Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH2:18][C:17]([CH3:20])=[CH:16]3)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.C([Cu])#N.Cl[Si:30]([CH:33]1[C:41]2[C:36](=[C:37]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:38]([O:45][C:46]3[C:51]([F:52])=[C:50]([F:53])[C:49]([F:54])=[C:48]([F:55])[C:47]=3[F:56])=[C:39]([CH:42]([CH3:44])[CH3:43])[CH:40]=2)[CH:35]=[C:34]1[CH3:63])([CH3:32])[CH3:31]>CCOCC.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:19]=2[CH:18]=[C:17]([CH3:20])[CH:16]3[Si:30]([CH:33]2[C:41]3[C:36](=[C:37]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:38]([O:45][C:46]4[C:51]([F:52])=[C:50]([F:53])[C:49]([F:54])=[C:48]([F:55])[C:47]=4[F:56])=[C:39]([CH:42]([CH3:44])[CH3:43])[CH:40]=3)[CH:35]=[C:34]2[CH3:63])([CH3:31])[CH3:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1=Cc2c(cc(C(C)C)c(Oc3c(F)c(F)c(F)c(F)c3F)c2-c2ccccc2)C1[Si](C)(C)Cl
Reactant: CC1=Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Agent: N#C[Cu]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC1=Cc2c(-c3ccc(C(C)(C)C)cc3)cccc2C1[Si](C)(C)C1C(C)=Cc2c1cc(C(C)C)c(Oc1c(F)c(F)c(F)c(F)c1F)c2-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
To a solution of 6.39 g (24.4 mmol) of 7-(4-tert-butylphenyl)-2-methyl-1H-indene in 200 ml of ether 9.80 ml (24.5 mmol) of 2.5 M nBuLi in hexanes was added in one portion at −40° C. This mixture was stirred overnight at room temperature, then cooled to −40° C., and 150 mg of CuCN was added. The resulting mixture was stirred for 1 h at −20° C., then cooled to −40° C., and a solution of 10.5 g (20.0 mmol) of chloro[6-isopropyl-2-methyl-5-(pentafluorophenoxy)-4-phenyl-1H-inden-1-yl]dimethylsilane in 200 ml of ether was added in one portion. Further on, this mixture was stirred overnight at ambient temperature, then 0.5 ml of water was added. This solution was filtered through a pad of silica gel 60 (40-63 um) which was then additionally washed by 2×75 ml of dichloromethane. The combined organic elute was evaporated to dryness, and the residue was dried in vacuum. The product was isolated by flash-chromatography on silica gel 60 (40-63 um; eluent: hexanes-dichloromethane=10:1, vol., then 5:1, vol.). This procedure gave 7.86 g (53%) of the title product (of ca. 90% purity as a ca. 1:1 mixture of the stereoisomers on the evidence of NMR spectroscopy) as a yellowish glass.
