Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(Cl)C=CC=1C([C:13]1[C:21]2[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[C:19](F)[CH:20]=2)[NH:15][CH:14]=1)CCO.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)O)=[C:29]([CH3:42])[CH:28]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=C(C)C=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:13]2[C:21]3[C:16](=[C:17]([CH2:23][S:24][CH3:25])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[C:29]([CH3:42])[CH:28]=1
Reactant: CSCc1cc(F)cc2c(C(CCO)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: Cc1cc(Cl)ccc1C(O)c1ccc(F)cc1
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3C)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3C)c[nH]c12

Procedure:
The title compound was prepared starting from 380 mg (2.14 mmol) of the compound from Example 8 and 591 mg (2.36 mmol) of the compound from Example 83A in analogy to the synthesis of the compound from Example 101. 307 mg (35% of theory) of the target compound were obtained.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[CH3:14][S:15]([O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[NH:1][N:2]=[N:3][N:4]=2)[CH:7]=1)(=[O:17])=[O:16]
Reactant: OCc1cccc(-c2nnn[nH]2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
50 mg (0.28 mmol) of the compound from Example 49A are dissolved in 5 ml of dry dichloromethane, and 33 μl (0.43 mmol) of methanesulfonyl chloride and 0.06 ml (0.43 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 10 h. The reaction mixture is then diluted with 10 ml of dichloromethane and washed in each case once with in each case 5 ml of water, 1 N hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. Removal of the solvent on a rotary evaporator gives a solid which is used in the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:19][C:5]1[C:6]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH3:10])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[C:23]([CH2:24][OH:25])[CH:26]=[CH:27][CH:28]=2)=[N:3][CH:4]=1
Reactant: COc1cccc([C@@H](C)Nc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 100.2 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-[(1R)-1-(3-methoxyphenyl)ethyl]pyrimidin-4-amine (0.21 g, 0.70 mmol), 1,4-dioxane (20 mL), 3-aminobenzyl alcohol (0.13 g, 1.0 mmol), and p-toluenesulfonic acid monohydrate (0.049 g, 0.26 mmol). The mixture was heated at 105° C. for 2 days. To the reaction mixture was added NaHCO3 (saturated aqueous solution) and the organic solvent was removed under vacuum. Water and EtOAc were added to the residue. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give the desired product (0.27 g, 96%). LCMS for C20H22ClN4O2 (M+H)+: m/z=385.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccn2)nc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc(-c2ccccn2)nc1
Temperature: 25 °C
Yield: 46.7 %

Procedure:
A solution of 5-methyl-[2,2′]bipyridinyl (3.96 g, 23.264 mmol) in CCl4 (80 mL) was bubbled with argon gas. NBS (5.507 g, 30.94 mmol, 1.33 eq) and (PhCOO)2 (0.2922 g, 1.21 mmol, 5 mol %) were added. The mixture was refluxed under argon atmosphere for 2 days. After being cooled to room temperature, the solid was removed by filtration, the filtrate was evaporated, and the residue chromatographed on a silica gel column eluted with a mixed solvent of CH2Cl2 and EtOAc (1:1, v/v). A mixture of three components was obtained (3.88 g). The mixture contained the desired monobromide of 5-(bromomethyl)-[2,2′]bipyridinyl (69.8 wt. %, 10.87 mmol, yield 46.7%), a dibromo by-product (20.2 wt. %, yield 10.3%) and the unreacted starting methylbipyridine (10 wt. %, 9.8% of starting amount). 1H NMR (CDCl3, 300.16 MHz) for the monobromide δ (ppm) 8.71-8.67 (m, 2H), 8.40 (d, J=8.0 Hz, 2H), 7.87-7.80 (m, 2H), 7.35-7.26 (m, 1H) and 4.54 (s, 2H) ppm. MS for the monobromide (ESI) m/z: 249 and 251 (M+).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C@@H:30]([CH2:32][OH:33])[CH3:31]>>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[C:11]([NH:29][C@H:30]([CH3:31])[CH2:32][OH:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(C)(=O)=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)nc(SCc2ccccc2)n1
Temperature: 80 °C

Procedure:
To a solution of the product of step i) (21.2 g) in NM) (40 ml) was added (R)-alaninol (10 g) and the whole heated at 80° C. for 4 h. The reaction mixture was then partitioned between EtOAc and H2O. The organic phase was collected, dried (MgSO4) and the solvent removed to leave a pale yellow oil. This was purified by silica gel chromatography (60:40 iso-hexane/EtOAc) to afford the subtitle compound as a colourless oil. Yield: 13.9 g.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[CH2:21][CH3:22].C([Sn](CCCC)(CCCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)CCC>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:21]([C:3]1[S:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[C:10]=2[C:2]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:22]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1-c1ccccn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 12.1 %

