Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[N:15]3[C:10]([C:11](=[O:16])[NH:12][CH:13]=[N:14]3)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:17]N1C(=O)CCC1=O>CN(C=O)C.O>[CH:1]1([C:7]2[N:15]3[C:10]([C:11](=[O:16])[NH:12][CH:13]=[N:14]3)=[C:9]([I:17])[N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=c1[nH]cnn2c(C3CCCCC3)ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]cnn2c(C3CCCCC3)nc(I)c12
Temperature: 55 °C
Reaction time: 20 h

Procedure:
To a solution of 7-cyclohexylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (130 mg, 0.6 mmol) in DMF (0.6 mL) was added N-iodosuccinimide (700 mg, 0.003 mol) and the reaction mixture stirred at 55° C. for 20 h. After this time the mixture was diluted with water (50 mL) and extracted with EtOAc (4×40 mL). The organic extracts were washed with water (4×40 mL), treated with sodium thiosulfate and brine, dried over Na2SO4 and concentrated in vacuo to afford 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H)-one. 1H NMR (400 MHz-DMSO-d6) δ 1.34-1.37 (m, 3H), 1.52-1.56 (m, 2H), 1.76-1.88 (m, 5H), 3.06-3.08 (m, 1H) 7.87 (s, 1H) 11.78 (s, 1H); MS (ES+): m/z: 344.95 (100) [MH+]. HPLC: tr=2.95 min (OpenLynx: polar—5 min).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH:7]1[O:9]C1)[CH:2]1[O:4][CH2:3]1.[CH2:10]([OH:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:10]([O:26][CH2:3][CH:2]1[O:4][C:7](=[O:9])[CH2:6][O:5][CH2:1]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCO
Reactant: C(OCC1CO1)C1CO1
Product: CCCCCCCCCCCCCCCCOCC1COCC(=O)O1

Procedure:
Prepared from the glycidyl ether of hexadecanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25]([O:27]C)=O)([O-:3])=[O:2].[NH3:29]>CO>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[Cl:21])=[CH:6][C:5]=1[NH:22][CH2:23][CH2:24][C:25]([NH2:29])=[O:27])([O-:3])=[O:2]
Reactant: COC(=O)CCNc1cc(Oc2ccc(S(C)(=O)=O)cc2Cl)ccc1[N+](=O)[O-]
Reactant: N
Solvent: CO
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(NCCC(N)=O)c2)c(Cl)c1
Reaction time: 48 h

Procedure:
The ester (7), obtained according to Example III, in an amount of 1.6 g was suspended in 40 ml of methanol. Ammonia was introduced until saturation and then the reaction mixture was stirred for two days. The solid material was sucked off and recrystallized from ethylacetate. The desired product was obtained in a yield of 0.9 g; melting point 196° C.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH3:5])=[N+]=[N-]>CCOC(C)=O.[Pd]>[C:15]1([C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)(=[O:22])=[O:23])[C:6]=2[CH:4]([NH2:1])[CH3:5])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(C(C)N=[N+]=[N-])c(-c3ccccc3)c3ccccc32)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(C(C)N)c(-c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.3 %

