Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:13][CH2:12][C@@H:11]([CH3:14])[CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(F)cc1
Reactant: C[C@H](CCl)CBr
Product: C[C@H](CCl)COc1ccc(F)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-fluorophenol and (2R)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:38]([NH:45][C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)=[O:16])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10.41 g, 45.4 mmol), HOBT (13.91 g, 91 mmol), and EDCI (17.41 g, 91 mmol) were dissolved in DCM (Volume: 150 ml). The reaction was stirred for twenty minutes before benzylamine (9.92 ml, 91 mmol) and triethylamine (18.99 ml, 136 mmol) were added. The reaction was allowed to overnight. The reaction was diluted with water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via column chromatography using 0-50% ethyl acetate:hexanes to obtain a white solid. (Yield: 6.9 g, white solid) 1H-NMR (400 MHz, DMSO-d6) 8.32, 7.329-7.207, 4.25, 3.96-3.93, 2.72, 2.38-2.32, 1.70-1.67, 1.48-1.37
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH:6]([OH:20])[CH2:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(N=[N+]=[N-])CC(O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(N)CC(O)C1
Temperature: 65 °C

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol, Intermediate 18 (3.4 g, 16 mmol) in THF (40 mL) and water (8 mL) was added triphenylphosphine (1.89 g, 7.2 mmol) and the mixture was heated at 65° C. behind a blast screen for 16 hr. The solvents were removed under reduced pressure to afford 5-amino-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-3-ol (contaminated with triphenylphosphine oxide) as a viscous oil. To this amine in DCM (40 mL) was added di-tert-butyl dicarbonate (4.49 g, 20.6 mmol) and DIPEA (4.78 mL, 27.4 mmol) and the mixture was stirred at room temperature for 60 hr. The solvent was removed under reduced pressure and the residue purified via silica gel column chromatography (0-100% EtOAc/isohexane) to give tert-butyl 6-hydroxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a yellow oil (1.2 g). To a solution of this oil (1.2 g) in DCM (25 mL) was added portionwise Dess-Martin periodinane (1.72 g, 1.51 mmol). After stirring at room temperature for 16 hr, the mixture was diluted with DCM (25 mL) and quenched with saturated aqueous NaHCO3 (40 mL) followed by 20% aqueous sodium thiosulphate (40 mL). The resulting mixture was stirred for 20 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-60% EtOAc/isohexane) gave tert-butyl 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-6-oxoazepan-4-ylcarbamate (0.56 g) as a yellow oil. To a solution of this oil (0.51 g, 1.46 mmol) in DCM (15 mL) was added deoxo-Fluor® (50% in THF, 1.85 mL, 5.1 mmol) and the mixture was stirred at room temperature for 16 hr. The mixture was diluted with DCM (30 mL), cooled in an ice/water bath and quenched by dropwise addition of saturated aqueous NaHCO3 (30 mL). The resulting mixture was stirred for 10 min. The organic layer was separated, dried over Na2SO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-50% EtOAc/isohexane) gave tert-butyl 6,6-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate (510 mg, 64% over four steps) as an oil. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 4.18-4.01 (m, 1H), 3.84 (s, 3H), 3.79-3.19 (m, 4H), 2.56-2.42 (m, 1H), 2.38-1.99 (m, 4H), 1.46 (s, 9H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)=[O:7].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[S:1]1[CH:5]=[CH:4][C:3]2[C:10](=[O:12])[C:9]3[C:8]([C:6](=[O:7])[C:2]1=2)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C(O)c1ccccc1C(=O)c1cccs1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1c2ccccc2C(=O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.9 %

