Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][S:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][CH:27]2[N:20]3[C:21]4[C:17]([CH:18]5[CH2:31][NH:30][CH2:29][CH2:28][CH:19]53)=[CH:16][C:15]([NH2:14])=[CH:23][C:22]=4[CH2:24][S:25][CH2:26]2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Product: Nc1cc2c3c(c1)C1CNCCC1N3C(Cc1ccc(F)cc1C(F)(F)F)CSC2

Procedure:
Using 4-fluoro-2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)Carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 154. 1H NMR (CDCl3) δ: 9.30 (broad s, 1H), 9.15 (broad s, 1H), 7.60-7.52 (m, 1H), 7.38-7.25 (m, 1H), 7.13 (broad t, 1H, J=8.0 Hz), 6.30-6.15 (broad m, 2H), 4.45-4.25 (broad m, 2H), 4.17-3.98 (broad m, 2H), 3.70-3.30 (m, 4H), 3.30-2.70 (broad m, 5H), 2.60-2.47 (m, 1H), 2.20-2.00 (m, 2H). LRMS (ES)+: 438.4 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[N:14]=[CH:13][CH:12]=[N:11][C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1.[CH2:15]([S:17]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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>[CH2:15]([S:17]([C:20]1[CH:25]=[C:24]([C:2]2[C:3]3[C:4]4[N:14]=[CH:13][CH:12]=[N:11][C:5]=4[NH:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:19])[CH3:16]
Reactant: CCS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Brc1cccc2[nH]c3nccnc3c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cccc3[nH]c4nccnc4c23)c1
Temperature: 150 °C
Yield: 68.2 %

Procedure:
Compound 80 (50 mg, 0.2 mmol), 3-ethanesulfonyl-phenylboronic acid (65 mg, 0.3 mmol), tetrakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol), and potassium carbonate (83 mg, 0.6 mmol), were combined in dioxane (2 mL) and H2O (0.2 mL) in a sealed tube under nitrogen. The reaction was heated at 150° C. in the microwave for 20 min and then concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/CH2Cl2) gave 46 mg (68%) of the title compound as a light orange solid. 1H NMR (400 MHz, CH3OD) δ 8.42 (t, 1H, J=2.8 Hz), 8.31 (d, 1H, J=2.8 Hz), 8.24 (d, 1H, J=2.8 Hz), 8.06 (d, 1H, J=7.6 Hz), 7.96 (d, 1H, J=7.6 Hz), 7.60-7.75 (m, 3H), 7.31 (dd, 1H, J=7.2, 1.2 Hz), 3.33 (q, 2H, J=7.2 Hz), 1.37 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C18H15N3O2S, 338; found 338.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([O:18]COC)=[C:15]([O:22][CH3:23])[CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O>CC(C)=O>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[C:16]([OH:18])=[C:15]([O:22][CH3:23])[CH:14]=[CH:13]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1c(OC)ccc2cccc(Cc3ccccc3)c12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc2cccc(Cc3ccccc3)c2c1O
Reaction time: 1.5 h
Yield: 74.8 %

Procedure:
79.5 g of 8-benzyl-2-methoxy-1-methoxymethoxynaphthalene was dissolved in 300 ml of acetone to give a solution. 120 ml of 6N hydrochloric acid was added to the solution at room temperature. The obtained mixture was stirred for 1.5 hours, followed by the addition of 400 ml of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent. The obtained solid was washed with hexane/diisopropyl ether (1:1) to give 51 g of the title compound as a colorless crystal.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([CH3:22])[C:12]([O:14][C:15]3([CH3:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.N[C:24]1[CH:29]=CC(C(C)C(OC23CC4CC(CC(C4)C2)C3)=O)=C[CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH:11]([CH3:22])[C:12]([O:14][C:15]34[CH2:21][CH:24]5[CH2:29][CH:19]([CH2:18][CH:17]([CH2:25]5)[CH2:16]3)[CH2:20]4)=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C(=O)OC1(C)CCCCC1)c1ccc2nc(N)sc2c1
Reactant: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc(N)cc1
Product: CC(C(=O)OC12CC3CC(CC(C3)C1)C2)c1ccc2nc(N)sc2c1
Yield: 83 %

