Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[S:2]([C:9]1[CH:34]=[CH:33][C:12]([CH2:13][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1)([C:5]([F:8])([F:7])[F:6])(=[O:4])=[O:3].[Li][CH2:36][CH2:37][CH2:38][CH3:39].[OH:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45](C1C=CC(C=CC=O)=CC=1)[CH2:46][CH2:47][CH2:48][CH3:49].O>C1(C)C=CC=CC=1>[OH:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]([C:13]([C:12]1[CH:11]=[CH:10][C:9]([S:2]([C:5]([F:6])([F:7])[F:8])(=[O:3])=[O:4])=[CH:34][CH:33]=1)=[CH:39][CH:38]=[CH:37][C:36]1[CH:33]=[CH:34][CH:9]=[CH:10][CH:11]=1)[CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: [Li]CCCC
Reactant: O=S(=O)(c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1)C(F)(F)F
Reactant: CCCCN(CCCCO)c1ccc(C=CC=O)cc1
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCN(CCCCO)C(=CC=Cc1ccccc1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 110 g (0.2 mole) of 4-triflylbenzyltriphenylphosphonium bromide in toluene is added dropwise 0.2 moles of n-BuLi at room temperature. After 2 hours a solution of 27.5 g (0.1 mole) of 4[N-4-hydroxybutyl-N-butylamino]cinnamaldehyde in toluene is added dropwise to the mixture, and the reaction is stirred for 18 hours at room temperature. Water is added, and compound C is isolated by vacuum filtration, washed with 60% ethanol/water, dried under vacuum, and purified by recrystallization from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[CH:17]([CH3:19])[CH3:18]>>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH:17]([CH3:19])[CH3:18])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1ccccc1Br
Product: CCOC(=O)C1=C(C(C)C)Nc2n[nH]cc2C1c1ccccc1Br

Procedure:
The title compound was prepared from 2-bromobenzaldehyde, 3-aminopyrazole and ethyl isobutyrylacetate in the same manner as in Example 275.
Reaction SMILES: C1COCC1.[I:6][C:7]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:8]=1[NH2:9].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>N1C=CC=CC=1>[I:6][C:7]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:8]=1[NH:9][C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:15])([F:26])[F:27])[CH:18]=1)=[O:25]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Br)cc1I
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1I
Temperature: 65 °C
Yield: 92.3 %

Procedure:
To a 100 mL of anhydrous THF in a 250 mL round bottom flask containing a stirring bar, 2-iodo-4-bromoaniline (2.00 g, 6.70 mmol) was added along with 3-trifluoromethylphenylisocyanate (1.51 g, 7.00 mmol) and 52 mg of pyridine. The resulting solution was heated at 65° C. overnight. THF was removed by rotary evaporation and the product was recrystallized from ethyl acetate to give 3.0 g (92%) of 1-(2-iodo-4-bromophenyl)-3-(3-trifluoromethylphenyl)urea as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:6](=[C:11]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH3:4].[CH3:25]I.O>O1CCCC1.C(OCC)(=O)C>[C:3]([C:6](=[C:11]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:12]([CH3:25])[C:13]([O:15][CH3:16])=[O:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH3:4]
Reactant: COC(=O)CC(NCc1ccccc1)=C(C(C)=O)C(=O)OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(C(C)=O)=C(NCc1ccccc1)C(C)C(=O)OC
Reaction time: 0.25 h

Procedure:
Under nitrogen stream, 60 % sodium hydride (1.68 g; 42 mmole) was added to dry tetrahydrofuran (10 ml), and a solution of dimethyl 2-acetyl-3-benzylamino-2-pentenedioate (6.2 g; 20 mmole) in dry tetrahydrofuran (40 ml) was portionwise added thereto with ice-cooling, followed by stirring at the same temperature for 15 minutes. Methyl iodide (5.68 g; 40 mmole) was added thereto at room temperature, and the resultant mixture was stirred at room temperature for 1 hour and at 40° C. for 1 hour. Water was added to quench the reaction, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed successively with water, dilute hydrochloric acid and an aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give dimethyl 2-acetyl-3-benzylamino-4-methyl-2-pentenedioate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[C:18]([CH:19]=O)=[CH:17][N:16]=[C:15]([CH3:21])[N:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:10]([NH2:11])=[N:12][C:13]2[N:14]=[C:15]([CH3:21])[N:16]=[CH:17][C:18]=2[CH:19]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: N#CCc1c(Cl)cccc1Br
Product: Cc1ncc2cc(-c3c(Cl)cccc3Br)c(N)nc2n1

