Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:20][C:21]1[C:22]([C:26]2[N:27]([C:46]3[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=3)[C:28]3[CH:33]=[C:32]([O:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=4)[N:31]=[CH:30][C:29]=3[N:45]=2)=[N:23][O:24][N:25]=1.C([NH:60][CH2:61][CH2:62]O)(OC(C)(C)C)=O.O>O1CCOCC1>[NH2:60][CH2:61][CH2:62][O:52][C:49]1[CH:50]=[CH:51][C:46]([N:27]2[C:28]3[CH:33]=[C:32]([O:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:44])[CH3:43])[CH:38]=[CH:39][CH:40]=4)[N:31]=[CH:30][C:29]=3[N:45]=[C:26]2[C:22]2[C:21]([NH2:20])=[N:25][O:24][N:23]=2)=[CH:47][CH:48]=1
Reactant: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc(O)cc2)c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc(Oc2cc3c(cn2)nc(-c2nonc2N)n3-c2ccc(OCCN)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
Triphenylphosphine (260 mg, 1.0 mmol) was added to a solution of the product from Step 5 (220 mg, 0.5 mmol) and N—BOC-ethanolamine (161 mg, 1.0 mmol) in dioxane (4 mL) followed by addition of di-isopropylazodicarboxylate (197 uL, 1.0 mmol) and the resulting solution was allowed to stir at rt overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic phases were combined, washed with brine, dried (MgSO4), filtered and the filtrate concentrated. The crude material was dissolved in dichloromethane (2 mL) and treated with TFA (1 mL) for 30 min, then concentrated and the residue was purified by reverse phase HPLC to give the title compound (38 mg, 16%). MS (ES+) m/e 487 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[C:7]([O:28][CH3:29])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)=[C:18]([C:25](=[O:27])[CH3:26])[CH:19]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Oc2ccnc3cc(OCCCCl)c(OC)cc23)c(C(C)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Oc2ccnc3cc(OCCCN4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
1-(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methoxyphenyl)-1-ethanone (compound 121) (100 mg), morpholine (63 mg), and potassium carbonate (166 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (55 mg, yield 49%).
Reaction SMILES: [C:1]([C:8]([NH2:15])(O)[CH2:9]CCCO)(OC(C)(C)C)=[O:2].[OH:16][C:17]([CH:19]([C:21]1[CH:34]=[CH:33][CH:32]=[C:23]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:22]=1)[CH3:20])=[O:18].[ClH:35].C([O:39][CH2:40][CH3:41])(=O)C.CCCCCC>ClCCl>[NH2:15][CH:8]([CH2:9][CH2:41][CH2:40][OH:39])[CH2:1][OH:2].[ClH:35].[OH:18][C:17]([CH:19]([C:21]1[CH:34]=[CH:33][CH:32]=[C:23]([C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:22]=1)[CH3:20])=[O:16]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)C(N)(O)CCCCO
Agent: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Product: NC(CO)CCCO
Reaction time: 3 h