Procedure:
2-(thiophene-2-carbonyl)benzoic acid (1, 14.0 g, 60.3 mmol, 1.0 equiv.), nitrobenzene (400 mL), and phosphorus pentachloride (18.8 g, 90.4 mmol. 1.5 equiv.) were added to a schlenk flask. Aluminum chloride was then added (12.1 g, 90.4 mmol, 1.5 equiv.), and the reaction was stirred for 1 hour at room temperature followed by 4 hours at 140° C. The solvent was distilled off under vacuum, and the black residue was sonicated in dichloromethane (500 mL) and filtered through CELITE®. The filtrate was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane:hexanes (1:1)→dichloromethane). The product was further purified by recrystallization from methanol to give 2 as brown needle-shaped crystals (6.45 g, 50%). 1H NMR (500 MHz, CDCl3) δ8.26-8.24 (m, 2H), 7.78-7.77 (m, 2H), 7.75-7.71 (m, 2H). m.p. 232-234° C.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31]>>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][O:28][C:27]4=[O:31])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Brc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1O2
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Br)ccc3Oc3ccccc32)CC1

Procedure:
In an analogous manner to that described in Example 6, from 1-[2-bromo-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine and 3-(2-chloro-ethyl)-2-oxazolidinone, there is obtained 3-[2-{4-[2-bromo-10,11-dihydro-dibenz[b,f]-oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone having a melting point of 150°-152° C. The dihydrochloride, prepared in ethanol, melts at 175°-176° C.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([C@@:11]1([CH2:25][CH3:26])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[O:23][CH3:24])[CH2:12]1)=[O:10].C(N(CC)CC)C.Cl[C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=1>CS(C)=O>[CH2:25]([C@:11]1([C:9]([N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][N:36]=2)=[O:10])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[C@H:18]([O:23][CH3:24])[CH2:19][O:20][CH2:21][CH2:22]2)[CH2:12]1)[CH3:26]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3)CC[C@@H](N[C@@H]2CCOC[C@H]2OC)C1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC[C@]1(C(=O)N2C[C@@H]3C[C@H]2CN3c2cc(C(F)(F)F)ccn2)CC[C@@H](N[C@H]2CCOC[C@H]2OC)C1
Temperature: 120 °C
Yield: 24.4 %

Procedure:
To a solution of HCl salt of (1S,4S)-2,5-diaza-bicyclo[2.2.1]heptan-2-yl((1S,3R)-1-ethyl-3-((3S,4R)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)methanone (118 mg, 0.33 mmol) in DMSO (2 ml) was added triethylamine (0.15 ml, 1.08 mmol) and the 2-chloro-4-(trifluoromethyl)pyridine (183 mg, 1.01 mmol). The reaction was heated to 120° C. for 15 hours. The reaction was cooled to room temperature, and added to stirring ice water. The mixture was extracted with ethyl acetate (3×). The combined organics were washed with brine, dried over MgSO4 concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate, 15 column volumes) to give the product as a brown foam (40 mg 26%). LC/MS (M+H)=497.2739 exp, 497.2884 obs; 1H NMR (400 MHz, CDCl3) δ ppm 8.25-8.24 (1H), 6.75-6.74 (1H), 6.51-6.45 (1H), 5.13-4.76 (2H), 4.10-4.03 (1H), 3.95-3.90 (1H), 3.72-3.16 (11H), 2.82-2.67 (1H), 2.58-2.36 (1H), 2.06-1.36 (12H), 0.86-0.67 (3H)
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[CH:35]([OH:37])[CH3:36])[NH:29][C:28](=[O:39])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[NH:33][C:34](=[O:38])[C@@H:35]([OH:37])[CH3:36])[NH:29][C:28](=[O:39])/[C:27]/2=[CH:21]\[C:3]1[NH:4][C:5]2[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[C:7](=[O:20])[C:6]=2[C:2]=1[CH3:1]
Reactant: CC(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Product: Cc1c(/C=C2\C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CCC2
Yield: 58 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 10 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c obtained from step 3 of Example 10 and (S,Z)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b obtained from step 2 of Example 8 as starting materials to obtain (S,Z)—N-{5-fluoro-3-[3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydro xy-propionamide 21 (44 mg, yield 58%) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1.[OH-].[Na+].I[CH3:20]>C(O)C>[CH3:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([Cl:14])([Cl:13])[Cl:12])[NH:8][C:7](=[O:15])[C:6]=2[CH:16]=1
Reactant: O=C1NC(C(Cl)(Cl)Cl)Oc2ccc(O)cc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)NC(C(Cl)(Cl)Cl)O2