Procedure:
Following the procedure for Example 1, 2-bromo-6-chlorophenylacetonitrile is condensed with 4-amino-2-methylpyrimidin-5-carboxaldehyde to give 6-(2-bromo-6-chlorophenyl)-2-methylpyrido[2,3-d]-pyrimidin-7-amine, mp 272°-274° C., after recrystallization from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:40]=[CH:39][C:38]([C:41](=[O:44])[NH:42][CH3:43])=[CH:37][C:9]=2[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([O:35]C)=[O:34])=[CH:32][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:40]=[CH:39][C:38]([C:41](=[O:44])[NH:42][CH3:43])=[CH:37][C:9]=2[CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[N:22]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]4[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CNC(=O)c1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3nc4cc(C(=O)OC)ccc4n3C3CCCCC3)cc2)c1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2ccc(Cl)cc2)c(COc2ccc(-c3nc4cc(C(=O)O)ccc4n3C3CCCCC3)cc2)c1
Product: Cl
Yield: 181.3 %

Procedure:
Methyl 2-{4-[2-(4-chlorophenyl)-5-methylcarbamoylbenzyloxy]-phenyl}-1-cyclohexylbenzimidazole-5-carboxylate (150 mg) obtained in Example 247 and tetrahydrofuran (2 ml) were treated in the same manner as in Example 2 to give the title compound (141 mg, yield 90%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]([CH3:29])[C@@H:10]([OH:28])[CH2:11][N:12]([CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH2:13][C:14]([F:17])([F:16])[F:15])C1C=CC=CC=1.CC(O)=O.CCOCC>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C@H:9]([CH3:29])[C@@H:10]([OH:28])[CH2:11][N:12]([CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[CH2:13][C:14]([F:15])([F:16])[F:17]
Reactant: C[C@H]([C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](N)[C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F
Reaction time: 72 h
Yield: 7.9 %

Procedure:
Pd(OH)2 was carefully wetted down under N2 with 20 mL of MeOH and the product of Step d (3.78 g) dissolved in 50 mL of MeOH was added followed by 70 mL of HOAc. The mixture was hydrogenated for 3 days on a Parr shaker at 50 PSI. Worked up by filtering off the catalyst under N2 and vacuum through a fiberglass filter paper to obtain an oil. To the oil was added Et2O/saturated NaHCO3 (100 mL) The layers were separated. The aqueous was basified further with 1N NaOH to pH=12 then extracted 3 times with Et2O. The Et2O extracts from the 1N NaOH layer were combined, dried (Na2SO4) and stripped to give 2.46 g of and amber oil. The oil was purified by flash chromatography in 9:1 Hexanes/EtOAc to 100% EtOAc. Obtained 192 mg of an oil. MS (ESI) detects (M+H)+=323.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3](=O)[CH:4]=[CH:5][NH:6][CH:7]=[CH:8][C:9]#[N:10].[OH-].[Na+].CCCCCC.CC(C)=[O:24]>CO>[F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9]([NH2:10])=[O:24])=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: CC(C)=O
Reactant: N#CC=CNC=CC(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: NC(=O)c1cnccc1C(F)(F)F
Yield: 65.6 %