Procedure:
Using the methpod similar to that used in the preparation of 1-methylcyclohexyl 2-amino-α-methylbenzothiazole-6-acetate, 19.1 g of 1-adamantyl 2-(p-aminophenyl)propionate were reacted to obtain 18.97 g (83% yield) of 1-adamantyl 2-amino-α-methylbenzothiazole-6-acetate as a creamy white solid melting at 151°-153° C.
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[N:13]=[C:14]([NH:18][CH2:19][CH3:20])[N:15]=[C:16]([CH3:17])[C:11]=3[CH:10]=[CH:9][C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br>CC(O)=O.C(Cl)Cl>[Br:22][C:9]1[C:8](=[O:21])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]2[N:13]=[C:14]([NH:18][CH2:19][CH3:20])[N:15]=[C:16]([CH3:17])[C:11]=2[CH:10]=1
Reactant: BrBr
Reactant: CCNc1nc(C)c2ccc(=O)n(C3CCCCC3)c2n1
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNc1nc(C)c2cc(Br)c(=O)n(C3CCCCC3)c2n1
Yield: 80 %

Procedure:
To 8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one in AcOH and CH2Cl2 was added Br2 (22 uL, 0.42 mmol) at 80° C. Standard workup and purification by column chromatography gave 65 mg (0.17 mmol, 80% yield) of 6-bromo-8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11](=[N+]=[N-])[C:12](=[O:19])[CH2:13][CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C([O-])(=O)C.[Rh+2].C([O-])(=O)C.C1C=CC=CC=1>[N:17]12[C:16](=[O:18])[CH2:15][CH:14]1[CH2:13][C:12](=[O:19])[CH:11]2[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: [N-]=[N+]=C(C(=O)CC1CC(=O)N1)C(=O)OCc1ccccc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Temperature: 80 °C
Yield: 77.5 %

