reaction of 2-chloro-1-phenethyl-5-(trifluoromethyl)-1H-benzo[d]imidazole from step (b) above (98 mg, 0.3 mol) with 8-amino-naphthalen-2-ol (64 mg, 0.2 mmol, Aldrich) under the condition of Example 21(b) afforded the title compound. MS (ESI, pos. ion) m/z: 448(M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3([CH2:20][NH2:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[S:12][CH:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:22][C:23]([F:39])([F:38])[C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=2)[C:32](O)=[O:33])[N:25]=1>>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]=[C:11]([C:14]3([CH2:20][NH:21][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([C:26]5[N:25]=[C:24]([C:23]([F:39])([F:38])[F:22])[O:28][N:27]=5)[CH:30]=4)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[S:12][CH:13]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3cc(F)cc(F)c3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3cc(F)cc(F)c3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 10 %

Procedure:
This compound was synthesized from (4-(4-(3,5-difluorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (20 mg, 10% yield). 1H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 8.24 (d, J=8.3 Hz, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.64-7.54 (m, 2H), 7.35 (d, J=5.5 Hz, 1H), 6.73 (m, 2H), 3.95 (m, 2H), 3.85 (d, J=5.5 Hz, 2H), 3.70 (m, 2H), 2.28 (m, 2H), 2.05 (m, 2H). MS (ESI) m/z: Calculated for C25H19F5N4O3S: 550.11. found: 551.1 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:32](=[O:40])[CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:7](=[O:31])[N:8]2[C:11](=[C:28]([CH3:30])[CH3:29])[C:12]([O:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[NH:5]1)([OH:3])=O.C(Cl)(=O)[C:42]([Cl:44])=O.[N+](=CC(C1OC2C(C(=O)CC3C=CC=CC=3)(C(=O)N2C(=C(C)C)C(OC(C2C=CC=CC=2)C2C=CC=CC=2)=O)N1)=O)=[N-].Cl>C1C=CC=CC=1.CN(C)C=O.CCOCC>[Cl:44][CH2:42][C:1]([CH:4]1[O:10][CH:9]2[C:6]([C:32](=[O:40])[CH2:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:7](=[O:31])[N:8]2[C:11](=[C:28]([CH3:30])[CH3:29])[C:12]([O:14][CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[NH:5]1)=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)O)OC12
Agent: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)C=[N+]=[N-])OC12
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(C)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)CCl)OC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a solution of 1.774 g of diphenylmethyl α-(3ξ-carboxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate dissolved in a mixture of 18 ml of benzene and 0.1 ml of N,N-dimethylformamide is added 0.43 ml of oxalyl chloride, and the mixture stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The residue (diphenylmethyl α-(3ξ-chlorocarbonyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate) is dissolved in 10 ml of methylene chloride and mixed with 15 ml of ether solution of diazomethane, which has been prepared from 1.5 g of nitrosomethylurea, under ice-cooling, and the mixture stirred for 30 minutes. To the resulting solution of diphenylmethyl α-(3ξ-diazoacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate is is added an ether solution of hydrogen chloride until the spot of diazoketone disappears, and the mixture concen rated under reduced pressure. The residue is purified by chromatography on 40 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 1.59 g of diphenylmethyl α-(3ξ-chloroacetyl-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 84.7% yield.
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[CH:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[H-].[Na+]>O>[CH:18]1([O:24][C:7]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=2[C:9]#[N:10])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: OC1CCCCC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])ccc1OC1CCCCC1
Reaction time: 1 h
Yield: 61 %

Procedure:
To dimethylformamide solution (35 ml) containing 2-chloro-5-nitrobenzonitrile (14.1 g) and cyclohexanol (8.5 g) was added sodium hydride (60% content, 3.7 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give 2-cyclohexyloxy-5-nitrobenzonitrile (11.6 g), melting point: 97–98° C.
Reaction SMILES: [O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C:23]2=[O:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123.[BH4-].[Na+].Cl>O1CCCC1.O>[O:1]1[C:24]2=[C:25]3[C@:20]([CH3:27])([CH2:21][CH2:22][C@@H:23]2[OH:26])[C@@H:19]2[C@H:4]([C@H:5]4[C@:16]([CH3:28])([CH2:17][CH2:18]2)[C@@H:8]([CH:9]([CH3:15])[CH:10]([O:13][CH3:14])[O:11][CH3:12])[CH2:7][CH2:6]4)[C@@H:3]2[O:29][C@:2]123
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CC[C@@H]4O)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of 0.402 g (1 mmole) of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3-one in 30 ml of tetrahydrofuran was added 38 mg (1 mmole) of sodium borohydride at a temperature of 0° C. and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was diluted with water and neutralized by adding cold 1N-hydrochloric acid in small portions. From this mixture, the tetrahydrofuran was distilled off under reduced pressure at a temperature not exceeding 20° C. and the residue was diluted with water and extracted with methylene chloride. The extract was washed with aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane =1:10, v/v) to recover 0.250 g of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy- 20-methylpregn-4-en-3β-ol (yield: 62%).