Procedure:
3-[(4,4,4-Trifluoro-3-oxo-1-butenyl)amino]-2propenenitrile (a mixture of IIa and IIb; 1.90 g, 10 mmol) was dissolved in methanol (15 ml), and sodium hydroxide (600 mg, 15 mmol) was added. The mixture was heated under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a eluting solvent: hexane/acetone=1/1) to obtain 1.25 g (yield 65.6%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.CN(C)C=O.[OH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]=[C:19]=[S:20]>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:3]([C:19]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:12])=[S:20])[N:4]=[CH:5][N:6]=1
Reactant: Nc1nc[nH]n1
Reactant: OCCCCCN=C=S
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1ncnn1C(=S)NCCCCCO
Yield: 18.9 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (4.00 g), dimethylformamide (25 ml) and 5-hydroxypentyl isothiocyanate (9.24 g) were used as reagents. After the reaction, silica gel column chromatography (chloroform-methanol) was applied to give 2.06 g of white crystals (yield 19%). The crystals were subjected to recrystallization from chloroform to give white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[H-].[Na+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C>O1CCCC1.C(OCC)(=O)C.O>[Br:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:7][CH:6]=1
Reactant: N#Cc1nc(Br)cnc1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1nc(Br)cnc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 80 mL of tetrahydrofuran was dissolved 4.0 g of 3-amino-6-bromo-2-pyrazinecarbonitrile synthesized according to the procedure mentioned in U.S. Pat. No. 3,341,540. While cooling the solution with ice, 1.2 g of 60% sodium hydride and 2.8 mL of benzoyl chloride were successively added, and further 0.8 g of 60% sodium hydride was added. The mixture thus obtained was stirred at an ice-cooled temperature for one hour and thereafter at room temperature for 30 minutes. Then, 0.4 g of 60% sodium hydride was added additionally, and the mixture thus formed was stirred at room temperature for 30 minutes. After cooling the reaction mixture with ice, the mixture was poured into a liquid mixture consisting of 50 mL of ethyl acetate and 100 mL of water, and pH was adjusted to 5 with 6 mol/L hydrochloric acid. The deposited matter was collected by filtration, and the residue thus obtained was dissolved in a mixture of 50 mL of ethyl acetate and 100 mL of tetrahydrofuran, treated with active charcoal, and filtered, after which the solvent was removed under reduced pressure. The residue thus obtained was washed with diisopropyl ether to obtain 1.7 g of N-(5-bromo-3-cyano-2-pyrazinyl)-benzamide as a light yellow-colored solid product. Furthermore, organic layer was separated from the filtrate obtained above, and organic layer was washed successively with water and saturated aqueous solution of sodium chloride, treated with active charcoal and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was washed with diisopropyl ether to obtain 2.9 g of N-(5-bromo-3-cyano-2-pyrazinyl)-benzamide as a yellow-colored solid product.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:18])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[CH2:20]1COCC1.C([Mg]I)C.O>C(OCC)C>[OH:18][C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:19])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)([CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)O)ccc21
Reactant: C1CCOC1
Agent: CC[Mg]I
Solvent: CCOCC
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(C)(O)C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3.1 g (12 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid and 50 ml of THF are introduced into a three-necked flask. At 0° C. and under a stream of nitrogen, 16 ml (48 retool) of a solution of ethylmagnesium iodide in ethyl ether (3M) are added dropwise and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and ethyl ether (20:80). After evaporation of the solvents, 2.6 g (79%) of the expected product, melting point 168°-169° C., are collected.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[N:13](C2CCCCO2)[N:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:10]=1[C:24]1[NH:25][C:26]2[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][C:31]=3[NH:30][C:29]3[N:37]=[CH:38][CH:39]=[CH:40][C:28]=3[C:27]=2[N:41]=1.Cl>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[NH:13][N:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:10]=1[C:24]1[NH:25][C:26]2[C:32]3[CH:33]=[CH:34][N:35]=[CH:36][C:31]=3[NH:30][C:29]3[N:37]=[CH:38][CH:39]=[CH:40][C:28]=3[C:27]=2[N:41]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: Cc1c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(C(F)(F)F)nn1C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cc1[nH]nc(C(F)(F)F)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[5-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine trifluoroacetate (715 mg, 1.23 mmol) in methanol (16 mL) was added 1.25 mL concentrated HCl and the reaction was stirred at 50° C. for 3 h. The reaction was reduced in vacuo and then purified by preparative LCMS to obtain the desired product as a bis-TFA salt (548 mg, 73%). 1H NMR (400 MHz, DMSO-d6): δ 13.8 (bs, 1H), 8.60 (bs, 1H), 8.10 (d, 1H), 8.01 (s, 1H), 7.94 (dd, 1H), 7.61 (m, 2H), 6.88 (dd, 1H), 2.35 (s, 3H). 19F NMR (400 MHz, DMSO-d6): δ-59.476 (3F), −74.791 (6F). MS (EI) m/z=384. (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[C:34]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=4)[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:33]=[CH:32][N:31]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: COc1cccc(Cc2ccn3nc([C@H](C)N)n(-c4ccccc4)c(=O)c23)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Cc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)c1
Yield: 57.4 %