Procedure:
The Boc-amino-1,5-pentanediol-ketoprofen (1.95 mmol) obtained above was dissolved in dichloromethane (1 ml), and 4 N hydrochloric acid/ethyl acetate (4 ml) was added thereto under ice-cooling, followed by stirring for 3 hours while gradually returning to room temperature. Hexane was added to the reaction solution, and the thus formed white precipitate was centrifuged. The thus obtained precipitate was dried under reduced pressure to give the titled compound (1.20 g, yield 98%). The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:17]1[S:21][C:20]([C:22]([OH:24])=O)=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:5]([C:17]1[S:21][C:20]([C:22]([Cl:3])=[O:24])=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCc1ccc(C(=O)O)s1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCCCCCc1ccc(C(=O)Cl)s1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
4 ml of thionyl chloride was added to 0.57 g (1.93×10-3 ml) of 5-dodecylthiophene-2-carboxylic acid, followed by heat-stirring for 4 hours at 70° C. and removal of excessive thionyl chloride by reduced-pressure distillation to obtain 5-dodecylthiophene-2-carboxylic chloride.
Reaction SMILES: [NH:1]([C:56]([O:58]C(C)(C)C)=O)[C@H:2]([C:18]([NH:20][C@@H:21]([C:34]([NH:36][C@H:37]([C:45]([N:47]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH3:48])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]=[O:33])[CH:24]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[CH2:64](Cl)Cl>>[NH:1]([C:56]([CH3:64])=[O:58])[C@H:2]([C:18]([NH:20][C@@H:21]([C:34]([NH:36][C@H:37]([C:45]([N:47]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[CH3:48])=[O:46])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:35])[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH:32]=[O:33])[CH:24]=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1cn(C=O)c2ccccc12)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: ClCCl
Agent: Cl
Product: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of Boc-Lys(Z)-D-Trp(CHO)-Phe-NMeBzl (1.04 g) in methylene chloride (10 ml) was added 4N-HCl/DOX (10 ml) under ice-cooling. The mixture was stirred for an hour at room temperature. After evaporation, the residue was pulverized with diisopropyl ether, filtered, washed with diisopropyl ether and dried. The obtained HCl.H-Lys(Z)-D-Trp(CHO)-Phe-NMeBzl (0.94 g) was dissolved in methylene chloride (15 ml) and cooled in an ice-bath. To the solution were added triethylamine (0.34 ml) and Ac2O (0.11 ml) and the mixture was stirred for an hour at the same temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with water, 2% hydrochloric acid, water, 2% sodium hydrogencarbonate, water and saturated sodium chloride, and then dried over magnesium sulfate. The evaporated residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (50 ml). The fractions containing the object compound were combined and evaporated. The residue was pulverized with n-hexane, filtered, washed with n-hexane and dried to give Ac-Lys(Z)-D-Trp(CHO)-Phe-NMeBzl (0.82 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.O1CCCC1.[Br:16]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:16][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[NH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2cc[nH]c12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1ncnc2c(Br)c[nH]c12
Reaction time: 1 h

Procedure:
To 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (100 mg), tetrahydrofuran (5 mL) was added, and N-bromosuccinimide (116 mg) was further added thereto, followed by stirring for 1 hour. After completion of the reaction, the reaction mixture was mixed with ethyl acetate and washed with water. The washed mixture was dried over anhydrous sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:19])CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([F:19])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC1(c2ccc(Br)cc2)CCC1
Solvent: ClCCl
Product: FC1(c2ccc(Br)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 64.1 %

Procedure:
To a solution of 5.66 g of 1-(4-bromophenyl)-cyclobutanol (24.92 mmol, described in example S2-A) in 70 ml DCM were added 4.23 g of (diethylamino)sulfur trifluoride (95%, 24.92 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 35 min, then sat. NaHCO3— solution was added and the resulting mixture was extracted with DCM. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (100% pentane) to give 1-bromo-4-(1-fluoro-cyclobutyl)-benzene (3.66 g, 64%) as a colorless liquid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][C:16]=2[C:22]2[N:26]([CH3:27])[C:25]([CH2:28][CH3:29])=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:30]([Cu])#[N:31].CN(C=O)C>CCOC(C)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:30]#[N:31])=[CH:17][C:16]=2[C:22]2[N:26]([CH3:27])[C:25]([CH2:28][CH3:29])=[N:24][N:23]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nnc(-c2cc(I)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nnc(-c2cc(C#N)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A 4 mL scintillation vial was charged with 4-tert-butyl-N-[4-iodo-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C, 18 mg, 0.034 mmol), CuCN (15 mg, 0.17 mmol), and DMF (500 μL). The reaction was then heated to 100° C. and stirred for 48 hours. The solution was then diluted with EtOAc and washed with an aqueous solution of EDTA (5% wt/wt). The organic layer was then concentrated and the residue purified by preparative TLC to afford 4-tert-butyl-N-[4-cyano-2-(5-ethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide as a white solid: MS (ES) M+H expected 424.2, found 424.4.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:22][C:23]#[N:24].[K+]>O>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:23]([NH2:24])=[O:22])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#C[O-]
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Agent: [K+]
Solvent: O
Product: NC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 60 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine and potassium cyanate are added to stirring water, and the mixture is heated to 60° C., then cooled to room temperature. The resulting precipitate is collected by filtration, washed with cold water, and dried under vacuum to give (6-benzenesulfonyl-naphthalen-1-ylmethyl)-urea.
Reaction SMILES: Cl[CH2:2][CH:3]=O.C([O:9][C:10](=[O:27])[C:11]1[C:16]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[CH:15][C:14]([NH2:26])=[N:13][CH:12]=1)(C)(C)C>CCO.CCOC(C)=O>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16]2[C:11]([C:10]([OH:9])=[O:27])=[CH:12][N:13]3[CH:2]=[CH:3][N:26]=[C:14]3[CH:15]=2)=[C:19]([Cl:25])[CH:20]=1
Reactant: O=CCCl
Reactant: CC(C)(C)OC(=O)c1cnc(N)cc1Nc1ccc(Br)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)c1cn2ccnc2cc1Nc1ccc(Br)cc1Cl
Temperature: 80 °C
Reaction time: 5 h
Yield: 32.7 %

