Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:5])[CH3:2].C(=O)([O-])[O-:26].[K+].[K+].[CH3:31][N:32]([CH3:36])[C:33](Cl)=[O:34].O>CN(C)C=O>[CH3:31][N:32]([CH3:36])[C:33]([O:17][C:13]1([OH:26])[CH:14]=[CH:15][C:16]2[CH:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:8]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:9][CH2:10][C:11]=2[CH2:12]1)=[O:34]
Reactant: CN(C)C(=O)Cl
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC1c2ccc(O)cc2CCN1C(=O)OC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1C2=C(CCN1C(=O)OC(C)(C)C)CC(O)(OC(=O)N(C)C)C=C2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
To a solution of t-butyl 1-ethoxycarbonylmethyl-6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate (1.70 g, 5.07 mmol) synthesized in step (d) of Example 187 in dimethylformamide (5 ml) were added potassium carbonate (1.03 g, 7.50 mmol) and N,N-dimethylcarbamoyl chloride (0.69 ml, 7.5 mmol), and the resulting mixture was stirred for 2.5 hours at room temperature under a nitrogen atmosphere. After stirring, water (20 ml) was added, and the resulting mixture was extracted with ethyl acetate (20 ml×2). The organic layer was washed with saturated aqueous sodium chloride solution (30 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1-1:1) as the eluent to afford the title compound (1.97 g, yield: 95%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH2:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.[O:22]=[C:23]([CH2:29][C:30](=[O:32])[CH3:31])[C:24](OCC)=[O:25]>C(O)(=O)C>[C:30]([C:29]1[CH:18]([C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)[N:12]([C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[CH:7]=2)[C:24](=[O:25])[C:23]=1[OH:22])(=[O:32])[CH3:31]
Reactant: Cc1cc(N)cn2c(C)nnc12
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CC(=O)O
Product: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A mixture of 3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-amine (Step 67.4) (2 g, 12.33 mmol), 4-chlorobenzaldehyde (1.576 g, 11.21 mmol) and ethyl 2,4-dioxopentanoate (1.773 g, 11.21 mmol) in acetic acid (10 mL) was stirred for 2 hr at 100° C. The reaction mixture was concentrated, diluted with CH2Cl2/1N NaOH and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, evaporated and discarded as they contained no desired product. The aqueous was acidified to pH 3 with 6N HCl and extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4 and concentrated to afford the title compound (3.88 g, 8.80 mmol, 79% yield) as a beige foam. tR: 0.70 min (LC-MS 2); ESI-MS: 397 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3H) 2.44 (s, 3H) 2.63 (s, 3H) 6.14 (s, 1H) 7.27 (d, J=8.44 Hz, 2H) 7.33-7.40 (m, 3H) 8.53 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=1.[H-].[Na+].[CH2:22](Br)[CH2:23][CH3:24]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:22][CH2:23][CH3:24])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=1
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)cc1Cl
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1nc(-c2ccc(OC)c(Cl)c2)c2cccc(Cl)c21

Procedure:
Prepared according to Method D Step B from 7-chloro-3-(3-chloro-4-methoxyphenyl)-1H-indazole (1.0 g, 3.4 mmol), sodium hydride (0.15 g, 60% in oil) in DMF followed by propyl bromide (0.4 mL). The title compound was obtained as an oil (0.94 g, 2.8 mmol, 82%).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].[BrH:17]>C1CCCCC1>[Br:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: Br
Reactant: OCCCCCCCCCCCCCCO
Solvent: C1CCCCC1
Product: OCCCCCCCCCCCCCCBr
Yield: 67 %