Procedure:
A suspension of 3,4-dihydro-6-hydroxy-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one (prepared as described in Example 3--2.5 g.) in ethanol (125 ml.) was stirred, ethanolic sodium hydroxide (32 ml. of a 0.36 M solution) was added, and the mixture was stirred for 30 minutes. Iodomethane (1.5 ml.) was added, and the solution was heated on a steam-bath for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in a mixture of diethyl ether (100 ml.) and N sodium hydroxide solution (50 ml.). The ether layer was separated, the aqueous layer was re-extracted with ether (100 ml.), and the ether extracts were combined and dried. The solvent was evaporated, and the sticky residue was stirred for 15 minutes with petroleum ether (b.p. 60°-80°, 100 ml.). then filtered and washed with more petroleum ether to yield 3,4-dihydro-6-methoxy-2-trichloromethyl-2H-benzo[e]-[1,3]-oxazin-4-one, m.p. 162°-165° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([O-:11])=[O:10])[CH:8]=1)#[N:2].[Na+].[CH3:34][O:35][CH2:36][CH2:37]Br>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:12]2[C:17]([C:18]#[N:19])=[C:16]([CH3:20])[N:15]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[C:14](=[O:31])[N:13]2[CH3:32])=[C:7]([S:9]([CH2:37][CH2:36][O:35][CH3:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: COCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C(C#N)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Temperature: 115 °C

Procedure:
The reaction was carried out under argon. Sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (100 mg, 73 μmol; purity 32%) was suspended in DMF (0.5 ml). 2-Bromoethyl methyl ether (148 mg, 1.06 mmol) was then added, and the mixture was heated in a closed tube at 115° C. for 15 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (27.3 mg, 73% of theory).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.ClCCl>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][Cl:5])=[CH:16][CH:15]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(O)CCCCCl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(CCCCCl)Nc1ccc(Br)cc1
Reaction time: 15 h

Procedure:
366 mmol (26.7 ml) of thionyl chloride are added dropwise to 183 mmol (25 g) of 5-chlorovaleric acid in 250 ml of toluene heated at reflux. The mixture is stirred at reflux until the evolution of gas has ceased and is then cooled. The solvent is evaporated off. The product obtained is then redissolved in 250 ml of dichloromethane and the temperature is lowered to 5° C. A solution of 183 mmol (31.5 g) of 4-bromoaniline in 100 ml of dichloromethane and 183 mmol (25.5 ml) of triethylamine are added in succession. The reaction mixture is stirred for 4 hours at 5° C. and then for 15 hours at room temperature. Hydrolysis, washing the organic phase with a 1N hydrochloric acid solution and evaporating off the solvents yields the expected product, which is used without being purified.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH:23]2[CH2:25][CH2:24]2)[CH2:18][CH2:17][C:16]3([CH3:27])[CH3:26])=[CH:7][CH:6]=1)C.[OH-].[Na+]>C(O)C>[CH:23]1([N:19]2[C:20]3[C:15](=[CH:14][C:13]([CH2:12][CH2:11][C:8]4[CH:7]=[CH:6][C:5]([C:4]([OH:28])=[O:3])=[CH:10][CH:9]=4)=[CH:22][CH:21]=3)[C:16]([CH3:27])([CH3:26])[CH2:17][CH2:18]2)[CH2:24][CH2:25]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCN3C2CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCN(C2CC2)c2ccc(CCc3ccc(C(=O)O)cc3)cc21