Procedure:
Chloroacetaldehyde (12 μL, 0.188 mmol) was added to a mixture of 6-amino-4-(4-bromo-2-chlorophenylamino)-nicotinic acid tert-butyl ester (42) (50 mg, 0.125 mmol) in EtOH (630 μL). After stirring the reaction mixture at 80° C. for 5 hours, an additional 12 μL of chloroacetaldehyde were added and heating was continued for 10 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc to give a cloudy semi-solution. The organic layer was washed with water, saturated NaHCO3 and brine. The organic layer contains a precipitate, which was collected by filtration to give the desired product (43) (15 mg, 33%).
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11](Br)=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:10][C:9]=2[N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]c(Br)nc2n(CCCC)c1=O
Reactant: C1CCNC1
Product: CCCCn1c(=O)c2[nH]c(N3CCCC3)nc2n(CCCC)c1=O

Procedure:
The title compound was prepared from 1,3-di-n-butyl-8-bromo xanthine (1 g, 0.0029 ml) and pyrrolidine (0.041 g, 0.0057 mol) using an analogous procedure to that described in Example 19. The title product was obtained as a crystalline solid, m.pt. >250° C.
Reaction SMILES: [F:1][OH:2].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4]>N1C=CC=CC=1>[S:3]([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)([O:2][F:1])(=[O:5])=[O:4]
Reactant: OF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OF)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
The solution of 9.8 g of partial-fluoro alcohol in 40 ml of pyridine was cooled down to 0° C. in ice-salt water and 6 g of TsCl was added in small portion. After addition the resulting mixture was stirred at 0° C. for two hours and then placed in freezer (−20° C.) for two days. The reaction mixture was poured into ice water and the product was extracted with ethyl acetate twice. The combined organic phase was washed with brine, 10% HCl and again brine three times, and then dried over MgSO4. After evaporation of solvent, pure partial-fluoro tosylate was obtained in yield of 98%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=O)[C:7]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:6]=2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[S:19])[C:7]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:6]=2[O:5]1
Reactant: CN1CC(CCCl)Oc2ccc(F)cc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ccc(F)cc2C1=S
Reaction time: 2 h
Yield: 125.6 %