Procedure:
1,14-Tetradecandiol (1.5 g) was dissolved in 16.5 ml of cyclohexane, and 57% aqueous hydrobromic acid solution (16.5 ml) was added to this solution. The reaction mixture was refluxed for six hours while stirring. After the reaction, the mixture was extracted three times with diethyl ether. The organic layer was neutralized with saturated sodium hydrogen carbonate solution, washed with saline solution, dried over magnesium sulfate, and filtered, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel flash chromatography (hexane:ethyl acetate=7:3) gave 14-bromotetradecan-1-ol as white crystals at a 67% yield.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[CH3:23][N:24]1[C:28](=[O:29])[CH2:27][S:26][C:25]1=[S:30]>C(O)(=O)C.C(O)C.O>[CH3:13][C:12]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:3])([CH3:1])[CH3:4])[N:6]=[C:7]([CH:16]=[C:27]2[S:26][C:25](=[S:30])[N:24]([CH3:23])[C:28]2=[O:29])[N:8]=1)([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Reactant: CN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN1C(=O)C(=Cc2nc(C(C)(C)C)c(O)c(C(C)(C)C)n2)SC1=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
A mixture of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (0.50 g, 2.1 mmol), sodium acetate (0.60 g, 7.3 mmol), and 3-methylrhodanine (0.31 g, 2.1 mmol) in glacial acetic acid (10 mL) is placed under nitrogen atmosphere and warmed to reflux. After refluxing 21 hours, the mixture is cooled to room temperature and diluted with a 1:1 mixture of ethanol and water. The resulting slurry is stirred 0.5 hours and filtered. The precipitate is recrystallized from methanol and water to give 0.36 g (47%) of the title compound, mp 226°-228° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([NH2:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.N([O-])=[O:20].[Na+].Cl>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([NH:15][OH:20])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1
Reactant: O=N[O-]
Reactant: Cc1cc(-c2ccccc2F)cc([N+](=O)[O-])c1N
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2F)cc([N+](=O)[O-])c1NO

Procedure:
Reflux of a combination of starting compounds 4-Bromo-2-methyl-6-nitro-phenylamine 160 and aromatic boronic acid 161 in the presence of Pd(Ph3P)4, K3PO4, Benzene, dimethylformamide gives rise to intermediate 2′-Fluoro-5-methyl-3-nitro-biphenyl-4-ylamine 162. Tricyclic intermediate 5-(2-Fluoro-phenyl)-7-nitro-2H-indazole 165 is formed from intermediate 162 by using one of two reactions. One reaction involves treating intermediate 162 with sodium nitrite, acetic acid, and hydrochloric acid to form intermediate N-(2′-Fluoro-5-methyl-3-nitro-biphenyl-4-yl)-hydroxylamine 163 then refluxing intermediate 163 in benzene to form intermediate 165. The second reaction involves treating intermediate 162 with HBF4 and sodium nitrite forming intermediate 2′-Fluoro-5-methyl-3-nitro-biphenyl-4-diazonium+ BF4− 164 then treating intermediate 164 with potassium acetate and 18-Crown-6 in chloroform to form intermediate 165. Intermediate 165 is treated with Pd—C in ethanol and hydrogen, which reduces the nitro substituent of intermediate 165 to an amine forming intermediate 5-(2-Fluoro-phenyl)-2H-indazol-7-ylamine 166. Treatment of intermediate 166 with Bu4NBr3 (TBATB) and DMF-H2O brominated intermediate 166 to form intermediate 4-Bromo-5-(2-fluoro-phenyl)-2H-indazol-7-ylamine 167. The bromine of intermediate 167 is replaced with a carbonitrile group by refluxing in coppercyanide in pyridine forming intermediate 7-Amino-5-(2-fluoro-phenyl)-2H-indazole-4-carbonitrile 168. Reductive alkylation of intermediate 168 is accomplished by treating intermediate 168 with the appropriate aldehyde in the presence of zinc chloride and sodium cyano borohydride forming intermediate 169, which is brominated by treatment with Bu4NBr3 (TBATB) in DMF-H2O forming target compound 7-Amino-3-bromo-5-(2-fluoro-phenyl)-2H-indazole-4-carbonitrile derivative 170
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(N(CC)CC)C>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2([NH:19][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: Cc1ccc(C2(N)CCCC2)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(C2(NC(=O)C(C)(C)C)CCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
Into a 200 ml four-necked flask, there were charged benzene (100 ml), 1-(p-methylphenyl)cyclopentylamine (8.8 g) and triethylamine (6.1 g), and trimethylacetyl chloride (6.0 g) was dropwise added thereto while stirring at room temperature. Stirring was continued for 3 hours. After completion of the reaction, the reaction mixture was washed with water to remove triethylamine hydrochloride. After the benzene layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol to give 10.8 g of N-[1-(p-methylphenyl)cyclopentyl]trimethylacetamide. M.P., 166°-167° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([NH2:15])=[C:13]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.CCCCCCC.C[CH2:37][O:38]C(C)=O>CC(OC)(C)C>[CH2:17]([N:16]1[C:13]2[CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[N:10]=[C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]=2[NH:15][C:37]1=[O:38])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1NCc1ccccc1
Reactant: CCOC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCCCCCC
Product: O=c1[nH]c2c(NCc3ccccc3)nc(C(F)(F)F)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N2,N4-Dibenzyl-6-trifluoromethyl-pyridine-2,3,4-triamine (9.02 g, 24.2 mmol) was dissolved in TBME (180 ml) and CDl (19.6 g, 121 mmol) was added. The reaction mixture was stirred at room temperature for 72 h. Water (100 ml) was added to the reaction mixture and the layers were separated. The aqueous was extracted with EtOAc (200 ml). The combined organics were washed with brine (50 ml), dried over MgSO4 and concentrated in vacuo to give the crude (25 g). Column chromatography through silica eluting with 30:70→60:40 Heptane:EtOAc gave the title compound (2.64 g) as a white fluffy solid.
Reaction SMILES: Br[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[C:11]([O:24][CH3:25])[C:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:13][C:4]=2[CH:3]1O.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].[H-].[Na+].CS(C)=[O:37]>>[CH3:9][C:7]1([CH3:8])[O:6][C:5]2[CH:10]=[C:11]([O:24][CH3:25])[C:12]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=3)(=[O:15])=[O:16])=[CH:13][C:4]=2[C@@H:3]([N:27]2[CH2:31][CH2:30][CH2:29][C:28]2=[O:32])[C@@H:2]1[OH:37]
Reactant: COc1cc2c(cc1S(=O)(=O)c1ccc(C)cc1)C(O)C(Br)C(C)(C)O2
Reactant: O=C1CCCN1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Product: COc1cc2c(cc1S(=O)(=O)c1ccc(C)cc1)[C@@H](N1CCCC1=O)[C@H](O)C(C)(C)O2
Temperature: 40 °C
Reaction time: 3 h

