Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(=O)(=O)C.[Si]([O:13][CH:14]1[CH2:17][N:16]([CH2:18][C@H:19]([O:30][C:31]2[N:36]=[CH:35][N:34]=[C:33]3[N:37]([C:40]4[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=4[Cl:47])[N:38]=[CH:39][C:32]=23)[C:20]([NH:22][C:23]2[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=2)=[O:21])[CH2:15]1)(C(C)(C)C)(C)C.C1COCC1.CS(O)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O.COC(C)(C)C>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[N:37]1[C:33]2[N:34]=[CH:35][N:36]=[C:31]([O:30][C@@H:19]([CH2:18][N:16]3[CH2:17][CH:14]([OH:13])[CH2:15]3)[C:20]([NH:22][C:23]3[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=3)=[O:21])[C:32]=2[CH:39]=[N:38]1
Reactant: Cc1cnc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)cn1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1cnc(NC(=O)[C@H](CN2CC(O)C2)Oc2ncnc3c2cnn3-c2c(Cl)cccc2Cl)cn1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of (S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2,6-dichlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamide mesylate (16.5 g), THF (50.00 mL), water (20.0 mL) and methanesulfonic acid (2.62 g) was stirred for 19 hours at ambient temperature. tert-Butyl methyl ether (40.0 mL) was added followed by the dropwise addition of a solution of potassium carbonate (3.77 g) in water (20.0 mL) over 20 mins with stirring. The aqueous phase was removed and the organic phase was washed with water (20.0 mL) then evaporated under reduced pressure at 50° C. THF (80 mL) was added to the residue and then removed by evaporation under reduced pressure. This process was repeated. THF (20.0 mL) was added to the residue followed by tert-butyl methyl ether (60.0 ml). The mixture was filtered then stirred whilst cyclohexane (50.0 mL) was added dropwise. The solid was collected by filtration and washed with a mixture tert-butyl methyl ether (50.0 mL) and cyclohexane (50.0 mL) and dried to give (2S)-2-[1-(2,6-dichlorophenyl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-(3-hydroxyazetidin-1-yl)-N-(5-methylpyrazin-2-yl)propanamide in an overall yield for steps a) and b) of 69%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[O:34])[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=[O:34])[CH2:23][CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C(=O)CCC4)cc2)CCC1
Reaction time: 0.01 h
Yield: 118 %

Procedure:
tert-butyl(1-(4-(5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (11 mg, 0.023 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (10 mg, 91% yield). 1H-NMR (500 MHz, CD3OD) δ 8.29 (1H, s), 7.51 (2H, d), 7.45 (2H, d), 7.31 (3H, t), 7.21 (2H, dd), 3.26 (2H, t), 2.80 (2H, t), 2.72-2.81 (2H, m), 2.53-2.62 (2H, m), 2.30 (2H, t), 2.20-2.30 (1H, m), 1.92-2.01 (1H, m). LCMS (Method A) RT=4.09 min, M+H+=368.91.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:11]([CH:15]1[CH2:26][CH2:25][C:18]2([O:22][CH:21]([CH2:23]Br)[CH2:20][O:19]2)[CH2:17][CH2:16]1)([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:11]([CH:15]1[CH2:26][CH2:25][C:18]2([O:22][CH:21]([CH2:23][N:8]3[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]3)[CH2:20][O:19]2)[CH2:17][CH2:16]1)([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)C1CCC2(CC1)OCC(CBr)O2
Reactant: CC(C)(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCN(CC2COC3(CCC(C(C)(C)C)CC3)O2)CC1

Procedure:
17.4 g (123.6 mmol) of 4-tert-butylpiperidine, 9.0 g (30.9 mmol) of 8-tert-butyl-2-bromomethyl-1,4-dioxaspiro[4,5]decane (cis/trans mixture) and 4.3 g (30.9 mmol) of potassium carbonate in 100 ml of absolute dimethylformamide were heated at 150° C. for 8 hours. Some of the solvent was distilled off under reduced pressure, the residue was taken up with dilute aqueous sodium hydroxide solution/methylene chloride and the solution was worked up in a conventional manner.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:22])=O)=[CH:18][CH:17]=1>>[ClH:22].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:20]([C:19]3[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(-c2nc(C3CCN(C(C)C)CC3)no2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and 4-methoxybenzoyl chloride.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](OC(C)(C)C)=O)[C:11]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[H-].[Na+].C(O)(=O)[CH2:27][C:28]([CH2:33]C(O)=O)([C:30](O)=O)[OH:29].[O:39]1CCC[CH2:40]1>>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][CH2:15][C:40]([O:29][C:28]([CH3:27])([CH3:30])[CH3:33])=[O:39])[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CC(C)(C)OC(=O)CN[C@H](COCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
(2R)-3-Benzyloxy-2-tert-butoxycarbonylaminopropionic acid (7.0 g; 23.7 mmol) was dissolved in dry tetrahydrofuran and iodomethane (11.9 mL; 189 mmol) was added. The reaction mixture was cooled to 0° C. and sodium hydride (60% in mineral oil) (2.73 g; 71 mmol) was added. The reaction mixture was left 3 days without stirring at 0° C. Citric acid (5%) was added until pH 2.5. Tetrahydrofuran was removed in vacuo and the residue was extracted with methylene chloride (3×100 mL). The organic phase was dried (magnesium sulfate) and evaporated in vacuo. The residue was dissolved in diethyl ether (20 mL) and dicyclohexylamine (10 mL) and heptane (100 mL) were added. The reaction mixture was left 3 days without stirring at 0° C. The reaction mixture was filtered to afford 5.78 g of (2R)-3-benzyloxy-2-(tert-butoxycarbonylmethylamino)propionic acid.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:14][N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[C:16]=3[CH2:17][OH:18])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[NH:38][N:37]=[N:36][N:35]=1.C[N+]1([O-])CCOCC1.ClCCl.C(#N)C>ClCCl.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:6]2[CH:7]=[C:8]([CH2:11][C:12]3[C:13]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:14][N:15]([CH2:19][C:20]([F:21])([F:23])[F:22])[C:16]=3[CH:17]=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[NH:38][N:37]=[N:36][N:35]=1
Reactant: CCCCc1nn(CC(F)(F)F)c(CO)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1nn(CC(F)(F)F)c(C=O)c1Cc1ccc2oc(-c3ccccc3-c3nnn[nH]3)c(Br)c2c1
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
A mixture of the product of Example 5 (0.55 g), 4Å molecular sieves (powdered) (2.5 g), N-methylmorpholine-N-oxide (0.65 g) in a mixture of dry dichloromethane (10 ml) and dry acetonitrile (10 ml) was treated with tetrapropylammonium perruthenate (40 mg) at 0°. The mixture was stirred at 0° to ambient temperature for 1.5 h and filtered through "hyflo", and the solvent was evaporated. The residue was purified by flash column chromatography eluting with System F (400:400:10:10) to give a residue which was dissolved in a mixture of dichloromethane:ethyl acetate (2:1;25 ml) and washed with water (50 ml). (The pH of the aqueous solution was adjusted to 4 with aqueous sodium carbonate (2N)). The organic phase was, dried, filtered and evaporated to give the title compound as an off-white solid (0.31 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([CH3:14])=[C:5]([N:9]([CH3:15])[S:10]([CH3:13])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NS(C)(=O)=O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(N(C)S(C)(=O)=O)c1C
Reaction time: 0.17 h
Yield: 106.4 %

Procedure:
A slurry of N-(3-methoxy-2-methylphenyl)methanesulfonamide 7a (Blondet, D.; Pascal, J. -C. Tetrahedron Lett. 1994, 35, 2911) (4.5 g, 20.9 mmol), K2CO3 (4.33 g, 31.4 mmol) and Mel (6.52 mL, 105 mmol) in DMF (100 mL) was stirred vigorously for 5 days. The reaction was poured onto H2O (250 mL), stirred for 10 minutes and then extracted with ether. The combined organic extracts were washed with water and brine and dried over MgSO4 to give 7b (5.10 g) after removal of the solvent.