Procedure:
A mixture of 4-(3-benzyloxycarbonyl-3-diazo-2-oxopropyl)-azetidin-2-one (718 mg. 2.5 mMol), rhodium (II) acetate (5 mg) and anhydrous benzene (50 ml) is deoxygenated by bubbling nitrogen through it for 45 minutes. The mixture is then stirred and heated in an oil bath maintained at 80° C. for 70 minutes. After cooling to room temperature, the mixture is filtered and the filtrate is evaporated under vacuum to an oil. Crystallization from ethyl acetate (5 ml)-diethylether (20 ml) provides benzyl 1-azabicyclo[3.2.0]heptan-3,7-dione-2-carboxylate (502 mg, 77% yield) as small, white prisms: mp 100°-102°; IR (CH2 Cl2) 1770; 1741 cm-1 ; UV (dioxane) 220 nm; NMR (CDCl3, 300 MHz) α2.43 (dd, 1, J=8 and 19, H4a), 2.94 (dd, 1, J=6.5 and 19, H4b), 2.99 (dd, 1, J=2 and 16, H6B), 3.63 (dd, 1, J=5 and 16, H6α), 4.18 (m, 1, H5), 4.76 (S, 1, H2), 5.23 (S, 2, CH2 φ), and 7.40 (S, 5, ArH); MS m/e 259 (M+), 231 (M+-28), 217 (M+-42), 203, 187, 186, 168 (M+-91), 124, and 91.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[O:18])[N:12]([CH3:17])[CH2:13][CH2:14][C:15](=O)[C:9]=2[CH:8]=[CH:7]1.C([O-])(=O)C.[Na+].Cl.[CH2:25]([O:32][NH2:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([O:32][N:33]=[C:15]1[CH2:14][CH2:13][N:12]([CH3:17])[C:11](=[O:18])[C:10]2[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[CH:7]=[CH:8][C:9]1=2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN1CCC(=O)c2ccn(CCCCCl)c2C1=O
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CCC(=NOCc2ccccc2)c2ccn(CCCCCl)c2C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 13.44 g (50 mmol) of Compound 23 obtained in Example 14, 8.20 g (100 mmol) of sodium acetate and 15.96 g (100 mmol) of O-benzylhydroxylamine hydrochloride in 250 ml of methanol was stirred for 4 hours at room temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][CH2:12][OH:13])=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.N1C=CC=CC=1>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([O:13][CH2:12][CH2:11][S:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=2)=[O:20])=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(SCCO)nc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCSc1ccc([N+](=O)[O-])cn1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A homogeneous mixture of 2-[(5-nitro-2-pyridinyl)thio]ethanol (7) (45 mg, 0.22 mmol), 4-chlorobenzoyl chloride (33 μL, 0.26 mmol) and pyridine (45 μL, 0.56 mmol) in anhydrous dichloromethane (1.5 mL) was stirred at room temperature for 48 h. The reaction mixture was quenched with 1N HCl and the organic phase was washed with saturated aqueous solution of NaHCO3, brine and then dried over anhydrous MgSO4. The crude product was purified by silica gel chromatography to give 2-[(5-nitro-2-pyridinyl)thio]ethyl 4-chlorobenzoate (8). LCMS: purity: 90%; MS (m/e): 340 (M+)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[CH:21][C:22]([F:37])=[C:23]([NH:25][S:26]([C:29]3[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=3[F:36])(=[O:28])=[O:27])[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)(=[O:41])=[O:40]>C1COCC1>[F:36][C:30]1[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=1[S:26]([NH:25][C:23]1[CH:24]=[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:48][CH:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:7]=2)[CH:20]=[CH:21][C:22]=1[F:37])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: O=S(=O)(Nc1cc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)ccc1F)c1cc(F)ccc1F
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCC(Nc2nccc(-c3sc(C4CCOCC4)nc3-c3ccc(F)c(NS(=O)(=O)c4cc(F)ccc4F)c3)n2)CC1

Procedure:
Following a procedure analogous to the procedure described in Example 1 using N-{5-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (120 mg, 0.212 mmol) and 1-(methylsulfonyl)-4-piperidinamine (377 mg, 2.12 mmol) in THF (1 mL) the title compound was obtained as a light yellow solid (89 mg, 0.12 mmol, 59% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1H), 8.14 (d, J=4.9 Hz, 1H), 7.46-7.73 (m, 3H), 7.34-7.45 (m, 3H), 7.22-7.34 (m, 1H), 5.99-6.51 (m, 1H), 3.95 (dd, J=11.4, 2.0 Hz, 2H), 3.41-3.58 (m, 4H), 3.18-3.33 (m, 1H), 2.69-2.93 (m, 5H), 1.81-2.06 (m, 5H), 1.66-1.81 (m, 2H), 1.42-1.65 (m, 2H). MS (ESI): 709.18 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:15]([NH2:16])[C@@H:14]2[CH2:17][C@H:11]1[CH2:12][CH2:13]2.[N:19]1([S:24]([C:27]2[S:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:15]([NH:16][C:32]([C:30]2[S:31][C:27]([S:24]([N:19]3[CH:23]=[CH:22][CH:21]=[CH:20]3)(=[O:26])=[O:25])=[CH:28][CH:29]=2)=[O:33])[C@@H:14]2[CH2:17][C@H:11]1[CH2:12][CH2:13]2
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cccc2)s1
Reactant: COC(=O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CCC/C=C\C[C@H]1[C@@H]2CC[C@@H](C2)[C@@H]1NC(=O)c1ccc(S(=O)(=O)n2cccc2)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 251 mg (1.0 mmol) of (5Z)-7-[(1R,2S,3S,4S)-3-aminobicyclo[2.2.1]hept-2-yl]-5-heptenoic acid methyl ester (1) in 4 ml of tetrahydrofuran were added 257 mg (1.0 mmol) of 5 -(pyrrol-1-ylsulfonyl)thiophen-2-carboxylic acid and 13.5 mg (0.1 mmol) of 1-hydroxybenzotriazole. Under ice-cooling, 186 mg (1.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide was added thereto. The mixture was warmed to room temperature and stirred at 25° C. for 16 h. The mixture was diluted with water and extracted with toluene. The organic layer was washed with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel (toluene/ethyl acetate=6:1) to give 412 mg of (5Z)-7-{(1R,2S,3S,4S)-3-[5-(pyrrol-1-ylsulfonyl)-thiophen-2-ylcarbonylamino]-bicyclo[2.2.1]hept-2-yl}-5-heptenoic acid methyl ester (I-la). Yield 83.9%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH2:18][CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:37]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH:38]([CH3:40])[CH3:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:44]2[CH2:45][CH2:46][N:41]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]2)=[O:15])=[CH:11][C:10]=1[CH2:18][CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccccc1
Reactant: CC(C)CN1CCNCC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccccc1
Reaction time: 0.67 h
Yield: 100.2 %