Procedure:
(S)-2-(1-Aminoethyl)-5-(3-methoxybenzyl)-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (120 mg, 0.29 mmol) was treated with 4-amino-6-chloropyrimidine-5-carbonitrile (49 mg, 0.32 mmol), and N,N-diisopropylethylamine (152 μl, 0.87 mmol) in tert-butanol according to the method described in Example 17. The crude was purified by reverse phase using SP1® Purification System to give 82 mg (57% yield) of the title compound as solid. Purity 99%.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:9]1[CH2:14][CH:13]2[CH:11]([C:12]2([C:16]2[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([NH:22]C(=O)C)[CH:21]=2)[CH3:15])[CH2:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO.O>[CH2:3]([N:9]1[CH2:14][CH:13]2[CH:11]([C:12]2([C:16]2[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([NH2:22])[CH:21]=2)[CH3:15])[CH2:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(N)c1
Yield: 76.1 %

Procedure:
To a solution of potassium hydroxide (100 mg, 1.79 nrnol) in methanol (5.0 ml) and water 2.0 ml) was added N-[5-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenyl]acetamide (Preparation 46, 534 mg, 1.49 mmol) in methanol (5 ml). The mixture was heated under reflux for 30 minutes and then was allowed to cool. The solvent was removed in vacuo, water (5 ml) was added and the aqueous solution was extracted with ethyl acetate (3×5 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (360 mg, 76%) as a crude oil which was used without further purification.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:71][O:72][C:73](=[O:85])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])[CH2:16][S:17][CH2:18][C@H:19]([NH:53]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:52])[NH:21][CH2:22][CH2:23][CH2:24]OCCCCOCCCNC(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:86]1CCC[CH2:88][CH2:87]1>C(#N)C>[C:73]([O:72][CH2:71][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH2:53])[C:20]([NH:21][CH2:22][CH2:23][CH2:24][CH2:88][CH2:87][NH2:86])=[O:52])(=[O:85])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCCCOCCCNC(=O)OCC1c2ccccc2-c2ccccc21)OC(=O)CCCCCCCCCCC
Reactant: C1CCNCC1
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCN)OC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (19R,23R)-19-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(9H-fluoren-9-yl)-3,18-dioxo-2,8,13-trioxa-21-thia-4,17-diazatetracosane-23,24-diyl didodecanoate in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the product was purified by mass triggered HPLC using a 50-100% MeCN in H2O (0.1% TFA) gradient to give (R)-3-((R)-2-amino-3-(5-aminopentylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate). 1H NMR (DMSO d-6): δ 8.49 (t, 1H), 5.12 (m, 1H), 4.26-4.32 (dd, 1H), 4.08-4.12 (m, 1H), 3.85 (t, 1H), 3.32-3.41 (m, 7H), 3.20 (m, 2H), 3.11 (m, 1H), 2.91 (dd, 1H), 2.82 (m, 4H), 2.73 (m, 1H), 2.52 (m, 2H), 2.29-2.34 (q, 4H), 1.71-1.79 (m, 2H), 1.62-1.68 (m, 2H), 1.49-1.52 (m, 8H), 1.21-1.34 (m, 32H), 1.18-1.21 (t, 2H), 0.88 (t, 6H). LRMS [M+H]=747.1.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:25]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](=[O:43])[CH2:41]Br)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:25]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40](=[O:43])[CH2:41][N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([N:16]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])(=[O:32])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(Oc1ccccc1C(=O)CBr)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccccc1OC(=O)c1ccccc1
Yield: 34.3 %

