Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][N:5]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.O.[OH-].[Li+].O.Cl>C1COCC1>[CH:27]1([CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:5]([CH2:4][C:3]([OH:30])=[O:2])[CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N:13]([CH3:15])[CH3:14])=[CH:11][CH:12]=3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)[CH2:29][CH2:28]1
Reactant: COC(=O)CN(Cc1ccc(N(C)C)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 74.6 g (172.4 mmol) of the compound of Stage 1.4 in 800 ml of THF, 14.5 g (345.6 mmol) of lithium hydroxide monohydrate and 400 ml of H2O are successively added at 0-5° C. After stirring for 4 h at r.t., the mixture is neutralized with aqueous 2 mol HCl at 0-5° C. and extracted with CH2Cl2 several times. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give the title compound.
Reaction SMILES: CS([O:5][C@@H:6](C)[C:7]([C:15]1C=CC=CC=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)O)(=O)=O.[CH3:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C([Al](CC)CC)C>C(Cl)Cl.P([O-])([O-])([O-])=O.C(OCC)(=O)C>[C:24]1([C:6](=[O:5])[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:15])[CH:23]=[CH:22][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCC
Reactant: C[C@H](OS(C)(=O)=O)C(O)(c1ccccc1)c1ccccc1
Agent: CC[Al](CC)CC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C(=O)c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
To (S)-2-methanesulfonyloxy-1,1-diphenyl-1-propanol (153 mg, 0.5 mmol) present in 5 ml of CH2Cl2 in Referential example 3 was added a hexane solution of triethylaluminum (0.6 mmol, 0.7 ml) slowly at -78° C. The color of the solution changed to yellow. After stirred further for 30 minutes, the reaction was stopped with three drops of phosphate buffer solution having a pH value of 7. The suspension obtained was diluted with ethyl acetate, dried over anhydrous Na2SO4, filtered and concentrated. Oily residue was subjected to the chromatography treatment with Florisil column to obtain 1,2-diphenyl-1-propanone (100 mg, 96%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@@H:14]([CH2:16][OH:17])[O:13][C:12]3=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(OC[C@H]1OC1)(=[O:23])CCC.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C.CC1(C)N([O])C(C)(C)CCC1.C([O-])([O-])=O.[Na+].[Na+]>CC(=O)OCC.O.CC#N>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@@H:14]([C:16]([OH:23])=[O:17])[O:13][C:12]3=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCCC(=O)OC[C@@H]1CO1
Reactant: O=C1O[C@H](CO)CN1c1ccc2c(c1)OCCO2
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)[C@@H]1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 0 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of (S)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one (enantiomeric antipode of intermediate 1.iii), prepared from (S)-glycidyl butyrate, 985 mg, 3.92 mmol) in 1:1 water/MeCN (20 mL) cooled to 0° C. was added diacetoxyiodobenzene (2.83 g, 2.2 eq) and TEMPO (122 mg, 0.2 eq). The mixture was stirred at 0° C. for 30 min and at rt overnight. EA and sat. Na2CO3 were added and the phases separated. The aq. layer was washed once more with EA and then carefully acidified with 1M aq. HCl. The aq. phase was then extracted 2× with EA. The combined org. layers were washed with brine and dried over MgSO4 and concentrated to afford the desired intermediate as colourless solid (847 mg, 81%).
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[C:7]([CH3:31])[C:8]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([N+:21]([O-])=O)=[CH:19][C:18]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:17][N:16]=2)=[N:9][CH:10]=1>[Ni].CO.C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH3:31])[C:8]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[C:20]([NH2:21])=[CH:19][C:18]([CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)=[CH:17][N:16]=2)=[N:9][CH:10]=1
Reactant: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)cnc1CCCNc1ncc(Cc2cccnc2)cc1N