Procedure:
4-benzyloxy-3-isobutylbenzoic acid (4.94 g) was dissolved in a mixture of chloroform (60 ml) and triethylamine (4.83 ml). To this mixture, diphenylphosphinic chloride (3.66 ml) was added while being cooled with ice. After being stirred for 40 minutes, the mixture, with 1-isobutylpiperazine (2.48 g) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained residue was purified by silica gel column chromatography (chloroform: methanol=50:1), thereby yielding 7.11 g of the aimed compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([Br:15])=[CH:9][CH:8]=3.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH:30]2[CH2:32][O:31]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[H-].[Na+]>>[C:16]([O:20][C:21]([N:23]1[CH2:24][CH2:25][N:26]([CH2:29][CH:30]([OH:31])[CH2:32][N:6]2[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[C:10]([Br:15])[CH:11]=3)[CH2:27][CH2:28]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Reactant: Brc1ccc2[nH]c3ccc(Br)cc3c2c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(CC(O)Cn2c3ccc(Br)cc3c3cc(Br)ccc32)CC1
Yield: 72 %

Procedure:
The same method as employed in the preparation of Example 1 but starting from 3,6-dibromo-9H-carbazole, (±)-4-oxiranylmethyl-piperazine-1-carboxylic acid tert-butyl ester and sodium hydride gives after flash chromatography the title compound as a white foam in a 72% yield. M.p: 90-95° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1>CS(C)=O.O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 533.4 %

Procedure:
Piperidine (362 mg, 0.2 mmol) was added to a solution of 1-fluoro-4-nitro-benzene (200 mg, 1.4 mmol) in DMSO (10 mL) and the mixture was stirred at 80° C. for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated to afford 220 mg (75%) of 1-(4-nitro-phenyl)-piperidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@@:9]1([CH3:16])[C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH2:25][C:26]1[CH:30]=[C:29]([Br:31])[S:28][C:27]=1[C:32]([NH2:34])=[O:33].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[Br:31][C:29]1[S:28][C:27]2[C:32](=[O:33])[NH:34][C:10]([C:9]3([CH3:16])[CH2:13][CH2:14][CH2:15][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:25][C:26]=2[CH:30]=1
Reactant: NC(=O)c1sc(Br)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC[C@@]1(C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1(C)c1nc2cc(Br)sc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)-2-methylproline (425 mg), triethylamine (0.425 ml) and tetrahydrofuran (10 mL) was added 2-methylpropyl chlorocarbonate (0.2 mL) with stirring at room temperature. After 1 hr, 3-amino-5-bromothiophene-2-carboxamide (337 mg) produced in Example 1, step D, was added, and the mixture was stirred at 60° C. overnight. Thereafter, the mixture was stirred in a microwave reactor at 120° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (5 mL), 2M aqueous sodium hydroxide solution (2.04 mL) was added, and the mixture was stirred at 60° C. for 1 hr and at 80° C. for 1 hr. Ethanol (4 mL) was added to the reaction mixture, and the mixture was stirred at 100° C. for 4 hr. The reaction mixture was allowed to cool to room temperature, and poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate/tetrahydrofuran mixture. The extract was dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/hexane and methanol/ethyl acetate) to give the title compound (109 mg) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37])([O-:33])=[O:32]>ClCCl>[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1)=[O:37])([O-:33])=[O:32]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 110 h