Procedure:
4,3 g (0.0097 mole) of 3-bromo-3,4-dihydro-2,2-dimethyl-7-methoxy-6-(p-tolylsulfonyl)-2H-benzo[b]pyran-4-ol are dissolved in 28 ml of dimethyl sulfoxide, and 3.5 ml of 2-pyrrolidinone (0.0465 mole) and 0.78 g of sodium hydride (80% suspension in oil) (0.0325 mole) are added, and the mixture is stirred at 40° C. for 3 hours. It is left to stand overnight and then poured onto ice-water and filtered with suction. The precipitate is recrystallized from isopropanol. White crystals of melting point: 263°-65° C.
Reaction SMILES: [O:1]1[CH2:12][C@H:2]1[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:13]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCCCCC>[CH2:5]([O:4][CH2:3][C@H:2]([OH:1])[CH2:12][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[O:17][CH2:16][CH:13]1[CH2:14][CH2:15]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: Oc1ccccc1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: O[C@@H](COCc1ccccc1)COc1ccccc1OCC1CC1
Temperature: 25 °C

Procedure:
A mixture of (S)-benzyl 2,3-epoxypropyl ether (8.95 g as described in Heterocycles Vol. 16, 381, 1981), o-cyclopropylmethoxyphenol (8.95 g) in 36 ml acetone and 4 ml hexane, to which is added powdered potassium carbonate (6.9 g), is stirred at reflux in nitrogen atmosphere for 74 hours. After cooling to room temperature the solid is filtered off and washed with acetone. The filtrate is concentrated under reduced pressure, the residue is dissolved in ether, the ether solution is washed 2x with water and dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness. The crude oil is distilled in vacuo, at 199°-212°/0.2 mm to yield (S)-1-benzyloxy-3-[o-(cyclopropylmethoxy)phenoxy]-2-hydroxypropane.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:13]2[O:12][CH2:11][O:10][C:9]=2[CH:8]=1)(=[O:3])[CH3:2].C=O.Cl.C(Cl)[CH2:20][Cl:21]>>[Cl:21][CH2:20][C:15]1[C:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:8][C:9]2[O:10][CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: CC(=O)NCCc1ccc2c(c1)OCO2
Reactant: ClCCCl
Agent: C=O
Agent: Cl
Product: CC(=O)NCCc1cc2c(cc1CCl)OCO2
Temperature: 0 °C

