Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[CH:3]=1.CCO[CH2:15][CH3:16].[NH4+].[Cl-]>>[CH3:11][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([C:5]2[CH:10]=[CH:9][C:15]([CH3:16])=[CH:7][CH:6]=2)=[CH:3]1
Reactant: CCOCC
Reactant: Cn1cc(Br)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1ccc(-c2cn(C)c3ccccc23)cc1

Procedure:
A mixture of 4.31 g (0.02 mol) of 3-bromo-1-methyl-1H-indole and 0.22 g (0.0004 mol) of NiCl2dppp was added to a solution of p-TolylMgBr in ether (prepared from 0.6 g of Mg (0.025 mol) and 4.21 g of TolylBr (0.024 mol) in 40 mL of ether) under stirring. The reaction mixture was stirred overnight. The resulting mixture was treated with 10% aqueous NH4Cl, the organic layer was separated, washed with 10% aqueous NH4Cl and then dried over anhydrous Na2SO4. The solution was evaporated to give an oil that crystallized. The product was washed with methanol and dried. Yield 2.2 g (49%) of colorless crystalline solid.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:32][C@H:33]([C:42]([CH2:44][Cl:45])=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1.Cl.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(CCl)=O)CC(C)C)=O)CC(C)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:32][C@H:33]([C:42]([CH2:44][Cl:45])=[O:43])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)CCl
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: Cl
Product: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)CCl

Procedure:
Z-Phe-Gly-Ala-OH (0.77 g, 1.80 mmoles) was coupled to H-TyrCH2Cl.HCl by a mixed anhydride coupling procedure substantially similar to that used for the preparation of Z-Phe-Gly-Leu-LeuCH2Cl in Procedure E. Product was crystallized from ethyl acetate to yield 0.73 g of Z-Phe-Gly-Ala-TyrCH2Cl, which slowly decomposed from 140°-160° and melted with complete decomposition at 160°-160.5°.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](I)=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:17])[CH3:2].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[C:4]([CH:10]3[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]3=[O:17])[CH:5]=2)=[C:21]([F:26])[CH:20]=1
Reactant: Oc1ccc(Cl)cc1F
Reactant: CCc1ccc(I)cc1C1C(=O)CCCC1=O
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCc1ccc(Oc2ccc(Cl)cc2F)cc1C1C(=O)CCCC1=O
Temperature: 160 °C

Procedure:
To a mixture of 2-(2-ethyl-5-iodophenyl)cyclohexane-1,3-dione (0.250 g, 0.73 mmol), 4-chloro-2-fluorophenol (0.535 g, 3.65 mmol) and cesium carbonate (0.477 g, 1.46 mmol) is added powdered 3 Å molecular sieves (0.300 g) and copper (II) trifluoromethanesulfonate (0.012 g, 0.037 mmol). After degassing with nitrogen anhydrous toluene (4 ml) is added, and the suspension is heated at 160° C. for 1 hour under microwave irradiation. The reaction mixture is acidified with 2M aqueous hydrochloric acid and extracted with dichloromethane (×2). The organic phase is separated then evaporated under reduced pressure to yield a crude product which is purified by preparative reverse-phase HPLC to afford 2-[5-(4-chloro-2-fluoro-phenoxy)-2-ethylphenyl]cyclohexane-1,3-dione.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[CH:4]=[N:3]1.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:38]=[CH:37][C:19]([C:20]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:38]=[CH:37][C:19]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:21])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Reactant: Cc1c(C=O)cnn1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(CN2CCC(c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)CC2)cnn1C
Reaction time: 2.5 h
Yield: 83.8 %