Reaction SMILES: [NH2:1][NH2:2].[CH:3]1([C:6](=O)[CH2:7][CH:8]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:16][CH2:15]2)[C:9](OCC)=[O:10])[CH2:5][CH2:4]1>C(O)(=O)C>[CH:3]1([C:6]2[CH2:7][CH:8]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[CH2:16][CH2:15]3)[C:9](=[O:10])[NH:1][N:2]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C(CC(=O)C1CC1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Solvent: CC(=O)O
Product: O=C1NN=C(C2CC2)CC1C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hydrazine (0.3 mL, 9.6 mmol) was added to a solution of benzyl 4-[3-cyclopropyl-1-(ethoxycarbonyl)-3-oxopropyl]piperidine-1-carboxylate (186 mg, 0.48 mmol) in acetic acid (7 mL). The reaction mixture was heated at 50° C. After 1 h, the reaction mixture was concentrated. The residue was diluted with dichloromethane and neutralized by saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound. MS 356.2 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3](OCC)([O:38]CC)[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3](=[O:38])[C:4](=[N:35][O:36][CH3:37])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([OH:19])=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)C(CBr)(OCC)OCC)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)C(=O)CBr)[C@H]2SC1
Yield: 74.1 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3,3-diethoxy-2-methoxyiminobutyramido)-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.36 g) and anisole (2.1 g) in methylene chloride (20 ml) was added trifluoroacetic acid (8.0 g) under ice-cooling with stirring, and the stirring was continued at ambient temperature for an hour. After removal of the solvent, the residue was dissolved in a mixture of ethyl acetate and water. To the separated ethyl acetate solution was added water, followed by adjusting to pH 7 with a saturated aqueous sodium bicarbonate. To the separated aqueous solution was added ethyl acetate, followed by adjusting to pH 2 with 10% hydrochloric acid. The ethyl acetate layer was separated out, washed with an aqueous sodium chloride and then dried over anhydrous magnesium sulfate. Removal of the solvent gave 7-(4-bromo-2-methoxyiminoacetoacetamido)-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N:14]([CH3:20])[C:15](=O)[O:16]CC)=[CH:4][CH:3]=1.[O-]CC.[Na+].[Na]>C(O)C.O>[NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][C:15](=[O:16])[N:14]([CH3:20])[C:8]=23)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N(C)c1c(Oc2ccc(N)cc2)ccnc1N
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Cn1c(=O)[nH]c2nccc(Oc3ccc(N)cc3)c21
Temperature: 100 °C
Yield: 33.8 %

Procedure:
Ethyl 4-(4-aminophenoxy)-2-aminopyridin-3-yl-methyl-carbamate (180 mg, 0.6 mmol) was suspended in a solution of sodium ethoxide in ethanol, obtained from dissolving sodium (480 mg, 21 mmol) in ethanol (9 ml). The suspension was heated under microwave irradiation for 40 minutes (100° C., 150 W). The mixture was cooled at room temperature, diluted with water and evaporated. The residue was triturated with acetone, and the washings discarded. The solid was dissolved in water and the insoluble solid was filtered off. The filtrate was acidified with HCl 1 M to pH 1, then brought to pH 10 with saturated aqueous Na2CO3. The precipitate formed was recovered by filtration, to afford the title compound (52 mg, 34%). 1H-NMR (δ, ppm, DMSO-d6): 3.49 (s, 3H, CH3N), 5.11 (s, 2H, NH2), 6.29 (d, 1H, HPy,6, J=6.0 Hz), 6.63 (d, 2H, Harom,Ph,3+5, J=8.69 Hz), 6.90 (d, 2H, Harom,Ph,2+6, J=8.73 Hz), 7.74 (d, 1H, HPy,6, J=5.96 Hz), 11.53 (s, 1H, NHPy2). LC-MS (m/z): 257 (M+H, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][C:33]([CH3:38])([CH3:37])[C:34]([OH:36])=O)=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:40])[CH3:39])=[CH:4][CH:3]=1.Cl.C[N:44](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O.C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:41])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4=[CH:24][CH:25]=[CH:26][NH:27][C:22]4=[CH:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][C:33]([CH3:37])([CH3:38])[C:34]([NH2:44])=[O:36])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:40])[CH3:39])=[CH:4][CH:3]=1
Reactant: CC(C)(Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)c1cccnc1CO2)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)(C)C1)C1=CC=CNC1=CO2)C(N)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 30.5 %

Procedure:
To a solution of 2-(5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yloxy)-2-methyl-propionic acid (72 mg, 0.125 mmol) in dimethyl formamide (3 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (48 mg, 0.25 mmol), 1-hydroxybenzotriazole (34 mg, 0.25 mmol), and ammonium hydroxide (170 μL, 0.50 mmol) and triethylamine (100 μL). Stir at rt 48 h. The mixture was poured into chloroform and washed with water. The organic phase was washed with additional water and brine; dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride—90:10 methylene chloride/methanol gradient) to yield the titled compound (22 mg, 31%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.O.[CH:16](O)=O>C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]1
Reactant: OC1(c2cccc(F)c2F)CCNC1
Reactant: O=CO
Agent: C=O
Solvent: O
Product: CN1CCC(O)(c2cccc(F)c2F)C1
Reaction time: 5 h

Procedure:
Preparation according to Example 11: Enantiomer E2 of 3-(2,3-difluorophenyl)pyrrolidin-3-ol (0.5 g, 2.5 mmol) in formic acid (7.2 mL) and aqueous formaldehyde (40%, 6.5 mL). 65° C. for 5 h. Water was added (50 mL), and the mixture was washed with diethyl ether. The water phase was basified with NaOH (5 M), extracted with ethyl acetate, dried (MgSO4) and evaporated. The crude compound was again treated with the same amount of formic acid and aqueous formaldehyde as above for 5 h. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 4:1 to 2:1). Yield: 0.7 g. [α]D=−21.5° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether: M.p. 134.3° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 20), 58 (27), 141 (16), 127 (11), 57 (bp).