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][CH2:6][C:7]1[N:8]=[CH:9][N:10]([CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)([CH3:18])[CH3:17])[CH:11]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]([NH:15][CH2:14][CH2:13][CH2:12][N:10]2[CH:11]=[C:7]([CH2:6][CH2:5][NH:4][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[N:8]=[CH:9]2)([CH3:18])[CH3:17])=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(NCCCn1cnc(CCN)c1)c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NCCCn1cnc(CCNS(=O)(=O)c2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (0.46 g) was added to a stirred suspension of 3-[4-(2-aminoethyl)imidazol-1-yl]-N-[1-(4-chlorophenyl)-1-methylethyl]propylamine trihydrochloride (0.65 g) in dichloromethane (20 ml). The solution was cooled to 0° C. and benzenesulphonyl chloride (0.27 g) in dichloromethane (10 ml) was added dropwise with stirring. The mixture was stirred at 0° C. for 30 minutes and then at ambient temperature for 3 hours. The mixture was washed with water, sodium bicarbonate solution and then dried, filtered and evaporated to give a yellow oil which was dissolved in alcohol and treated with ethereal hydrogen chloride. The resulting salt was hygroscopic and so was converted back to the free base by treatment with aqueous sodium hydroxide solution to give N-[2-(1-{3-[1-(4-chlorophenyl)-1-methylethylamino]-propyl}imidazol-4-yl)ethyl]benzenesulphonamide as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:12]([O:14]C)=[O:13])[C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([C:8]([OH:10])=[O:9])[C:12]([OH:14])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Cc1ccc(Br)cc1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
A mixture of dimethyl 2-(4-bromobenzyl)malonate (22 g, 73.33 mmol, 1.00 equiv) and potassium hydroxide (12.3 g, 219.64 mmol, 3.00 equiv) in ethanol (140 mL) and water (140 mL) was stirred at 60° C. overnight. The resulting solution was diluted with 300 mL of ice and water then extracted with 1×500 mL of ethyl acetate. The organic layer was washed with 2×150 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 18.2 g (91%) of 2-(4-bromobenzyl)malonic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([CH2:15][CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([C:18]3[S:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:10]=2)=[CH:4][C:3]=1[CH2:24][OH:25].[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O>[C:26]([O:25][CH2:24][C:3]1[CH:4]=[C:5]([NH:8][C:9]2[C:14]([CH2:15][CH3:16])=[C:13]([CH3:17])[N:12]=[C:11]([C:18]3[S:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:10]=2)[CH:6]=[CH:7][C:2]=1[Br:1])(=[O:28])[CH3:27]
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(CO)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(COC(C)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.3 %

Procedure:
A 18-mL vial was charged with [2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methanol (93 mg, 0.21 mmol), acetyl chloride (100 mg, 1.27 mmol, 6 eq.). Pyridine (1 ml) was added followed by 4-(dimethylamino)pyridine (5 mg, 0.2 eq.). The resulting mixture was stirred at rt for 2 hr. Then water was (5 ml) added. The precipitate was collected and washed with water. The crude product was purified by chromatography on silica gel using dichloromethane as eluent to give the tile compound (73 mg, 72% yield).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.CO>ClCCl.O>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C@H:2]([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: C[C@@H](O)c1ccc(Br)cc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of 4-bromoacetophenone (5.0 g, 25 mmol) and (S)-2-Methyl-CBS-oxazaborolidine (1.25 mL, 1 M) in anhydrous dichloromethane (80 mL) was added borane-methyl sulfide complex (2.1 g, 27 mmol) over 1 hour at −20° C. After addition completed, the mixture was stirred at −20° C. for 2 hours, then stirred at room temperature for 12 hours. After the reaction, methanol (20 mL) was added, and stirred for 0.5 hour. Then the mixture was diluted with water (100 mL) and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:8) to give pure product (R)-1-(4-bromophenyl)ethanol as a white solid (4.6 g, 92%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([CH:13]=[O:14])=[CH:10]2)=[CH:5][CH:4]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].CCN(CC)CC.