Procedure:
A mixture of 2-(1-azidoethyl)-3-phenyl-1-(toluene-4-sulfonyl)-1H-indole (1.34 g, 3.22 mmol) and 10% Pd/C (200 mg) in EtOAc (80 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 20 h. The suspension was then filtered and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) affording 1-[3-Phenyl-1-(toluene-4-sulfonyl)-1H-indol-2-yl]ethylamine as a white solid (960 mg, 76%). 1H NMR (CDCl3, 400 MHz): δ 8.18 (1H, d, J=8.44 Hz), 7.73 (2H, d, J=8.44 Hz), 7.49-7.15 (10H, m), 4.72 (1H, q, J=6.96 Hz), 2.35 (3H, s), 1.45 (3H, d, J=7.40 Hz)
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].O=[C:15]([CH2:21][CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[CH2:19]([O:18][C:16]([CH:15]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:21][CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=O)CCc1cccs1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(CCc1cccs1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4 g of type 4A molecular sieves (powdered) are added to a mixture of L-alanyl-L-proline (0.93 g) and ethyl 2oxo-4-(2-thienyl)-butyrate (3.18 g) in 25 ml of anhydrous ethyl alcohol. The mixture is stirred for 45 minutes at room temperature, followed by slow addition (3.5 hours) of a solution of sodium cyanoborohydride (0.785 g) in 15 ml of anhydrous ethyl alcohol and stirring overnight at room temperature. The reaction mixture is made just slightly acidic with glacial acetic acid, filtered and the filtrate conc. in vacuo to an orange oil. Extraction of a chloroform solution of this oil with 10% potassium bicarbonate, followed by re-extraction of the acidified (pH 3) bicarbonate extracts with chloroform provide, after drying and evaporation of solvent, 400 mg of the desired substituted dipeptide. The nmr spectrum (CDCl3) shows the thienyl proton as multiplet at 7.0 ppm, two active protons in broad singlet at 6.2 ppm, six methyl protons as broad multiplet 1.22-1.43 ppm range, and a series of ill-defined multiplets ranging 1.8-4.4 ppm.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C([O-])([O-])=O.[Na+].[Na+]>>[F:16][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:21]2[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=2)[CH:7]=1)[NH2:13]
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)c(F)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1cc(-c2cc(Oc3ccc(N)cc3F)ccn2)cn1
Yield: 33.4 %

Procedure:
Using a procedure analogous to Example A1, 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3 g, 11.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.4 g, 16.4 mmol), Na2CO3 (2.7 g, 25.2 mmol) and Pd(Ph3)4 (1.5 g, 0.1 eq) were combined to give 3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (1.1 g, 34% yield). 1H NMR (400 MHz, DMSO-d6): δ (8.31 (d, J=5.6 Hz, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.14 (s, 1H), 6.98 (m, 1H), 6.55-6.49 (m, 2H), 6.42 (d, J=7.2 Hz, 1H), 5.44 (s, 2H), 3.86 (s, 3H); MS (ESI) m/z: (M+H+): 285.2.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][C@:5]1([CH3:33])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][O:26]COC)[C:19]=3[S:18](=[O:31])(=[O:30])[N:17]=2)[C:6]1=[O:32].Cl>O1CCOCC1>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][CH2:4][C@:5]1([CH3:33])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25][OH:26])[C:19]=3[S:18](=[O:31])(=[O:30])[N:17]=2)[C:6]1=[O:32]
Reactant: COCOCc1csc2c1S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)(C)C)C1=O)N2
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
A solution of Example 184 (2.84 g, 5.5 mmol) in 20 mL of dioxane was cooled to 0° C., treated with 60 mL of 4N HCl in dioxane, allowed to warm to room temp, stirred for 2 hrs, and concentrated in vacuo to afford the title compound (2.96 g, 100% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (m, 1 H), 0.72 (s, 9 H), 0.82 (m, 1 H), 1.56 (s, 3 H), 2.03 (m, 1 H), 2.22 (m, 1 H), 4.61 (s, 2 H), 7.26 (s, 1 H), 7.52 (m, 1 H), 7.74 (d, J=4.0 Hz, 2 H), 8.13 (d, J=7.7 Hz, 1 H), 14.07 (s, 1 H); MS (APCI+) m/z 475 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](O)=[O:27])(=[O:22])=[O:21]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([S:20]([CH3:19])(=[O:22])=[O:21])[CH:24]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(S(C)(=O)=O)c3)CC2)ccc1Cl
Yield: 49 %

Procedure:
The title compound (22 mg, 49%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 3-methylsulfonyl benzoic acid. MS: 451.4 (MH+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[Cl:20])([CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: CC1(O)CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: CC1(c2ccccc2Cl)CCN(Cc2ccccc2)CC1
Reaction time: 3 h
Yield: 10 %