Procedure:
In a 100 ml round-bottom flask provided with a stirrer, thermometer, gas inlet tube, and a condenser were placed 4.12 g of N-acetyl-homopiperonylamine (0.02 mole), 2.1 g of 37% formaldehyde solution, and 50 ml of ethylene chloride. The mixture was cooled to 3° and hydrogen chloride passed into the stirred mixture. After about 15 minutes a thick paste of crystals had formed. At this point, another 2.1 g of 37% formaldehyde was added and the mixture allowed to stir until all the solid had dissolved. The solution was then poured into ice water and the lower ethylene chloride layer separated, washed three times with water, then dried. The clear ethylene chloride solution was freed of solvent in the rotary evaporator, leaving the above-named product as a crystalline solid. After recrystallization from acetone, the solid melted at 116.5°-122°.
Reaction SMILES: [Cl-].C[CH:3]=[N+:4]=[CH:5]C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([NH:22][C:23]3[CH:32]=[CH:31][C:30]4[C:29](=[O:33])[CH2:28][CH2:27][CH2:26][C:25]=4[CH:24]=3)=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[BH4-].[Na+].O1CCC[CH2:37]1>C(#N)C>[CH3:3][N:4]([CH2:5][CH:28]1[CH2:27][CH2:26][C:25]2[CH:24]=[C:23]([NH:22][C:20]([N:17]3[CH2:18][CH2:19][CH:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)[CH2:15][CH2:16]3)=[O:21])[CH:32]=[CH:31][C:30]=2[CH:29]1[OH:33])[CH3:37]
Reactant: C1CCOC1
Reactant: CC=[N+]=CC
Reactant: O=C1CCCc2cc(NC(=O)N3CCC(c4ccc(F)cc4)CC3)ccc21
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)CC1CCc2cc(NC(=O)N3CCC(c4ccc(F)cc4)CC3)ccc2C1O
Reaction time: 1 h

Procedure:
N,N-Dimethylmethylene ammonium chloride(638 mg, 6.82 mmol) was added to a mixed solution of 4-(4-fluorophenyl)-N-(5-oxo-5,6,7,8-tetrahydro-2-naphthalenyl)-1-piperidinecarboxamide (1.00 g, 2.73 mmol) obtained in Reference Example 97 in tetrahydrofuran (10 ml) and acetonitrile (10 ml), which was stirred at room temperature for 1 day. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was dissolved in methanol (15 ml). Sodium borohydride (103 mg, 2.73 mmol) was added to the solution under ice-cooling, which was stirred for 1 hour. Then, the solvent was distilled out under reduced pressure. 1N Hydrochloric acid was added to the residue, which was washed with ethyl acetate. 4N Sodium hydroxide was added to the water layer to make it alkaline. The reaction mixture was extracted with ethyl acetate, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum B column chromatography (development solvent; ethyl acetate), powdered with hexane, to give the titled compound (231 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](CC3C=C(C=CC=3)C(O)=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[C:4](OCC2CCCC2)[CH:3]=1.FC1C=C(N)C(N)=CC=1F.[Br:46]C1C=CC=CC=1C(O)=O>>[Br:46][C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][C:5]=1[C:8]1[NH:12][C:11]2[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=2[N:9]=1
Reactant: O=C(O)c1cccc(Cn2c(-c3ccc(Cl)cc3OCC3CCCC3)nc3cc(F)c(F)cc32)c1
Reactant: O=C(O)c1ccccc1Br
Agent: Nc1cc(F)c(F)cc1N
Product: Fc1cc2nc(-c3ccccc3Br)[nH]c2cc1F

Procedure:
The title compound was prepared in analogy to Example 19, intermediate c, from 4,5-difluoro-benzene-1,2-diamine (CAS Reg. No. 76179-40-3) and 2-bromo-benzoic acid (CAS Reg. No. 88-65-3). Yellow solid (85%). MS (Turbo Spray): m/z=273.0 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:53])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH:45]C(OC(C)(C)C)=O)[C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]3[CH:31]=[N:32][CH:33]=[C:34]([C:36](=[O:44])[C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH:35]=3)=[O:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:53])[NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([NH2:45])[C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]3[CH:31]=[N:32][CH:33]=[C:34]([C:36](=[O:44])[C:37]4[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=4)[CH:35]=3)=[O:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@H]1c1cncc(C(=O)c2ccc(F)cc2)c1
Reaction time: 0.75 h