Procedure:
Into a 25 ml sealed tube containing a solution of 4-N-[5-bromo-6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (100 mg, 0.26 mmol, 1.00 equiv) in dioxane (5 mL) was added 2-(tributylstannyl)pyridine (96 mg, 0.26 mmol, 1.00 equiv) and Pd(dppf)Cl2 (30 mg, 0.04 mmol, 0.16 equiv) at room temperature under nitrogen. The sealed tube was heated with stirring overnight at 100° C. The reaction mixture was cooled to room temperature and diluted with 20 mL of H2O, extracted with 3×50 mL of ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (SHIMADZU): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% NH4HCO3 and CH3CN (6.0% CH3CN up to 49.0% in 27 min); Flow rate, 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated to remove water and CH3CN under reduced pressure. The residue was lyophilized overnight to give the corresponding 4-N-[6-ethyl-5-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (12 mg) as a light yellow oil. MS (ES, m/z): 382 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.75-8.41 (d, 1H), 7.90 (s, 1H), 7.89-7.84 (m, 1H), 7.46-7.38 (m, 2H), 6.73-6.71 (d, 1H), 3.95-3.89 (m, 1H), 2.89-2.81 (dd, 2, H), 2.29 (s, 6H), 2.25-2.04 (m, 3H), 1.90-1.86 (m, 2 H), 1.47-1.38 (m, 2H), 1.32-1.27 (m, 3H), 1.05-1.92 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH3:29])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[OH:28])=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)(O[CH2:41][CH2:42][F:43])(=O)=O>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:30])[N:7]([CH3:29])[C:8]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:14][C:13]=3[O:28][CH2:41][CH2:42][F:43])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2O)nc2cc(Br)ccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2OCCF)nc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.4 %

Procedure:
7-Bromo-2-[2-hydroxy-4-(3-piperidin-1-ylpropoxy)phenyl]-3-methylquinazolin-4(3H)-one (9.5 mg, 0.020 mmol) and potassium carbonate (8.3 mg, 0.06 mmol) were stirred in DMF (0.5 mL) at room temperature, and 2-fluoroethyl tosylate (6.6 mg, 0.03 mmol) was dropwise added thereto and stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline water, and the organic layer was dried with magnesium sulfate. The solvent was evaporated off, and the residue was purified through silica gel thin-layer chromatography (chloroform/methanol=9/1) to obtain the intended compound (4.5 mg, 47%) as a milky white solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH2:17])[CH3:12].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:18])[CH2:15][CH2:16][NH:17][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8])[CH3:12]
Reactant: CCOC(=O)CCN
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)CCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of benzenesulfonyl chloride (500 mg, 2.83 mmol) in pyridine (10 mL) is added 3-amino-propionic acid ethyl ester (672 mg, 8.49 mmol) and the mixture is stirred at room temperature for 18 hours. The mixture is poured into ethyl acetate and is washed with aqueous 1M HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography using a gradient of 10-50% heptane/EtOAc to afford 3-benzenesulfonylaminopropionic acid ethyl ester. MS 258.3 (M+1); 1H-NMR (400 MHz, CDCl3); δ ppm 1.24 (t, 3H), 2.53 (t, 2H), 3.21 (q, 2H), 5.22 (m, 1H), 7.51-7.61 (m, 3H), 7.87 (d, J=7.20Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].Cl.[NH2:33][OH:34].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:33][OH:34])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=NO
Temperature: 25 °C
Yield: 58.5 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (1.5 g, 3.64 mmol) obtained in Example 7 was dissolved in ethanol (100 mL), hydroxylamine hydrochloride (759 mg, 10.92 mmol) and pyridine (1.15 g, 15.56 mmol) were added thereto, refluxed for 1 hr, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 0.91 g of the titled compound (yield: 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:31]=CC=C[CH:27]=1.C(O)(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH:26]([CH3:31])[CH3:27])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)c1ccc(OC(C)C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 81.7 %