Procedure:
A solution of 1-Benzyl-4-methyl-piperidin-4-ol (4.5 g, 22 mmol) in chlorobenzene (60 mL) was treated with anhydrous AlCl3 (15 g, 110 mmol). This mixture was stirred for 3 hr at reflux, then quenched into ice (250 g), basified with sodium hydroxide, and extracted with ethyl acetate (3×100 mL). The combined organics were dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2→90:10 CH2Cl2/methanol) to yield 0.59 g (10%) of the title compound, ESI-MS m/z: 300 [M+1].
Reaction SMILES: [C:1]1([C:7]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)(O)[O-].[Na+].O>C(Cl)Cl>[C:1]1([C:7]2([CH:12]=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1(c2ccccc2)CCCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=CC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of (1-Phenyl-cyclopentyl)-methanol (1.0 g, 5.7 mmol) in DCM (20 mL) was added Dess-Martin Periodine (6.8 mmol, 1.2 eq) and sodium bicarbonate (6.8 mmol, 1.2 eq) at 0° C. The reaction mixture stirred at this temperature for 2 h and allowed to warm up slowly to room temperature. After completion of the reaction, the mixture was poured into water (50 mL) and extracted with DCM (50 mL). The organic mixture was then dried over sodium sulfate and concentrated under reduced pressure to give 1-Phenyl-cyclopentanecarbaldehyde (812 mg) which was immediately used to synthesize title compound (14 mg) from Intermediate B (20 mg, 0.025 mmol) following general procedures D and B. LC-MS (m/z): 923.
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:37]=[N+:38]=[N-])(C)C.N(OC(C)(C)C)=O>C(#N)C.O>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([N:20]=[N+:37]=[N-:38])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: O
Product: COc1cc2c(cc1N=[N+]=[N-])-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 1.75 g of 20b in 40 ml of acetonitrile was added dropwise at 0° C. 0.54 g of trimethylsilyl azide, followed by 0.6 gr of tertbutyl nitrite. The reaction was stirred for ½ hr at ambient temperature, and then diluted with water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The remainder was chromatographed on silicagel (using a gradient of heptane/ethyl acetate as eluent), to provide 1.14 g of 20c. LCMS-ESI: [M+1] 476.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=2[C:12](O)=[O:13])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[F:19][C:16]1[CH:17]=[CH:18][C:10]2[CH2:9][CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=3[C:12](=[O:13])[C:11]=2[CH:15]=1
Reactant: O=C(O)c1cc(F)ccc1CCc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1c2cc(F)ccc2CCc2ccc(F)cc21
Yield: 85 %

Procedure:
A mixture of 2-[2-(4-fluorophenyl)ethyl]-5-fluorobenzoic acid (2.02 g, 7.71 mmol, 1 equiv) and oxalyl chloride (1.37 g, 10.8 mmol, 1.4 equiv) in CH2Cl2 (20 mL) was refluxed for 30 min. The resulting solution was then added to a stirring suspension of aluminum chloride (1.44 g, 10.8 mmol, 1.4 equiv) in CH2Cl2 (50 mL). This mixture was refluxed for 1 h. The reaction mixture was then washed with 1N HCl (3×20 mL), aq. satd. NaCl (1×50 mL), and H2O (1×50 mL). The organic layer was dried (anhyd. Na2SO4) and rotary evaporated to provide 1.6 g of a light-orange-colored semisolid. This material was chromatographed (3:1 hexane/CHCl3) through silica gel (150 mm×25-mm dia.). Evaporation of the combined fractions containing product provided 0.93 g (49%) of the desired product as a light-yellow shiny solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CC(C)=O.C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH:17]([CH3:19])[CH3:18]
Reactant: Oc1ccc(Br)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC(C)Oc1cc(O)ccc1Br
Yield: 42 %