Reaction SMILES: Cl[C:2]1[C:13]2[NH:12][CH:11]=[N:10][C:9]=2[C:8]2[CH2:7][C@:6]34[CH2:24][C@H:16]([C:17](=[O:23])[C:18]([C:19]([F:22])([F:21])[F:20])=[C:5]3[C:4]=2[CH:3]=1)[CH2:15][CH2:14]4.C1C=CC=CC=1.CO>CN(C=O)C.[OH-].[OH-].[Pd+2].[Pd]>[F:21][C:19]([F:20])([F:22])[C:18]1[C:17](=[O:23])[C@H:16]2[CH2:24][C@:6]3([CH2:7][C:8]4[C:9]5[N:10]=[CH:11][NH:12][C:13]=5[CH:2]=[CH:3][C:4]=4[C:5]=13)[CH2:14][CH2:15]2
Reactant: O=C1C(C(F)(F)F)=C2c3cc(Cl)c4[nH]cnc4c3C[C@@]23CC[C@@H]1C3
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C1C(C(F)(F)F)=C2c3ccc4[nH]cnc4c3C[C@@]23CC[C@@H]1C3
Reaction time: 16 h

Procedure:
To a solution of (8R,10aS)-4-chloro-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d]imidazol-7(8H)-one (58 mg, 0.16 mmol) in DMF (5.8 mL) were added 20% Pd(OH)2 on carbon (27 mg) and 5% palladium on calcium carbonate (29 mg) and the mixture was hydrogenated at atmospheric pressure. After 16 hours, additional 20% Pd(OH)2 on carbon (12 mg) and 5% palladium on calcium carbonate (12 mg) were added. After another 3.5 hours, additional 20% Pd(OH)2 on carbon (5 mg) and 5% palladium on calcium carbonate (5 mg) were added. After 66 hours more, the mixture was filtered through a pad of Celite®, washing thoroughly with EtOAc. The filtrate was partitioned between EtOAc and water which had been acidified with a small amount of 1N hydrochloric acid. The aqueous layer was neutralized with 5% aqueous sodium bicarbonate and was then thoroughly extracted with EtOAc. After drying over MgSO4, the solvent was removed under reduced pressure to give a gum. Chromatography on silica gel (elution with 5% methanol in dichloromethane) gave a yellow oil which was lyophilized from benzene containing a small amount of methanol to provide (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d]imidazol-7(8H)-one as a yellow solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:14]([CH3:13])(=[O:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCc1ccccc1
Yield: 102.4 %

Procedure:
Operating analogously to example 19 using 5-phenylpentanol (7.18 ml, 7 g, 42.6 mmoles) in methylene chloride (8 ml) and methyl-sulfonyl chloride (3.63 ml, 5.37 g, 46.9 mmoles) in methylene chloride (4 ml), and also using triethylamine (6.82 ml, 4.96 g, 49 mmoles) to adjust the pH after the addition of methyl-sulfonyl chloride, 10.57 g of the title product were obtained after half an hour of reaction (stoichiometric yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][C@H:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[CH3:22])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1Oc1cncc(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2Oc2cncc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-[(5-fluoropyridin-3-yl)oxy]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 3 of Example 5): 1H-NMR (CDCl3) δ 8.33 (1H, d, J=2.3 Hz), 8.23 (1H, d, J=2.3 Hz), 8.11 (1H, d, J=2.7 Hz), 7.95 (2H, d, J=8.2 Hz), 7.45 (1H, dd, J=8.7, 2.8 Hz), 7.38–7.25 (1H, m), 7.30 (2H, d, J=8.2 Hz), 6.95 (1H, td, J=8.9, 2.3 Hz), 6.91 (1H, d, J=8.7 Hz), 5.38–5.25 (1H, m), 3.90 (3H, s), 1.50 (3H, d, J=6.9 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31]>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[O:31])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ccccn1
Product: C[C@@]1(c2cc(NC(=O)c3ccccn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=329.0 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:32])O[C:20](=[O:31])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:9]1)(=[O:3])[CH3:2].C[Si](C)(C)[NH:35][Si](C)(C)C.CO>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[C:18](=[O:32])[NH:35][C:20](=[O:31])[C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N+:28]([O-:30])=[O:29])=[CH:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)OC2=O)c2ccccc21