Procedure:
To a solution of methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-hydroxy-benzoate (0.735 g, 2.1 mmol), triphenylphosphine (0.551 g, 2.1 mmol), and isopropanol (0.158 mL, 2 mmol) in tetrahydrofuran was added diisopropyl azodicarboxylate (0.433 mL, 2.2 mmol) dropwise. The solution was sonicated for 30 minutes. The reaction mixture was purified without workup by RPLC (EtOAc/Hexane 3:7) to give 0.675 g (86%) of pure product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].Br[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].Cl>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]([Cl:14])=[C:12]2[C:8]([C:9]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:11]2[CH2:32][CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)[nH]c2c1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(OC)cc3)n(CCO[Si](C)(C)C(C)(C)C)c2c1Cl
Reaction time: 0.33 h
Yield: 84 %

Procedure:
To a mixture of Methyl-7-chloro-3-cyclohexyl-2-(4-methoxyphenyl)-1H-indole-6-carboxylate (115.7 mgs, 291 μmol) in 2 mL of DMSO under N2 was added NaH (95%, 2 equivalents, 582 μmol, 14.0 mgs), and the reaction mixture was stirred for 20 minutes. (2-bromoethoxy)-tert-butyldimethylsilane (1.5 equivalents, 436 μmol, 94 μL) was then along with KI (1.5 equivalents, 72.4 mgs), and the reaction was stirred at room temperature overnight. The crude product was acidified with 1 M HCl, diluted with water and extracted with dichloromethane. The extracted product was concentrated en vacuo then purified by automated flash chromatography (Biotage Horizon™, gradient elution, 5 to 40% Ethyl Acetate/Hexane) to give 136.0 mgs (86%) of Methyl-1-(2-(tert-butyldimethylsilyloxy)ethyl)-7-chloro-3-cyclohexyl-2-(4-methoxy phenyl)-1H-indole-6-carboxylate as a oily colorless solid. The LC/MS data was obtained on a Shimadzu analytical LC/Micromass Platform LC (ESI+) at 220 nm using the following set of conditions: Phenomenex 10 μm C18, 4.6×30 mm column, with a gradient of 0-100% B (B=90% HPLC grade methanol/0.1% trifluoroacetic acid/10% HPLC grade water), (A=90% HPLC grade water/0.1% trifluoroacetic acid/10% HPLC grade methanol), in 2 minutes with a 2 minute hold at a rate of 5 mL/minute. The NMR spectra was recorded at room temperature using a Bruker DRX300 spectrometer. Chemical shifts were reported in ppm relative to the deuterated solvent used. Coupling constants were reported in hertz. Peak multiplicity was reported using the following abbreviations: s (singlet), d (doublet), dd (doublet of doublets), t (triplet), m (multiplet), br (broad). 1H NMR (300 MHz, CDCl3) δ 7.90 (d, J=8.05 Hz, 1H), 7.73 (d, J=8.05 Hz, 1H), 7.50 (d, J=8.42 Hz, 2H), 7.24 (d, J=8.42 Hz, 2H), 4.69 (t, J=6.40 Hz, 2H), 4.17 (s, 3H), 4.12 (s, 3H), 3.95 (t, J=6.40 Hz, 2H), 2.79 (m, 1H), 1.96 (m, 6H), 1.41-1.56 (m, 3H), 1.11-1.20 (m, 1H), 0.95 (s, 9H), 0.03 (s, 6H). MS m/z 557.23 (M+H), Rf 3.05 min., 100% purity.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(O)(=O)C.[H][H]>[Rh].C(O)C>[CH2:9]([O:8][C:6]([C@H:5]1[CH2:11][CH2:12][C@@H:2]([OH:1])[CH2:3][CH2:4]1)=[O:7])[CH3:10]
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Rh]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1CC[C@@H](O)CC1

Procedure:
A mixture of 10 g of ethyl 4-hydroxybenzoate, 5 mL of acetic acid, 0.8 g of 5% rhodium on alumina, and 200 mL of ethanol was shaken under 55 psi of hydrogen for 48 h, filtered and concentrated under reduced pressure. The residue was taken up in 200 mL of toluene and again concentrated under reduced pressure to remove acetic acid. Drying under vacuum overnight gave 11 g of product, which was predominantly cis (83:17 cis: trans by HPLC), as a colorless oil: MS (m+1)=173.2; 1H NMR (400 MHz, CDCl3) 4.1 (dd, 2H), 3.9 (m, cis isomer, 0.85H), 3.6 (m, trans isomer, 0.15H), 2.4 and 2.2 (m, 1H), 2.0 (m, 2H), 1.62 (m, 6H), 1.2 (t, 3H).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[C:10]=1[CH:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)C1C=CC=CC=1>ClCCl.C(O)C>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][N:11]1[CH:12]=[CH:13][C:14](=[O:15])[C:9]([OH:8])=[C:10]1[CH:21]([OH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1ccn(CC(O)CO)c(C(O)c2ccccc2)c1OCc1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: O=c1ccn(CC(O)CO)c(C(O)c2ccccc2)c1O