Procedure:
To a solution of 4-bromo-benzene-1,3-diol (1.50 g, 7.94 mmol) in acetone (10 mL) were added potassium carbonate (1.1 g, 7.94 mmol) and 2-iodopropane (1.58 mL, 15.87 mmol). The reaction mixture was heated at gentle reflux for 12 h. The solvent was removed to give a white paste. It was then taken in diethyl ether (50 mL). The white solids were filtered off and the filtrate was concentrated. Purification of the residue by Biotage flash chromatography eluting with 10% ethyl acetate in hexanes gave 4-bromo-3-isopropoxy-phenol (0.77 g, 42%).
Reaction SMILES: NC(N)=O.[C:5]([O:9][C:10]([NH:12][CH:13]([C:31]([OH:33])=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][S:19]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[C:24]([NH2:29])[C:23]=1[OH:30])(=[O:21])=[O:20])=[O:11])([CH3:8])([CH3:7])[CH3:6].[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]=[C:42]=[O:43]>>[Br:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH:41][C:42]([NH:29][C:24]1[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([S:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[C:31]([OH:33])=[O:32])(=[O:20])=[O:21])[C:23]=1[OH:30])=[O:43]
Reactant: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(N)c1O)C(=O)O
Reactant: O=C=Nc1ccccc1Br
Agent: NC(N)=O
Product: CC(C)(C)OC(=O)NC(CCCCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2ccccc2Br)c1O)C(=O)O
Yield: 7.3 %

Procedure:
Following the general procedure for urea formation outlined in example 15, N-[5-(tert-butoxycarbonylamino)-5-carboxypentyl]-3-amino-6-chloro-2-hydroxybenzenesulfonamide (189 mg, 0.42 mmol) and 2-bromophenylisocyanate (84 mg, 0.42 mmol) were coupled to form the desired urea (20 mg, 7%). LC-MS (m/z) 651.2 (M+).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]=[O:15].[OH-].[Ca+2].[OH-]>>[CH2:14]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[OH:15]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: C=O
Agent: [Ca+2]
Agent: [OH-]
Product: OCn1c2ccccc2c2ccccc21

Procedure:
105 parts of carbazole, 145 parts of formalin (40% W/V formaldehyde in water) and 265 parts of IMS were thoroughly mixed and then 10 parts of calcium hydroxide added. The mixture was heated with stirring at a temperature of 56° to 58° C. for an hour and thereafter filtered to remove unreacted carbazole and the calcium hydroxide. As the IMS cooled, the product N-methylol carbazole crystallised out of solution. The white crystals were separated by filtration and dried under vacuum at 50° C. for 2 hours. The crystals were identified by proton NMR and IR spectroscopy as NMC, m.p. 127°-129° C., and contained less than 1% carbazole according to gel permeation chromatography, which was used with a U.V. detector. (λ=254 mm).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([CH2:11]O)[CH:8]=[CH:7][C:6]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=1)([CH3:4])[CH3:3].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:11][C:9]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:20][CH3:21])[CH:14]=2)=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1cccc(-c2ccc(CO)cc2C(C)(C)C)c1
Solvent: ClCCl
Product: CCOc1cccc(-c2ccc(CCl)cc2C(C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A dry, round bottom flask containing 41.2 (0.72 g, 2.53 mmol) and DCM (9.0 mL) was cooled to 0° C. After 15 minutes, thionyl chloride (1.0 mL, 13.7 mmol) was carefully added dropwise at 0° C. Upon complete addition of thionyl chloride, the mixture was allowed to warm to room temperature and stirred overnight. After 20 hours, the reaction was concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0%-15% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 41.3 as a colorless oil (0.57, 74%). 1H NMR (500 MHz, CDCl3) δ ppm 7.54 (1H, d, J=2.0 Hz), 7.25 (2H, m), 7.04 (1H, d, J=7.4 Hz), 6.90 (3H, m), 4.65 (2H, s), 4.05 (2H, m), 1.43 (3H, t, J=7.0 Hz), 1.24 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH:6]=[CH:7][C:8]=1[C:9]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10].Cl>C(O)C.[Fe]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([C:5]2[CH:6]=[CH:7][C:8]([C:9]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1OC)C(C)C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(N)cc2)cc1OC)C(C)C
Temperature: 25 °C