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(=O)OCCCn1cc(C2=C(c3ccccc3[N+](=O)[O-])C(=O)NC2=O)c2ccccc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
A solution of 0.411 g of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)furan-2,5-dione in 50 ml of chloroform was treated with a mixture of 1.53 g of 1,1,1,3,3,3-hexamethyldisilazane and 0.3 g of methanol and the mixture was heated at 60° C. for 1 hour. A further 1.53 g of hexamethyldisilazane and a further 0.3 g of methanol were added and the heating was continued overnight before adding further 1.53 g of hexamethyldisilazane and 0.3 g of methanol. The mixture was heated for a further 1 hour. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 5% methanol in dichloromethane to give 130 mg of 3-[1-(3-acetoxypropyl)-3-indolyl]-4-(2-nitrophenyl)-1H-pyrrole-2,5-dione, m.p. 77°-78° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[Cl:23][CH2:24][CH2:25][CH:26]1[O:30][C:29](=[O:31])[N:28]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:27]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].Cl>C(O)CCC>[ClH:23].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH:26]3[O:30][C:29](=[O:31])[N:28]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:27]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: O=C1OC(CCCl)CN1c1ccccc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: O=C1OC(CCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)CN1c1ccccc1
Yield: 79.4 %

Procedure:
This compound was prepared according to the procedure of Example 1. A mixture of 4.6 g (0.015 mole) of α,α-bis-(p-fluorophenyl)-4-piperidinemethanol, 3.4 g (0.015 mole) of 5-(2-chloroethyl)-3-phenyl-2oxazolidinone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was converted to the hydrochloride and the solid was recrystallized from absolute ethanol to yield 6.3 g (30%) of white solid, m.p. 148°-156° C., with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:23]([C:27]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[S:45](=[O:48])(=[O:47])[NH2:46])=[CH:35][CH:34]=2)=[C:30]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:29]([C:54]2[CH:59]=[C:58]([N+:60]([O-:62])=[O:61])[CH:57]=[CH:56][C:55]=2[Cl:63])[N:28]=1)[CH2:24][CH2:25][CH3:26].N12CCCN=C1CCCCC2>C1COCC1>[CH2:23]([C:27]1[C:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[S:45](=[O:48])(=[O:47])[NH:46][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:35][CH:34]=2)=[C:30]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[N:29]([C:54]2[CH:59]=[C:58]([N+:60]([O-:62])=[O:61])[CH:57]=[CH:56][C:55]=2[Cl:63])[N:28]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 47.8 %

Procedure:
A mixture of 675 mg (4.28 mmol) of 2-chlorobenzoic acid, 695 mg (4.28 mmol) of 1,1'-carbonyldiimidazole (CDI), and 2 mL of dry THF was stirred at 50° C. under N2 for 3 hours. Then a solution of 851 mg (1.43 mmol) of ethyl 3-n-butyl-1-(2-chloro-5-nitrophenyl)-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-1H-pyrazole-5-carboxylate (from Step G) and 640 μL (651 mg, 4.28 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU) in 5 mL of dry THF was added, and stirring under N2 at 50° C. was continued overnight. The cooled reaction mixture was partitioned between 75 mL of 5% citric acid (aqueous) and 75 mL of ethyl acetate. The organic phase was washed with H2O, dried (Na2SO4), filtered, and concentrated. The orange residue was flash chromatographed on silica gel (elution with 