Procedure:
Hydrazine hydrate (5.3 ml in 25 ml methanol) was added dropwise over 25 minutes to a stirred and cooled suspension under nitrogen of 2-[3-(5-bromo-3-methylpyrid-2-yl)propylamino]-3-nitro-5-(pyrid-3-ylmethyl)pyridine (5.07 g) and Raney nickel (10 g) in methanol (600 ml) and ethanol (100 ml) keeping the temperature at 5°-10° C. Reaction was allowed to stir at 5° C. for a further 45 minutes. Raney nickel was filtered off and the filtrate was concentrated to dryness to give an oil which was re-evaporated with n-propanol giving the title compound, theoretical yield, crude product used directly in next reaction.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:17])=[CH:9][C:10]=1[CH2:11][C:12]([O:14]CC)=[O:13])=[O:5])C.[Li+].[OH-].Cl>CO.O>[C:12]([CH2:11][C:10]1[CH:9]=[C:8]([CH3:17])[NH:7][C:6]=1[C:4]([OH:5])=[O:3])([OH:14])=[O:13]
Reactant: CCOC(=O)Cc1cc(C)[nH]c1C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(CC(=O)O)c(C(=O)O)[nH]1
Yield: 87.1 %

Procedure:
A solution of 3-ethoxycarbonylmethyl-5-methyl-1H-pyrrole-2 caboxylic acid ethyl ester (7 g, 29.26 mmol), LiOH (7 g, 10 eq.) in methanol (90 mL) and water (30 mL) was heated in a 70° C. oil bath for 3 hours. The cooled reaction was adjusted to pH 3 with 3N HCl, the resulted precipitate was collected by filtration, washed with water and dried to give 4.67 g (87%) of 3-carboxymethyl-5-methyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[K+].[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[N:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[S:19][CH:20]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:20]1[S:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:17][C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]#[N:9])[CH:11]=1
Reactant: BrBr
Reactant: CCOC(=O)c1nc(-c2cccc(C#N)c2)cs1
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2cccc(C#N)c2)c(Br)s1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
At room temperature, 3.18 g (19.9 mmol) of bromine and 1.95 g (19.9 mmol) of potassium acetate are added to 1.03 g (3.98 mmol) of the compound from Example 34A in 50 ml of conc. acetic acid. The mixture is stirred at 100° C. for 12 h, whereby after 6 and 9 h the same amount of bromine (in each case 3.18 g, 19.9 mmol) and potassium acetate (in each case 1.95 g, 19.9 mmol) are again added. A 1M aqueous sodium thiosulfate solution is subsequently added, and the reaction solution is extracted with dichloromethane. The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 20:1→10:1). 1.15 g (86% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:9][CH2:1][C:2]1[O:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(C)c(C)o1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc(CBr)oc1C
Temperature: 76 °C
Reaction time: 3 h
Yield: 7.8 %

Procedure:
A mixture of 2,4,5-trimethyloxazole (0.50 mL, 4.3 mmol), N-bromosuccinimide (0.77 g, 4.3 mmol) and benzoyl peroxide (0.21 g, 0.86 mmol) in carbon tetrachloride (4 mL) was heated at 76° C. under nitrogen atm. for 3 hrs. After cooling to rt, the solid was removed by filtration. The filtrate solution was washed with saturated aqueous NaHCO3 (20 mL) and concentrated. The residue was purified by flash column chromatography (SiO2; hexanes:ethyl acetate/4:1) to afford 2-(bromomethyl)-4,5-dimethyloxazole (64 mg) as an yellow oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C.O>C1COCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:8])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(Cl)c1ccc(Br)s1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)s1

Procedure:
The product from Example 241a (2.178 g, 10.25 mmol) was reacted with 4-fluoro-3-nitro-phenylamine (1.60 g, 10.25 mmol) dissolved in THF (25 mL) and Hunig's base (2.484 g, 19.22 mmol). Reaction mixture was stirred at room temperature for 1 hr at which time water was added and the title compound was collected by filtration (2.00 g, 78%).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].NC1CCC2C=CC=CC=2N(CC(OC(C)(C)C)=O)C1=O.C(=O)C1C=CC=CC=1>C(O)C>[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CC(C)(C)OC(=O)CN1C(=O)C(N)CCc2ccccc21
Solvent: O=Cc1ccccc1
Solvent: CCO
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 186.6 %