Procedure:
1,5-Dimethyl-1H-pyrazole-4-carbaldehyde (114 mg, 0.92 mmol) was added to a solution of tert-butyl 2-[(4-piperidin-4-ylbenzoyl)amino]phenylcarbamate (289 mg, 0.73 mmol) in dichloromethane (6 ml) followed by acetic acid (50 μl, 0.87 mmol). The reaction mixture was allowed to stir under nitrogen for 2.5 hours. Sodium triacetoxyborohydride (233 mg, 1.10 mmol) was added and the reaction mixture allowed to stir, at ambient temperature, for 18 hours (overnight). Saturated aqueous sodium bicarbonate solution (10 ml) was then added to the reaction and allowed to stir for 15 minutes. The organic phase was separated and the aqueous phase re-extracted with dichloromethane (10 ml). The combined organics were washed with water, dried over magnesium sulphate and evaporated to dryness to afford the product as a colourless gum (308 mg, 84%), which was used without further purification; Mass Spectrum: M+H+ 504.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[CH:22][CH:21]=1
Reactant: Cc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(Cc2ccccc2O)cc1
Reaction time: 24 h
Yield: 70.2 %

Procedure:
To a solution of (2-benzyloxyphenyl)-p-tolylmethanol (1.5 g, 4.43 mmol) in methanol (27 mL), a 20% palladium hydroxide catalyst (150 mg) was added and furthermore 2N—HCl (0.37 mL) was added thereto. The mixture was stirred under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (617 mg, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[O:6][CH2:7][CH2:8][N:9]1[CH2:17][CH2:16][CH:15]2[NH:18][CH:11]([CH2:12][CH2:13][CH2:14]2)[C:10]1=[O:19].CCN(C(C)C)C(C)C.[S:34]1[C:38]2[CH:39]=[C:40]([S:43](Cl)(=[O:45])=[O:44])[CH:41]=[CH:42][C:37]=2[N:36]=[CH:35]1>C(Cl)Cl>[S:34]1[C:38]2[CH:39]=[C:40]([S:43]([N:18]3[CH:15]4[CH2:14][CH2:13][CH2:12][CH:11]3[C:10](=[O:19])[N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]4)(=[O:44])=[O:45])[CH:41]=[CH:42][C:37]=2[N:36]=[CH:35]1
Reactant: O=S(=O)(Cl)c1ccc2ncsc2c1
Reactant: COc1ccc(OCCN2CCC3CCCC(N3)C2=O)cc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCCN2CCC3CCCC(C2=O)N3S(=O)(=O)c2ccc3ncsc3c2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(2-(3,4-Dimethoxyphenoxy)ethyl)-3,10-diazabicyclo[4.3.1]decan-2-one (24 mg, 0.07 mmol) in 3 ml DCM was treated with DIPEA (11 mg, 0.09 mmol) and stirred for 30 min at room temperature followed by addition of 1,3-benzothiazole-6-sulfonyl chloride (20 mg, 0.09 mmol). After stirring overnight at room temperature, the reaction was quenched with saturated NH4Cl solution (5 ml), extracted with DCM (4×10 ml). The organic layers were dried over MgSO4 and concentrated in vacuo. The mixture was purified with Preparative-TLC in 10% MeOH in CHCl3.
Reaction SMILES: [OH:1][CH2:2][C:3](OC)([O:25]C)[CH2:4][O:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]([CH:11]=[C:12]2[C:17]3([CH3:21])[C:18]([CH3:20])([CH3:19])[CH:14]([CH2:15][CH2:16]3)[C:13]2=[O:22])=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+]>O>[OH:1][CH2:2][C:3](=[O:25])[CH2:4][O:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH:11]=[C:12]2[C:17]3([CH3:21])[C:18]([CH3:20])([CH3:19])[CH:14]([CH2:15][CH2:16]3)[C:13]2=[O:22])=[CH:23][CH:24]=1
Reactant: COC(CO)(COCc1ccc(C=C2C(=O)C3CCC2(C)C3(C)C)cc1)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC12CCC(C(=O)C1=Cc1ccc(COCC(=O)CO)cc1)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-[4-(3-Hydroxy-2,2-dimethoxypropoxymethyl)benzylidene]-4,7,7-trimethylbicyclo[2.2.1]heptan-2-one from Example 8 (2 mmol) is dissolved in the H2O/3N HCl 2:3 mixture (10 ml) and stirred at room temperature for 2 h. A solution of sodium hydrogencarbonate in water is then added dropwise to the reaction mixture with stirring (to about pH=8), and the reaction mixture is extracted with dichloromethane (3×10 ml). The combined organic extracts are dried over magnesium sulfate. The solvent is removed in vacuo, and the residue is purified by column chromatography using (ethyl acetate:cyclohexane—1:1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]([CH3:25])=[N:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[ClH:26].[CH3:25][C:16]1[N:17]=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(=O)Nc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(NC2CCNCC2)c(C)n1