Procedure:
Following general procedure L and using 4-(1-cyclopropyl-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-6-ylethynyl)-benzoic acid ethyl ester (Compound 61, 0.05 g, 0.13 mmol), 5 mL of ethanol and 5M sodium hydroxide solution (2 mL) followed by recrystallization from hot ethyl acetate, the title compound was obtained as a solid (0.030 g, 64%).
Reaction SMILES: FC1C([N:8]2[C:12]3[CH:13]=[C:14]4[N:31]=[C:17]([CH:18]=[C:19]5[NH:30][C:22](=[CH:23][C:24]6[CH:25]=[CH:26][C:27]([N:29]=6)=[CH:28][C:9]2=[C:10](C2C(F)=C(F)C(F)=C(F)C=2F)[C:11]=3C2C(F)=C(F)C(F)=C(F)C=2F)[CH:21]=[CH:20]5)[CH:16]=[CH:15]4)=C(F)C(F)=C(F)C=1F.FC1C(C=O)=C(F)C(F)=C(F)C=1F.N1C=CC=C1>>[C:12]12[CH:13]=[C:14]3[N:31]=[C:17]([CH:16]=[CH:15]3)[CH:18]=[C:19]3[NH:30][C:22]([CH:21]=[CH:20]3)=[CH:23][C:24]3=[N:29][C:27]([CH:26]=[CH:25]3)=[CH:28][C:9]([NH:8]1)=[CH:10][CH:11]=2
Reactant: Fc1c(F)c(F)c(-c2c(-c3c(F)c(F)c(F)c(F)c3F)c3cc4nc(cc5ccc(cc6nc(cc2n3-c2c(F)c(F)c(F)c(F)c2F)C=C6)[nH]5)C=C4)c(F)c1F
Agent: O=Cc1c(F)c(F)c(F)c(F)c1F
Solvent: c1cc[nH]c1
Product: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)C=C4)[nH]3

Procedure:
Compound C is subjected to a second Lindsey-type tri(pentafluorophenyl)porphyrin-ring construction with pentafluorobenzaldehyde and pyrrole, to give the Gable porphyrin, orthodi [mesotri(pentafluorophenyl)porphin]-benzene. In this step, Compound C is reacted again with pyrrole and pentafluorobenzaldehyde in a 1,4,3 molar ratio with BF3 0Et2 catalyst to give the desired ##STR5##
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH:5]=O.[C:8]([O:11][C@@H:12]([C@:23]12[CH2:58][C:57](=[O:59])[C:56]([CH:60]([CH3:62])[CH3:61])=[C:24]1[C@@H:25]1[C@@:38]([CH3:41])([CH2:39][CH2:40]2)[C@@:37]2([CH3:42])[C@@H:28]([C@:29]3([CH3:55])[C@@H:34]([CH2:35][CH2:36]2)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:46](=[O:54])[CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=[O:50])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)(=[O:10])[CH3:9].C([BH3-])#N.[Na+]>CO>[C:8]([O:11][C@@H:12]([C@:23]12[CH2:58][C:57](=[O:59])[C:56]([CH:60]([CH3:62])[CH3:61])=[C:24]1[C@@H:25]1[C@@:38]([CH3:41])([CH2:39][CH2:40]2)[C@@:37]2([CH3:42])[C@@H:28]([C@:29]3([CH3:55])[C@@H:34]([CH2:35][CH2:36]2)[C:33]([CH3:44])([CH3:43])[C@@H:32]([O:45][C:46](=[O:54])[CH2:47][C:48]([CH3:52])([CH3:53])[C:49]([OH:51])=[O:50])[CH2:31][CH2:30]3)[CH2:27][CH2:26]1)[CH2:13][N:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[CH2:5][CH2:4][N:3]([CH3:7])[CH3:2])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@H](CNCc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Reactant: CN(C)CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(=O)O[C@H](CN(CCN(C)C)Cc1ccc(Cl)cc1)[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.6 %

Procedure:
To a solution of 2-(dimethylamino)acetaldehyde, hydrochloride (238 mg, 1.922 mmol) in methanol (12 mL) was added 4-(((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((S)-1-acetoxy-2-((4-chlorobenzyl)amino)ethyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl)oxy)-2,2-dimethyl-4-oxobutanoic acid (50) (150 mg, 0.192 mmol). The reaction mixture was stirred at rt for 2 h then sodium cyanoborohydride (121 mg, 1.922 mmol) was added and the mixture was stirred overnight. Upon completion, the mixture was purified preparative-HPLC to provide the title compound (50 mg, 24%). 1H NMR (400 MHz, CHLOROFORM-d) δ=7.35-7.12 (m, 4H), 5.65 (d, J=9.3 Hz, 1H), 4.49 (dd, J=5.8, 10.0 Hz, 1H), 3.83 (d, J=13.6 Hz, 1H), 3.55 (d, J=13.6 Hz, 1H), 3.25-2.91 (m, 7H), 2.91-2.73 (m, 7H), 2.73-2.52 (m, 3H), 2.33 (d, J=18.1 Hz, 1H), 1.99-0.72 (m, 48H); LC/MS: m/z calculated 850.5. found 851.4 (M+1)+.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([O:19]CC2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[C:27]([CH:29]1[CH2:31][CH2:30]1)=[O:28])C1C=CC=CC=1>O1CCCC1.[Pd]>[CH:29]1([C:27]([C:10]2[CH:11]=[CH:12][C:13]([OH:19])=[C:14]([C:15]([F:17])([F:18])[F:16])[C:9]=2[OH:8])=[O:28])[CH2:31][CH2:30]1
Reactant: O=C(c1ccc(OCc2ccccc2)c(C(F)(F)F)c1OCc1ccccc1)C1CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(c1ccc(O)c(C(F)(F)F)c1O)C1CC1
Reaction time: 4 h
Yield: 102.7 %