1% MeOH in CH2Cl2) to yield 503 mg (48%) of the title compound as a solid, mp>60° C. (gradual); homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 736 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.88 (t, J=7.3 Hz, 3H), 1.05 (t, J=7.1 Hz, 3H), 1.34 (m, 2H), 1.59 (m, 2H, partially obscured by H2O peak), 2.56 (t, J=7.8 Hz, 2H), 4.14 (q, J=7.1 Hz, 2H), overlapping 4.16 (s, 2H), 7.07 (d, J=8.1 Hz, 2H), 7.25-7.45 (m, 6H), 7.55-7.69 (m, 4H), 8.26 (dd, J=8.8, 2.6 Hz, 1H), 8.35 (dd, J=8.1, 1.3 Hz, 2H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:9]=2[CH2:8][CH2:7][CH2:6][CH2:5]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.C(=O)(O)[O-].[Na+].[C:50]1([C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)([SH:58])[CH3:57])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.[H-].[Na+].[Cl-].[NH4+]>C(Cl)Cl.CN(C=O)C>[C:59]1([C:56]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([S:58][CH2:2][CH2:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:9]=3[CH2:8][CH2:7][CH2:6][CH2:5]2)[CH3:57])[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=1
Reactant: CC(S)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc2c1CCCCN2CCO
Agent: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1cccc2c1CCCCN2CCSC(C)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
Methyl (1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-6-yloxy)acetate (370 mg) was dissolved in methylene chloride (15 ml), and the resultant solution was stirred at 0° C. Triphenylphosphine (1085 mg) and carbon tetrabromide (922 mg) were added to the solution, and the mixture was stirred at 0° C. After disappearance of the raw materials was confirmed, a saturated sodium bicarbonate aqueous solution (15 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=1/1) to obtain a crude product. 1,1-diphenylethanethiol (428 mg) was dissolved in DMF (10 ml) under an argon atmosphere, and the resultant solution was stirred at 0° C. Sodium hydride (65 mg) was added to the solution, and the mixture was stirred at 0° C. for 5 minutes. A solution of the crude product in DMF (3 ml) was added to the mixture at 0° C. After disappearance of the raw materials was confirmed, the reaction solution was added to a saturated ammonium chloride aqueous solution (30 ml), and then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=8/1) to obtain the object compound (532 mg, yield 84%).
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:16][C:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[Na+].[Na+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C.O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([C:21]3[CH:20]=[CH:19][N:18]=[C:17]([CH3:16])[CH:22]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Clc1ccc(Oc2ncccc2Br)cc1
Reactant: Cc1cc(B(O)O)ccn1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Solvent: O
Product: Cc1cc(-c2cccnc2Oc2ccc(Cl)cc2)ccn1

Procedure:
To a sealed tube, under nitrogen was added 3-bromo-2-(4-chlorophenoxy)-pyridine (7 g, 25 mmol), 2-methylpyridin-4-ylboronic acid (3.4 g, 25 mmol), sodium carbonate (7.8 g, 74 mmol), S-phos (1 g, 2.5 mmol), Pd2(dba)3 (1.1 g, 1.2 mmol), and 180 mL of acetonitrile/water (5:1). The resulting mixture was heated to 75 C overnight. The reaction mixture was filtered to remove the solids and concentrated by rotovap. The residue was diluted with DCM and washed with brine. The organic layer was dried over Na2SO4 and concentrated. The solid and the residue was combined and purified by silica gel chromatography (0-10% MeOH/DCM) to afford 2-(4-chlorophenoxy)-3-(2-methylpyridin-4-yl)pyridine as solid. MS (ESI, pos. ion) m/z: 296.8 (M+1).