Procedure:
To a solution of ((S)-5-tert-butoxycarbonylamino-6-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-6-oxo-hexyl)-carbamic acid 9H-fluoren-9-ylmethyl ester (I-1a) in dichloromethane (15 mL) was added trifluoroacetic acid (5 mL). After stirring for 45 minutes, the reaction mixture was concentrated in vacuo to afford crude ((S)-5-amino-6-{(S)-2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]pyrrolidin-1-yl}-6-oxo-hexyl)-carbamic acid 9H-fluoren-9-ylmethyl ester as a dark amber residue.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:6]#[N:7].[Br-:13].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:13][C:4]1[C:5]([C:6]#[N:7])=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C#N)cc(OC)c1
Reactant: [Br-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cc(C#N)c(Br)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.2 %

Procedure:
To a solution of 3,5-dimethoxybenzonitrile (2 g) in CH2Cl2 (100 mL) was added pyridinium tribromide (4 g). The mixture was stirred for 24 h at room temperature then washed successively with aqueous NaHCO3, water and brine, dried (MgSO4) filtered and evaporated. The residue was crystallized from CH2Cl2 and hexane to yield the title compound (1.8 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([NH2:17])([CH2:14][CH2:15]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.Cl[C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>ClCCl.O.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]2([N:17]([C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH2:15][CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)(CCO)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC2(CCN2C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of an optically-active compound of 3-amino-3-(2-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester (6.46 g), triphenylphosphine (12.5 g) and triethylamine (13.3 ml) in dichloromethane (226 ml) cooled to 0° C. was added carbon tetrabromide (15.8 g). The reaction mixture was stirred at room temperature for 40 minutes and cooled to 0° C. again. Then, thereto were added triethylamine (5.5 ml) and benzyl chloroformate (4.9 ml), and the mixture was stirred for 3.5 hours at room temperature. To the mixture was added water (200 ml), and the mixture was extracted with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium chloride solution, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give the titled compound (5.35 g).
Reaction SMILES: [C:1]1(=[O:5])[O:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:8]=1[OH:32].CC(C)([O-])C.[K+].Cl>C1COCC1.O>[Br:6][C:7]1[CH:12]=[C:11]([C:13]2[C:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[S:25][C:21]=3[C:20]([Br:30])=[C:19]3[C:14]=2[CH:15]=[CH:16][CH:17]=[CH:18]3)[CH:10]=[C:9]([Br:31])[C:8]=1[O:32][CH:2]([CH3:3])[C:1]([OH:4])=[O:5]
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Reactant: O=C1CCO1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br)C(=O)O
Yield: 44.3 %

Procedure:
β-Propiolactone (0.186 mL, 2.66 mmol) was added to a stirred, room temperature solution of 2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen- 11 -yl)-phenol (1.5 g, 2.66 mmol), potassium tert-butoxide (0.314 g, 2.66 mmol) in THF (33 mL) under a dry nitrogen atmosphere. After 2 days the reaction mixture was added to water, acidified with 10% aqueous HCl and extracted with ethyl acetate. To the ethyl acetate phase was added acid washed (2% phosphoric acid in methanol) silica gel and the solvent was removed. The adsorbate was flash chromatographed (2% phosphoric acid in methanol treated silica gel ; eluent: gradient: 9:1 to 8:2 petroleum ether:ethyl acetate) to provide the title compound as an off-white solid (0.748 g, 44%): mp 218-220° C.: NMR (DMSO-d6);δ12.48 (broad s, 1H), 8.28 (d, J=8 Hz, 1H), 8.08 (d, J=8 Hz, 1H), 7.83 (s, 2 H), 7.79 (ddd, J=7, 6, 1 Hz, 1 H), 7.64-7.57 (m, 2 H), 7.52 (ddd, J=8, 7, 1 Hz, 1H), 7.31 (ddd, =8, 7, 1 Hz, 1 H), 6.69 (d, J=8 Hz, 1 H), 4.44 (t, J=6 Hz, 2 H), 2.89 (t, J=6 Hz, 2 H); MS (+FAB): [M+], 3 bromine isotope pattern, 632 (30%), 634 (70%) 636 (80%) 638 (40%); Anal. Calc. for C25H15Br3O3S: C, 47.27, H, 2.38, N, 0.00. Found: C, 47.68, H, 2.36, N, 0.01.