Procedure:
Dissolve (2,4-bis-benzyloxy-3-trifluoromethyl-phenyl)-cyclopropyl-methanone (881 mg, 1.86 mmol) in anhydrous tetrahydrofuran (15 mL) and add palladium on carbon (594 mg, 557 μmole). Degas (3×) and hydrogenate at 138 kPa (guage) under hydrogen atmosphere for 4 hrs. Filter the reaction mixture through filter cel and concentrate to provide the crude title compound (470 mg, 1.91 mmol). MS (m/z): 245 (M−1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:27](O)=[O:28])=[N:21][CH:22]=[C:23]([C:25]#[N:26])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([C:25]#[N:26])=[CH:22][N:21]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@H]1F
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Product: C[C@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)ccc2F)N=C(N)OC[C@H]1F

Procedure:
The condensation of (4R,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) and 3-chloro-5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as an off-white foam. MS (ISP): m/z=406.2 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7])=[O:2].OO.[CH:18](O)=[O:19]>>[N+:13]([C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:1]([O:19][CH3:18])=[O:2])([O-:15])=[O:14]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Reactant: O=CO
Agent: OO
Product: COC(=O)c1ccc([N+](=O)[O-])c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred solution of methyl 3-formyl-4-nitrobenzoate (1.5 g, 7.18 mmol) in formic acid (2 mL) was added hydrogen peroxide (2.5 mL, 30% in water). The reaction mixture was stirred at r.t. for 16 h. Additional hydrogen peroxide (2.5 mL, 30% in water) was added, and the reaction mixture stirred at r.t. for 8 h before being concentrated in vacuo. The residue was dissolved in 2% HCl in MeOH (40 mL). The solution was stirred at 70° C. for 4 days, then concentrated in vacuo. The residue was dissolved in DCM (10 mL), and the solution washed with aqueous sat. NaHCO3 (2×10 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (1.52 g, 87%) as a colourless oil. δH (CDCl3) 8.43 (1H, s), 8.29 (1H, dd, J 1.8 and 8.6 Hz), 7.92 (1H, d, J 8.3 Hz), 3.99 (3H, s), 3.95 (3H, s). LCMS (ES+) 240.0 (M+H)+, RT 1.80 minutes (Method 12).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=O)[CH2:9]2)[CH:7]=1.[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH:8]2[CH2:17][C:16]3[N:15]=[CH:14][CH:13]=[C:12]([CH3:18])[C:11]=3[C:10](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[CH2:9]2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1CC(=O)c2c(C)ccnc2C1
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(Cl)cc1C1CC(=NNC(=N)N)c2c(C)ccnc2C1
Yield: 183.7 %

Procedure:
To a solution of 7-(5-chloro-2-methoxyphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.0 g) and aminoguanidine hydrochloride (0.44 g) in ethanol (30 ml) were added a concentrated hydrochloric acid (0.83 ml) and water (0.83 ml), and the mixture was refluxed for 7 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with ethyl acetate, and to the aqueous layer was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid (10 ml). The mixture was concentrated. And precipitated crystals were recrystallized from ethanol to give 7-(5-chloro-2-methoxyphenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 166) (1.2 g) as colorless crystals.