Procedure:
Iron powder (0.35 g, 6.2 mmol) was added to a solution of methyl N-[(3-methoxy-4′-nitrobiphenyl-4-yl)carbonyl]-L-valinate (0.30 g, 0.62 mmol) in ethanol (10 mL). Concentrated HCl (0.31 mL, 0.62 mmol) was added, and the mixture was heated at reflux for 1 h. Upon cooling to rt, the mixture was filtered through a pad of Celite®, and the filtrate was concentrated in vacuo. The material was purified by column chromatography (33% EtOAc in hexanes), yielding 0.296 g (quantitative) of the title compound. LC/MS m/z 357.2 (MI), retention time 2.34 min.
Reaction SMILES: [I:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([NH:11][O:12][CH3:13])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][N:24]1[CH:28]=[C:27]([C:29](Cl)=[O:30])[C:26]([C:32](F)([F:34])[F:33])=[N:25]1>ClCCl>[I:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]([N:11]([O:12][CH3:13])[C:29]([C:27]3[C:26]([CH:32]([F:34])[F:33])=[N:25][N:24]([CH3:23])[CH:28]=3)=[O:30])[C:4]=2[CH:3]=1
Reactant: CONC1CCCCc2ccc(I)cc21
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1CCCCc2ccc(I)cc21
Temperature: 24 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
To a stirred solution of N-(3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine (77 mg; 0.24 mmol), prepared as described in example P3c and triethylamine (0.037 ml; 0.26 mmol) in dichloromethane (1.6 ml) under nitrogen at 4° C. was added dropwise 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (47 mg; 0.24 mmol). The reaction mixture was stirred at 24° C. for 3 h under nitrogen. The mixture diluted with dichloromethane (10 ml), washed with 1M sodium hydroxide (1 ml), 1M hydrochloric acid (1 ml) and brine (1 ml). Organics were dried over sodium sulfate. The solvent was removed in vacuo. The crude (190 mg) was subject to flash chromatography (eluant: c-hexane/ethyl acetate 90:10 to 50:50) to afford 0.101 g (88% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (3-iodo-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-methoxy-amide as a yellow solid oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:32]=[CH:31][C:10]2[N:11]3[C:15]([CH2:16][NH:17][CH2:18][C:9]=2[CH:8]=1)=[N:14][N:13]=[C:12]3[CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21][CH2:20]1>ClCCl>[Cl:6][C:7]1[CH:32]=[CH:31][C:10]2[N:11]3[C:15]([CH2:16][N:17]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][C:9]=2[CH:8]=1)=[N:14][N:13]=[C:12]3[CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Solvent: ClCCl
Product: CS(=O)(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.2 %

Procedure:
Methanesulfonyl chloride (0.1 ml, 1.29 mmol) was added to an ice cooled solution of the amine of example 4 (200 mg, 0.53 mmol) in dichloromethane (5 ml) and stirred at room temperature for 20 hours. The dichloromethane was evaporated off under reduced pressure and the residue purified by chromatography on silica gel using methanol in dichloromethane (5:95) as eluant, to afford the title compound as a brown foam (71 mg).
Reaction SMILES: [C:1]1(=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[C:2]1=O.[C:15]1([CH2:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[OH-].[K+]>C(O)C>[C:24]1([C:23]2[C:22](=[O:30])[C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]3[C:3]4=[C:12]5[C:7](=[CH:6][CH:5]=[CH:4]4)[CH:8]=[CH:9][CH:10]=[C:11]5[C:1]=23)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: O=C1C(=O)c2cccc3cccc1c23
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(c2ccccc2)=C2C(=C1c1ccccc1)c1cccc3cccc2c13
Yield: 71.3 %

Procedure:
An amount of 5.9 g (32.4 mmol) of acenaphthenequinone and 7.5 g (35.7 mmol) of 1,3-diphenyl-2-propanone were suspended in 150 ml of ethanol and a solution of 2 g of potassium hydroxide in ethanol was added. After the mixture was heated to the reflux temperature, the same amount of the solution of potassium hydroxide in ethanol was further added and allowed to react for five minutes. The solid substance deposited after cooled on ice was filtered and washed with ethanol to obtain 8.24 g (23.1 mmol) of 7,9-diphenylcyclopenta[a]acenaphthylene-8-one. The yield was 71.3%.