Procedure:
A solution of 4-(6-acetylamino-2-methyl-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.38 g, 1.09 mmol) in dioxane (10 mL) and 4 M HCl in dioxane (10 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 249.3 [M+H]+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].[C:14]([C:17]1[CH:21]=[C:20]([CH2:22][OH:23])[O:19][N:18]=1)(=[O:16])[NH2:15].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:23][CH2:22][C:20]1[O:19][N:18]=[C:17]([C:14](=[O:16])[NH2:15])[CH:21]=1
Reactant: NC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
2.84 g (14.07 mmol) of 4-nitrophenyl chloroformate are added in small portions to a solution, cooled to approximately 0° C., of 2.00 g (14.07 mmol) of 3-carbamoylisoxazol-5-ylmethanol, 1.71 ml (21.11 mmol) of pyridine and 0.17 g (1.41 mmol) of N,N-dimethylaminopyridine in 15 ml of dichloromethane. The medium is kept stirred at 0° C. for 1 hour and then at ambient temperature for 1 hour. The precipitate formed is filtered off and then copiously rinsed with diisopropyl ether. After drying under vacuum at approximately 60° C., 3.12 g (72%) of the expected product are obtained in the form of a white solid used as is in the following stage.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[OH:11])=[CH:6][CH:5]=1.[C:20]([N:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:23]([O:22][C:20]([N:27]1[CH2:32][CH2:31][CH:30]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH:10]([OH:11])[C:7]3[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:19])=[CH:9][CH:8]=3)=[CH:13][CH:14]=2)[CH2:29][CH2:28]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1ccc(C(O)c2ccc(N)cc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COC(=O)c1ccc(C(O)c2ccc(NC3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1
Yield: 85.1 %

Procedure:
Using general procedure A, 4-[(4-amino-phenyl)-hydroxy-methyl]-benzoic acid methyl ester (see EXAMPLE 100) (1.40 g, 5.44 mmol) and 1-Boc-4-piperidone (1.63 g, 8.18 mmol) gave 4-{4-[hydroxy-(4-methoxycarbonyl-phenyl)-methyl]-phenylamino}-piperidine-1-carboxylic acid tert-butyl ester as a pale solid (2.04 g, 85%).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[N:12]1)=[O:5])[CH3:2].[OH-].[Li+]>O1CCCC1.O>[CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][CH:30]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=2)=[N:12]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)OC)cc3)ccc2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=O)O)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
42 g (22 mmol) of methyl 4-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzoate (contaminated with triphenylphosphine oxide) are dissolved in 300 ml of tetrahydrofuran and 30 ml of water, 1.6 g (66 mmol) of lithium hydroxide are added, and the mixture is stirred at room temperature for 15 h. The reaction mixture is evaporated. The residue is dissolved in 400 ml of water and 200 ml of ethyl acetate, the organic phase is separated off, and the aqueous phase is extracted with 2×200 ml of ethyl acetate. The organic phase is discarded, conc. HCl is added to the aqueous phase to pH 4-5. During this operation, a precipitate deposits, which is filtered off with suction, washed with water and dried.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=2[C:5]([CH3:13])=[C:4]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=1[CH3:22].[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>N1C=CC=CC=1.[Cu](I)I>[CH:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:10]3[O:9][C:8]([CH3:12])([CH3:11])[CH2:7][C:6]=3[C:5]([CH3:13])=[C:4]([NH:14][C:15](=[O:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:3]=2[CH3:22])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)CC(C)(C)O2
Reactant: CC(C)c1ccc(O)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1c2c(c(Oc3ccc(C(C)C)cc3)c(C)c1NC(=O)CC(C)(C)C)OC(C)(C)C2
Temperature: 140 °C
Reaction time: 60 h
Yield: 39.9 %