Procedure:
Using the procedure described in Example 5, treatment of L-proline-L-isoleucine benzylamide (200 mg, 0.63 mmol) with 2'-benzoyloxy-2-bromoacetophenone (302 mg, 0.95 mmol, 1.5 eq) provided 120 mg of L-isoleucine, N-[1-(2-(2-benzoyloxyphenyl)-2-oxoethyl)-L-prolyl] benzylamide as a foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10].F[B-](F)(F)F.[CH2:23]([O+](CC)CC)[CH3:24].C(=O)(O)[O-]>ClCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:12][C:13]([O:17][CH2:23][CH3:24])=[N:14][CH2:15][CH2:16]1)=[O:10]
Reactant: CC[O+](CC)CC
Reactant: O=C1CN(C(=O)c2cccc(Cl)c2Cl)CCN1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC1=NCCN(C(=O)c2cccc(Cl)c2Cl)C1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a suspension of 4-[(2,3-dichlorophenyl)carbonyl]-2-piperazinone (1 g, 3.66 mmol, e.g. prepared as described in Intermediate 3) in dry Dichloromethane (DCM) (9.15 ml) was added triethyloxonium tetrafluoroborate (1.739 g, 9.15 mmol). The suspension turned shortly to a yellow solution and it was stirred at room temperature under argon. After 5 minutes the mixture was diluted with Dichloromethane (20 mL) and treated with ice (15 mL). The pH was adjusted to circa 7 with saturated bicarbonate solution, the phases were separated and the aqueous extracted with Dichloromethane (50 mL). The combined organics were washed with brine and dried over MgSO4. Evaporation gave 1-[(2,3-dichlorophenyl)carbonyl]-5-(ethyloxy)-1,2,3,6-tetrahydropyrazine (0.98 g) as an orange oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]=[N+:15]=[N-:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[CH:30])=[CH:23][CH:22]=1)(=[O:20])=[O:19].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.CC(O)(C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:30]=[C:29]([CH2:28][O:27][C:24]3[CH:25]=[CH:26][C:21]([S:18]([CH3:17])(=[O:19])=[O:20])=[CH:22][CH:23]=3)[N:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CCOc1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(COc3ccc(S(C)(=O)=O)cc3)nn2)CC1
Reaction time: 8 h

Procedure:
4-Azido-piperidine-1-carboxylic acid tert-butyl ester (1 eq) and 1-methanesulfonyl-4-prop-2-ynyloxy-benzene (1 eq) were suspended in H2O/t-BuOH (1:1). Sodium ascorbate (0.1 eq) was added followed by CuSO4.5H2O (0.01 eq). The mixture was stirred vigorously overnight. The mixture was diluted with water and a precipitate formed. The precipitate was collected by filtration and purified on silica gel to give the desired product. 1H NMR (CDCl3): δ 7.88 (2H, d), 7.67 (1H, s), 7.14 (2H, d), 5.29 (2H, s), 4.64 (1H, m), 4.28 92H, m), 3.05 (3H, s), 2.94 (2H, m), 2.2 (2H, m), 1.96 (2H, m), 1.48 (9H, s).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][C:4]=1[CH3:15].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:47][C:48]1[CH:53]=[CH:52][C:51]([C:54]2[C:58]([C:59](O)=[O:60])=[CH:57][O:56][N:55]=2)=[CH:50][CH:49]=1>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([C:59]([C:58]3[C:54]([C:51]4[CH:52]=[CH:53][C:48]([CH3:47])=[CH:49][CH:50]=4)=[N:55][O:56][CH:57]=3)=[O:60])[CH2:10]2)=[CH:5][C:4]=1[CH3:15]
Reactant: Cc1cc(C2(O)CCNC2)ccc1F
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)c(C)c3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of 3-(4-fluoro-3-methylphenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z calcd for C22H21FN2O3: 380.1536, found 380.1532.