Procedure:
A solution of 12.65 g of L-(+)-tartaric acid in 54 ml of ethanol which had been heated to 650° C. was added to a solution, which had been heated to 65° C., of 24.5 g of the racemic tert-butyl 3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate (preparation, see Example II). The reaction mixture was stirred at room temperature for one hour. A solution of 1.72 ml of benzaldehyde in 1.3 ml of ethanol was then added dropwise. The resulting suspension was boiled under reflux at 800° C. for 14 hours and then cooled down to room temperature. The resulting crystalline precipitate was filtered out with suction and taken up in 80 ml of ethanol; this solution was boiled under reflux for a further 8 hours. It was then cooled down to room temperature and the crystals were filtered out with suction and dried at 50° C. under reduced pressure. 23.6 g of tartaric acid salt were obtained with a melting point of from 195° to 196° C. and an optical rotation value [α]20D of -152° C. (c=0.5 in methanol). In order to liberate the base, 23.6 g of the tartaric acid salt in a mixture consisting of 250 ml of water and 108 ml of dichloromethane were cooled down to 0° C., while being stirred, and adjusted to pH 9.6 by adding aqueous ammonium solution. The organic phase was separated, and the aqueous phase was extracted with a further 30 ml of dichloromethane; the organic phases were combined, dried over sodium sulfate and concentrated under reduced pressure. The remaining residue was crystallized from methyl tert-butyl ether and dried under reduced pressure. 12.2 g of tert-butyl (3S) -3-amino-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-acetate were obtained with a melting point of from 113° to 115° C. and an optical rotation value [α]20D of -276.2° (c=0.5 in methanol).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH2:28])[CH:25]=4)[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[OH-].[Na+]>C(#N)C.O>[F:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][NH:28][C:1](=[O:3])[CH3:2])[CH:25]=4)[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:8][CH:7]=1
Reactant: NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 54 %

Procedure:
Under ice cooling, acetyl chloride (6.6 ml) was added dropwise into a solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (30 g) obtained above and triethylamine (9.4 g) in acetonitrile (500 ml) and the resultant mixture was stirred at room temperature for 1 hr. After adding a 5 N aqueous solution (40 ml) of sodium hydroxide and water (500 ml) to the reaction solution, the resulting crystalline precipitates were collected by filtration, washed successively with water and ethyl acetate and then dried at 50° C. overnight to give the crude title compound (22.8 g). This crude product was recrystallized successively from ethyl acetate and ethanol to give the title compound (17.9 g) as white needles (yield: 54%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:14]([CH:20]=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([O:24]CC)=[O:23])[O:13][C:12]1([CH3:31])[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.C(OCC)(=O)C.[OH-].[K+].Cl>C(O)C.O>[CH2:1]([O:8][C:9]([N:11]1[C@@H:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[C@H:14]([CH:20]=[C:21]([CH:27]([CH3:29])[CH3:28])[C:22]([OH:24])=[O:23])[O:13][C:12]1([CH3:31])[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1CC(C)C)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCCCCC
Product: CC(C)C[C@H]1[C@H](C=C(C(=O)O)C(C)C)OC(C)(C)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
400 mg of ethyl 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoate was dissolved in 0.2 ml of ethanol and 2.32 ml of an ethanol/water (10/1) solution of 2N potassium hydroxide was added thereto. The mixture was stirred at room temperature for 3 hours and further stirred for 1 hour at 55° C. 24 ml of water was added to the reaction solution, and the reaction solution was adjusted to pH 2 with 1N hydrochloric acid under cooling with ice. The solution was extracted three times with ethyl acetate, and the organic layer was washed with sequentially water and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 375 mg of 3-[(4S,5S)-3-benzyloxycarbonyl-2,2-dimethyl-4-isobutyloxazolidin-5-yl]-2-isopropyl-2-propenoic acid as a colorless oily substance.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH:73](OC)[O:74]C)[CH2:67][C:68]1[CH:72]=[CH:71][S:70][CH:69]=1)=[O:64])[CH2:59][CH:60]([CH3:62])[CH3:61])=[O:56])[C:51]([CH3:54])([CH3:53])[CH3:52])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:34])[O:29]C(C)(C)C)=[O:23])[CH2:14][C:15](=[O:21])[O:16]C(C)(C)C)=[O:11])=[O:7])(C)(C)C.O>ClCCl.FC(F)(F)C(O)=O>[C:6]([CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:22]([NH:24][C@H:25]([C:35]([NH:37][C@H:38]([C:47]([NH:49][C@H:50]([C:55]([NH:57][C@H:58]([C:63]([NH:65][CH:66]([CH2:67][C:68]1[CH:72]=[CH:71][S:70][CH:69]=1)[CH:73]=[O:74])=[O:64])[CH2:59][CH:60]([CH3:61])[CH3:62])=[O:56])[C:51]([CH3:54])([CH3:52])[CH3:53])=[O:48])[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH3:46])=[O:36])[CH2:26][CH2:27][C:28](=[O:29])[OH:34])=[O:23])[CH2:14][C:15](=[O:16])[OH:21])=[O:11])([OH:7])=[O:5]
Reactant: COC(OC)C(Cc1ccsc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC(=O)O)NC(=O)CCC(=O)O)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)NC(C=O)Cc1ccsc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.8 %