Procedure:
A mixed solution of N-(7-bromo-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (500 mg, 1.36 mmol) obtained in Example 343, 4-isopropylphenol (556 mg, 4.08 mmol) and potassium carbonate (188 mg, 1.36 mmol) in pyridine (16 mL) was stirred at 140° C. under argon atmosphere for 1 hour. Copper iodide (259 mg, 1.36 mmol) was added to the reaction solution and the mixture was stirred at 140° C. for 60 hours. Water was added to the reaction solution and the product was extracted with ethyl acetate. The combined organic layers were washed with 1 N hydrochloric acid and an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) and Gilson HPLC to obtain 230 mg (yield: 40%) of the title compound. Melting point: 148-149° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.C(N(CC)CC)C>CO>[C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:10]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCCCCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCCCC(=O)O
Temperature: 60 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
NH2—(CH2)5—COOH (5.00 g, 38.2 mmol), (BOC)2O (9.16 g, 42.0 mmol) and triethylamine (4.24 g, 42.0 mmol) were dissolved in 200 mL of methanol, and the mixture was stirred at 60° C. for 12 hours. After the reaction completed, methanol was removed under reduced pressure, and the obtained material was redissolved in 100 mL of ethyl acetate. Then, the solution was subjected to separation using 0.2 mol/l HCl (twice) and water (twice), and dehydrating was carried out with anhydrous sodium sulfate. After that, recrystallization with hexane at 4° C. and collection using a glass filter (G6) were performed, thereby obtaining Boc-NH—(CH2)5—COOH (6.35 g, 27.5 mmol, yield: 72%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:17][C:11]2=[CH:12][N+:13]([O-])=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6].[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20]>>[CH3:1][N:2]([CH3:18])[CH:3]=[N:4][S:5]([C:8]1[S:17][C:11]2=[C:12]([O:22][C:19](=[O:21])[CH3:20])[N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1)(=[O:7])=[O:6]
Reactant: CN(C)C=NS(=O)(=O)c1cc2cc[n+]([O-])cc2s1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1nccc2cc(S(=O)(=O)N=CN(C)C)sc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of N,N-dimethyl-N'-(6-oxido-thieno[2,3-c]pyridine-2-sulfonyl)formamidine (3.5 g, 12.3 mmol) in acetic anhydride (20 ml), under a nitrogen atmosphere, was heated at 120° C. for 3 hours. The dark solution was poured into ice/water and stirred for 1/2 hour. The product was extracted into methylene chloride, washed with sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated to give 4.77 g of crude product. This residue was triturated with methylene chloride/diethyl ether to give 2.0 g (50% yield) of pure product. Recrystallization from ethyl acetate gave product with a broad melting point of 184°-191° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C@H:20]([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: C[C@@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(F)c(F)c1
Product: C[C@@H]1Cn2c(cc(OCc3ccc(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,4-difluorophenyl)methanol and (R)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28](O)=[O:29]>>[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:27]=1[C:28]([NH:5][C@H:4]([C:3]([OH:2])=[O:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:23])[N:15]([CH3:22])[C:16](=[O:21])[N:17]([CH3:20])[C:18]=2[CH3:19])=[CH:11][CH:12]=1)=[O:29]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester and 2,6-difluorobenzoic acid using the general procedures described in example 7 and was obtained as an amorphous white solid. ES-HRMS m/e calcd for C23H21F2N3O5 (M+Na) 480.1483, found 480.1489.
Reaction SMILES: [Br:1][CH2:2][CH:3]([CH2:14][O:15]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13].CC1C=CC(S(O)(=O)=O)=CC=1.O.C(Cl)(Cl)Cl.CO>CO>[Br:1][CH2:2][CH:3]([CH2:14][OH:15])[CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]1=[O:13]
Reactant: O=c1ccn(CCC(CBr)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1ccn(CCC(CO)CBr)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of compound 37 (22 g, 0.042 mol) in methanol (100 mL) was treated with PTSA.H2O (0.80 g, 0.0042 mol) and stirred for 6 h at RT. The reaction mixture was concentrated under vacuum and the crude compound was used for next reaction (10.5 g, crude product). TLC: Chloroform/Methanol, 1:1, Rf=0.2
Reaction SMILES: [Br-:1].ClC1C=CC=CC=1C(C1C=CC=CC=1Cl)(O)C(O[C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:16][CH2:17]2)[CH2:14]1)=O.[OH:38][C:39]([C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1)([C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=1)[C:40]([OH:42])=[O:41]>>[Br-:1].[OH:38][C:39]([C:43]1[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=1)([C:50]1[CH:51]=[CH:52][C:53]([CH3:56])=[CH:54][CH:55]=1)[C:40]([O:42][C@@H:17]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][C:22](=[O:29])[NH:23][C:24]3[CH:28]=[CH:27][O:26][N:25]=3)([CH2:14][CH2:13]2)[CH2:16]1)=[O:41]
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1Cl)c1ccccc1Cl)C2)Nc1ccon1
Reactant: Cc1ccc(C(O)(C(=O)O)c2ccc(C)cc2)cc1
Agent: [Br-]
Product: Cc1ccc(C(O)(C(=O)O[C@H]2C[N+]3(CC(=O)Nc4ccon4)CCC2CC3)c2ccc(C)cc2)cc1