Procedure:
To 1.0 g (0.0039 mole) of 2-(2-chloroethyl)-2,3-dihydro-7-fluoro-4-methyl-1,4-benzoxazepin-5(4H)-one in 30 ml of acetonitrile was added 0.7 g (0.0016 mole) of phosphorus pentasulfide and the reaction mixture heated to reflux. After 2 hr, another 0.4 g (0.009 mole) of phosphorus pentasulfide was added and heating continued for 2 hr. The reaction mixture was diluted with 70 ml of toluene and filtered. The filtrate was washed carefully with 3×50 ml of saturated sodium bicarbonate and 50 ml of water, dried over sodium sulfate, filtered, charcoaled, filtered and concentrated by rotary evaporation. The crude material was recrystallized from diisopropyl ether to give 0.55 g (52%) of yellow crystals, m.p. 135°-137° C.
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.[F:8][C:9]1[C:37]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:36][C:12]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][C:11]=2[CH:10]=1>ClCCl>[CH:1]1([CH2:4][C:5]([N:41]2[CH2:42][CH2:43][N:38]([C:37]3[C:9]([F:8])=[CH:10][C:11]4[N:15]=[C:14]([CH2:16][O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:13]([CH2:24][C:25]5[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=5)[C:12]=4[CH:36]=3)[CH2:39][CH2:40]2)=[O:7])[CH2:2][CH2:3]1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Reactant: O=C(O)CC1CC1
Solvent: ClCCl
Product: O=C(CC1CC1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
0.020 ml of cyclopropyl-acetic acid (0.2 mmol) and 40 mg of 1,1-carbonyldiimidazole (0.24 mmol) were refluxed in 4 ml dichloromethane under nitrogen for 40 minutes. 100 mg 5-Fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.2 mmol) were added and the resulting mixture refluxed for additional 26 h. The reaction mixture was then diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 129 mg yellow solid. This residue was purified by column chromatography (24 g silicagel, dichloromethane/methanol 24:1) leading to 77 mg light yellow solid (63%). MS (ISP) 583.3 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([CH2:37][NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:11][C@H:12]([NH:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([O:15]C)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:42]([O:41][C:39]([NH:38][CH2:37][CH:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][C@H:12]([NH:17][C:18]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:13]([OH:15])=[O:14])=[O:40])([CH3:44])([CH3:45])[CH3:43]
Reactant: COC(=O)[C@H](CC(CNC(=O)OC(C)(C)C)CNC(=O)OC(C)(C)C)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (2S)-5-{[(tert-butoxy) carbonyl]amino}-4-({[(tert-butoxy)carbonyl]amino}methyl)-2-[(triphenylmethyl)amino]pentanoate CV (180 mg; 0.29 mmol) in methanol (15 mL) was added 4 M aq NaOH (3 mL). The mixture was stirred at r.t. for 1 h. Water (20 mL) was then added and the methanol was removed under reduce pressure. The aqueous solution was acidified with 2 M HCl to pH˜5-6 and extracted with DCM. The combined organic layers were dried over anhydrous MgSO4 and evaporated to obtain the crude (2S)-5-{[(tert-butoxy)carbonyl]amino}-4-({[(tert-butoxy)carbonyl]amino}methyl)-2-[(triphenylmethyl)amino]pentanoic acid CVI (145 mg). This material was used directly for step 6. ESIMS found for C35H45N3O6 m/z 604.4 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:24]([O-])([OH:26])=[O:25]>O>[N+:24]([C:6]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(-c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]

Procedure:
To a mixture of 4-acetamido-1,1′biphenyl (21.1 g, 0.1 mol) and 150 mL of acetic anhydride maintained between 8° C. and 13° C. is slowly added dropwise over 32 minutes 12.7 mL of 70% nitric acid. The reaction mixture is added to 600 mL of a mixture of water and ice and the resultant precipitate is collected by filtration. The filter cake is washed with water and the residue is recrystallized from methanol (800 mL) to give 23.6 g of the title compound as a yellow crystalline solid melting at 129–132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])/[C:7](=[CH:13]/[CH2:14][NH2:15])/[CH2:6][CH2:5]2.[ClH:16].C(O)C>>[ClH:16].[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]([CH2:13][CH2:14][NH2:15])=[CH:6][CH2:5]2)=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc2c(cc1Br)CC/C2=C\CN
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1Br)CC=C2CCN
Yield: 81 %

Procedure:
(E)-2-(5-Bromo-6-methoxyindan-1-ylidene)ethylamine (5.0 g, 18.6 mmol) was dissolved in saturated HCl/ethanol (200 ml) and the solution was refluxed for 2 hours. After cooling, the solvent was distilled off under reduced pressure and the resulting crystals were washed with diethyl ether to provide the title compound (yield 4.61 g, 81%).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[OH:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[CH:28]=[C:27]([C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33])[CH:26]=[CH:25]2>>[C:32]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([O:21][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)[CH:31]=[CH:30]2)(=[O:33])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(c1ccccc1)c1ccc2cc(O)ccc2c1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3cc(C(=O)c4ccccc4)ccc3c2)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with (6-Hydroxy-naphthalen-2-yl)-phenyl-methanone under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C(NaOH) to give the title compound. MS(ES) for C30H28O6 [M+Na]+: 507, [M+H]+: 485.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.C(O)C>Cl>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[O:32][CH:33]=[CH:34][CH:35]=4)[O:28][C:29]=3[CH3:30])=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1nn(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazole-4-yl]propionate (381 mg), 1 N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for four hours, diluted with 1 N hydrochloric acid (2 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The obtained colorless crystals were collected by filtration, and 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-1H-pyrazol-4-yl]propionic acid was obtained (327 mg, yield: 91%). This was recrystallized from ethanol-hexane. Melting point: 129–130° C.