Procedure:
0.065 g (0.06 mmol) of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-[1(RS)-(dimethoxymethyl)-2-(3-thienyl)ethyl]-L-leucinamide wasdissolved in 10 ml of dichloromethane/trifluoroacetic acid (1:1) containing3 drops of water. The solution was stirred for 3 hours at room temperature.After removal of the solvent by evaporation the crude product was chromatographed on silica gel using dichloromethane:methanol:acetic acid:water (120:15:3:2) as the eluent to give 0.035 g of 2(RS)-[[N-[N-[N-[N-[N-(3-carboxypropionyl)-L-α-aspartyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucyl]amino]-3(3-thienyl)propionaldehyde as a white solid; MS: m/e 887.7 [M+H]+.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:36]>CO.[H][H]>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:22]([O:24][CH3:25])=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[ClH:36]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)[C@@H](N)C(C)C
Reaction time: 8 h

Procedure:
Pd-on-charcoal catalyst is added to a solution of 65 g (0.134 mole) of Z-Val-Tyr(But)-OMe in 300 ml of methanol and hydrogen is passed through the solution at pH 4.5 (autotitrator) while stirring and adding approx. 2 N methanolic hydrochloric acid, until no further methanolic hydrochloric acid is taken up. The catalyst is then filtered off and the filtrate is concentrated. The residue is triturated with ether, in the course of which the substance dissolves and, after standing overnight at 4°, precipitates out in crystalline form. The crystals are filtered off and dried over P2O5. The substance is hygroscopic. Yield 44.1 g (85%), melting point 88°-102°, [α]D21 =+31.0° (c=1, methanol).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.ClCCl>[C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: NCCCCCCO
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(NCCCCCCO)OCc1ccccc1
Reaction time: 8 h

Procedure:
6-Aminohexan-1-ol (11.7 g, 100 mmol) and potassium carbonate (16.58 g, 120 mmol) were dissolved in 100 mL water and 70 mL dichloromethane. Benzylchloroformate (14.27 mL, 100 mmol) was added dropwise over 30 minutes at a temperature of 25-30° C. The resulting mixture stood overnight, then the dichloromethane layer was separated, washed with water (3×200 mL), 2 N HCl (3×50 mL) and finally with water (3×100 mL), dried, and evaporated to give a white solid. The solid was recrystallized in hexane-ethylacetate (8:2) to give a solid, which was collected and dried under vacuum at room temperature. Yield: 23 g (91%).
Reaction SMILES: [NH2:1][C:2]1[C:9](Br)=[CH:8][C:7](Br)=[CH:6][C:3]=1[C:4]#[N:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[CH:8][C:9]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)cc(Br)c1N
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc(-c2cc(C#N)c(N)c(-c3ccc(OC)cc3)c2)cc1
Temperature: 80 °C
Yield: 89.2 %