Procedure:
This compound is prepared analogously to (R)-3-[2,2-bis-(2-chloro-phenyl)-2-hydroxy-acetoxy]-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide [Example 1] by substituting bis-(2-chloro-phenyl)-hydroxy-acetic acid with hydroxy-di-p-tolyl-acetic acid (Intermediate B).
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[OH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CC2OC2C1
Reactant: Nc1ccccc1
Product: OC1CCCC1Nc1ccccc1

Procedure:
Reaction of the cyclopentene oxide IIIa with an aniline under conditions well known in the art gives the N-(2-hydroxycyclopentyl)aniline IX which, when reacted with chlorosulfonic acid in a nonpolar organic solvent, e.g., methylene chloride, at 20°-30° C. followed by heating with a selected C1 to C3 -monoalkylamine (aqueous) or ammonium hydroxide (aqueous) at 100°-150° C. for 40-55 hours at elevated pressure (2-10 atm.), gives the diamine X. Reaction of diamine X with 2,2,2-trichloroethyl chloroformate, or equivalent N-blocking compound, at 20°-30° C. for 1-5 hours proceeds in the presence of an acid scavenger, e.g., triethylamine, to give the 2-(N-blocked amino) compound XI. Acylation of the N-blocked compound XI with the selected acid anhydride, ##STR44## by heating at 90°-120° C. for 12 to 30 hours gives the N-blocked anilide XII. Deprotection of the 2-amino function of the 2-N-blocked anilide XII is then accomplished by reaction with an N-deblocking agent such as metal dust in acid, e.g., zinc in acetic acid, in a polar organic solvent, e.g., methanol, at 20°-100° C. for 2 to 6 hours. Work-up, isolation and purification procedures are those standard in the art of organic chemistry.