Procedure:
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (250 mg, 809 μmol) in dichloromethane (15 mL) was added triethylamine (250 μL, 1.78 mmol) and 2-nitrobenzoyl chloride (240 μL, 1.78 mmol). The solution was stirred at room temperature for 110 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.23 min, MH+ 459].
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Cl)cc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of 4-chlorophenol and 20 ml of dry dimethylformamide. is stirred at room temperature for 21 hours, then poured into 60 ml of water and extracted four times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained p-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 241°-242°.
Reaction SMILES: [CH2:1]1[CH:5]2[C@@H:6]3C=C[C@H]([CH:4]2C=[CH:2]1)C3.[CH2:11]([O:15][C:16](=[O:19])[CH:17]=[CH2:18])[CH2:12][CH2:13][CH3:14].C1(C=CC(O)=CC=1)O>>[CH2:11]([O:15][C:16]([CH:17]1[CH2:4][CH:5]2[CH2:6][CH:18]1[CH:2]=[CH:1]2)=[O:19])[CH2:12][CH2:13][CH3:14]
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reactant: C=CC(=O)OCCCC
Agent: Oc1ccc(O)cc1
Product: CCCCOC(=O)C1CC2C=CC1C2
Temperature: 190 °C
Yield: 78 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 180 mL, 1.34 mol), butylacrylate (Junsei, 500 mL, 3.49 mol) and hydroquinone (2.7 g, 0.025 mol) were charged into a 2 L high-pressure autoclave, and the temperature was raised to 190° C. The resulting mixture was reacted for 5 hours with stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled and transferred to a distilling apparatus. The reaction mixture was distilled under a reduced pressure (1 torr) using a vacuum pump to yield the title compound at 80° C. (yield: 78%, exo/endo=55/45).
Reaction SMILES: C([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([O-:16])=[O:15])(OC(C)(C)C)=O.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]>C(Cl)Cl>[F:20][C:19]([F:22])([F:21])[C:17]([OH:23])=[O:18].[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([O:16][CH2:17][CH3:19])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@H]1CCC[C@H]1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-2-(Boc-amino)cyclopentanecarboxylate (CAS: 1140972-29-7, TCI) (1 mmol) was dissolved in CH2Cl2 (3 mL) followed by the slow addition of TFA (1 mL) at 0° C. The reaction mixture was stirred at rt for 1 hour and then the solvent was removed under vacuum to give the crude product 50-B, which was used directly in the next step.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)(=O)C>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:17]([CH2:23][CH3:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: CCOC(=O)C(Br)CC
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (18.3 g, 0.150 mol) was dissolved in N,N-dimethylformamide (150 mL). Subsequently, potassium carbonate (22.80 g, 0.165 mol), and then ethyl 2-bromobutyrate (29.26 g, 0.150 mol) were added thereto, and the resultant mixture was stirred overnight at 80° C. The temperature of the reaction mixture was returned to room temperature. Ethyl acetate was added. Washing was performed sequentially with water and brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=5/1), whereby a colorless oil was obtained (35.29 g, 0.149 mol, 99.6%).