Procedure:
3-Benzyloxy-1-(2,3-dihydroxy-propyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one: From 2.1 g of 3-benzyloxy-1-(2,3-dihydroxy-propyl)-2-[phenyl-(tetrahydropyran-2-yloxy)methyl]-1H-pyridin-4-one there is obtained analogously to Example 6e, after chromatography: 3-benzyloxy-1-(2,3-dihydroxy-propyl)-2-(hydroxy-phenyl-methyl)-1H-pyridin-4-one. Colourless foam, diastereoisomeric mixture. Rf value 0.22 (silica gel 60, dichloromethane/ethanol 4/1).
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:12])=CC=1)([O-])=O.[CH3:26][O:27][CH2:28][CH2:29][NH:30][CH3:31]>O1CCCC1>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:11](=[O:12])[N:30]([CH2:29][CH2:28][O:27][CH3:26])[CH3:31])[CH2:18][CH2:17]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: CNCCOC
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1CCOC1
Product: COCCN(C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70.9 %

Procedure:
To piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (500 mg) in tetrahydrofuran (5 mL) was added N-(2-methoxyethyl)methylamine (254 mg) and the reaction mixture was heated to reflux for 24 hours. The reaction mixture was reduced in vacuo and purified using flash chromatography to yield 4-[(2-methoxy-ethyl)-methyl-carbamoyl]-piperazine-1-carboxylic acid tert-butyl ester (304 mg). Treatment of this compound with HCl in dichloromethane/methanol yielded the title compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:11])=O)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1COCC1>[CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:11])=[S:21])(=[O:4])=[O:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)NCCCC(N)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCCC(N)=S
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 149.2 %

Procedure:
A suspension of 4-methanesulfonylamino-butyramide (0.50 g, 2.8 mmol) and Lawesson's reagent (0.56 g, 1.4 mmol) in THF (50 mL) was stirred at room temperature for 45 minutes. During this time all of the solid dissolved. The solution was concentrated and purified by flash chromatography (79:1 EtOAc:MeOH) to afford the title compound (0.41 g); 1H NMR (400 MHz, CDCl3) δ63.29 (s, 3H), 3.07-3.11 (m, 2H), 2.91 (s, 3H), 2.62-2.66 (m, 2H), 1.93-1.99 (m, 2H); MS 197 (M++1).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([N:14]1[CH2:39][CH2:38][CH2:37][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CN1CCOCC1.[N:54]1([C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:70])[CH2:68][CH2:67][CH2:66][C@H:55]1[C:56](ON1C(=O)CCC1=O)=[O:57]>Cl.CCOC(C)=O>[N:54]1([C:69]([O:71][CH2:72][C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:70])[CH2:68][CH2:67][CH2:66][C@H:55]1[C:56]([NH:1][C@H:2]([C:12]([N:14]1[CH2:39][CH2:38][CH2:37][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([NH:32][CH2:33][C:34]([NH2:36])=[O:35])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:57]
Reactant: O=C(ON1C(=O)CCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: N=C(NCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)NCC(N)=O)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 1.0 g of Boc-Ser(Bzl)-Pro-Arg(NO2)-Gly-NH2, 10 ml of 4N HCl-AcOEt, 0.34 ml of NMM and 0.54 g of Z-Pro-OSu in the same manner as in Example 26-(4).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11]Br)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:15]1([N:21]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:22](=[O:25])[CH2:23][CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][N:29]2[CH2:28][CH2:27][CH:26]([N:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:22](=[O:25])[CH2:23][CH3:24])[CH2:31][CH2:30]2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCC(=O)N(c1ccccc1)C1CCNCC1
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Product: CCC(=O)N(c1ccccc1)C1CCN(CCOc2ccc(NC(C)=O)cc2)CC1

Procedure:
Using the procedure of Example I step B and starting from (4-acetamidophenoxyethyl) bromide and 4-(N-phenyl N-propionylamino) piperidine, N-[(4-acetamidophenoxy) ethyl] 4-(N'-phenyl N'-propionylamino) piperidine is obtained which melts at 78°.