Procedure:
A mixture of 2-amino-3,5-dibromobenzonitrile (250 mg, 0.906 mmol), 4-methoxyphenylboronic acid (330 mg, 2.17 mmol), tetrakis(triphenylphosphine)-palladium(0) (52 mg, 0.045 mmol) and cesium fluoride (661 mg, 4.35 mmol) was placed in a vial and flushed with nitrogen. Dimethoxyethane (4.5 mL) was added and the reaction was heated at 80° C. for 7 hr. After cooling to room temperature, the reaction was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated, washed with saturated aqueous sodium bicarbonate solution, brine, and then dried with sodium sulfate. Removal of the solvent followed by silica gel radial chromatography (step gradient elution with hexane containing 0 to 20% ethyl acetate) afforded 4′-amino-4,4″-dimethoxy-[1,1′:3′,1″-terphenyl]-5′-carbonitrile (267 mg, 89% yield) as an oil. MS (ESI) m/z 331.1 (M+H). 1H NMR (CDCl3) δ ppm 7.54 (1H, d, J=2.14 Hz), 7.46 (1H, d, J=2.14 Hz), 7.42 (2H, d, J=8.55 Hz), 7.36 (2H, d, J=8.55 Hz), 7.01 (2H, d, J=8.55 Hz), 6.94 (2H, d, J=8.55 Hz), 4.50 (2H, s), 3.86 (3H, s), 3.83 (3H, s).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:23])[C:15]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1>C1COCC1>[F:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:13])[N:23]([CH2:14][C:15]1[CH:22]=[CH:21][C:18]([O:19][CH3:20])=[CH:17][CH:16]=1)[CH2:11]2
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1ccc(F)cc1CBr
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3cc(F)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a stirred solution of 2-bromomethyl-4-fluoro-benzoic acid methyl ester (17 g, 68.8 mmol) in THF (200 mL) was added PMBNH2 (23.6 g, 172 mmol) at 0° C. After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo to give a crude product which was then purified by column chromatography to give the title compound (13 g, yield 69%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][O:30][CH3:31])[CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:31][O:30][CH2:29][CH2:28][CH:25]1[CH2:24][CH2:23][N:22]([CH2:21][CH2:20][CH2:19][O:17][C:14]2[CH:15]=[CH:16][C:11]([C:5]3([CH2:4][N:2]([CH3:1])[CH3:3])[CH2:6][CH2:7][O:8][CH2:9][CH2:10]3)=[CH:12][CH:13]=2)[CH2:27][CH2:26]1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Reactant: COCCC1CCN(CCCCl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCC1CCN(CCCOc2ccc(C3(CN(C)C)CCOCC3)cc2)CC1
Yield: 45.9 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (500 mg, 2.13 mmol), 1-(3-chloro-propyl)-4-(2-methoxy-ethyl)-piperidine (466 mg, 2,13 mmol), DMF (10 ml) and K2CO3 (1.18 g, 8.52 mmol) were reacted together according to general procedure B. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:4:1) provided the title compound (409 mg, 46%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.86 (d, 2H), 3.99 (t, 2H), 3.75 (dt, 2H), 3.55 (td, 2H), 3.41 (t, 2H), 3.33 (s, 3H), 2.97-2.86 (m, 2H), 2.49 (t, 2H), 2.40 (s, 2H), 2.15-1.78 (m, 8H), 1.97 (s, 6H), 1.74-1.17 (m, 7H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]2[C:29]3[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)[CH:16]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([NH:13][C:15]2[CH:16]=[C:17]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:19][N:20]=2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(Cl)ncn1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Temperature: 90 °C
Yield: 13.5 %

Procedure:
A mixture of 18b (1.1 g, 5.9 mmol), 6a (1.5 g, 4.84 mmol) and diisopropylethylamine (3 mL, 18.1 mmol) in 15 mL of DMF was heated at 80° C. for 17 h and at 90° C. for 24 h. The mixture was diluted with 100 mL of DCM, washed with brine (3×50 mL) and the extracts were dried, filtered and concentrated under vacuum. The residue was purified by flash chromatography (elution with 50-100% ethyl acetate and 0.1% TEA in hexanes) and finally purified on preparative HPLC to afford 0.3 g (14%) of 18-1. tR=5.21 (Method 5). EC50: 611 nM.