[NH4+].[Cl-]>C(Cl)Cl>[CH:13]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][C:3]([CH2:2][O:1][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:12]2)=[CH:7][CH:8]=1)=[O:14]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1ccc2ccc(CO)cc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2ccc(C=O)cc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of the product of step 6 (430 mg, 2.31 mmol) in CH2Cl2 (5 mL) was added MsCl (318 mg, 2.7 mmol) and Et3N (559 mg, 5.5 mmol). The mixture was stirred at 0° C. for 2 h. Aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried (anhyd. MgSO4) and concentrated in vacuo. The crude product was used in the next step without further purification.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[CH2:16]([S:19](Cl)(=[O:21])=[O:20])[CH2:17][CH3:18].[CH:23]1([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1>>[CH:23]1([C:26]2[CH:32]=[CH:31][C:29]([N:30]3[CH2:13][CH2:12][C:6]4([CH2:7][CH2:8][N:9]([S:19]([CH2:16][CH2:17][CH3:18])(=[O:21])=[O:20])[CH2:10][CH2:11]4)[C:4]3=[O:5])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1
Reactant: Nc1ccc(C2CC2)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: CCCS(=O)(=O)Cl
Product: CCCS(=O)(=O)N1CCC2(CCN(c3ccc(C4CC4)cc3)C2=O)CC1

Procedure:
Off-white solid. MS (ESI): 377.19 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 1-propanesulfonyl chloride and 4-cyclopropyl-aniline.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH2:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:38]([O:45][C:46]([NH:48][C:49](N1C=CC=N1)=[N:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([NH:22][C@@H:23]([C:25]([NH:27][CH2:28][C@@H:29]([NH:37]/[C:49](/[NH:50][C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])=[N:48]\[C:46]([O:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:47])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:26])[CH3:24])=[O:21])[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(N=C(NC(=O)OCc1ccccc1)n1cccn1)OCc1ccccc1
Reactant: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@@H](N)Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C)c1C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C)C(=O)NC[C@H](Cc1ccccc1)N/C(=N\C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a solution N-(tert-butoxycarbonyl)-2,6-dimethyl-L-tyrosyl-N-[(2S)-2-amino-3-phenylpropyl]-D-alaninamide (330 mg, 0.64 mmol) from preparation 33 in THF (5 mL) was added N,N′-Bis(benzyloxycarbonyl)-1H-pyrazole-1-carboxamidine (268 mg, 0.71 mmol) and N,N-diisopropylethylamine (173 uL, 0.97 mmol). The reaction was stirred for 2 hours at 60° C. and then quenched by the addition of water (5 mL). The mixture was extracted with ethyl acetate (10 mL), the extract was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 25% ethyl acetate in heptane as eluent increasing to 33%) to afford the title compound as a colourless oil in 81% yield, 430 mg. 1H NMR (400 MHz, MeOH-d4) δ : 1.05 (d, 3H), 1.28 (s, 9H), 2.22 (s, 6H), 2.73-3.11 (m, 4H), 3.41-3.52 (m, 1H), 3.95-4.23 (m, 2H), 4.38-4.59 (m, 2H), 4.98-5.28 (m, 4H), 6.45 (s, 2H), 7.09-7.46 (m, 15H). LRMS APCI m/z 823 [MH]+
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:33]2[CH2:45][CH2:44][N:36]3[C:37]4[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=4[CH:43]=[C:35]3[C:34]2=[O:46])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:30]=[C:22]3[CH2:23][N:24]([C:27](=[O:29])[CH3:28])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[C:27]([N:24]1[CH2:25][CH2:26][N:21]2[N:20]=[C:19]([NH:18][C:16]3[C:15](=[O:31])[N:14]([CH3:32])[CH:13]=[C:12]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:33]5[CH2:45][CH2:44][N:36]6[C:37]7[CH2:38][CH2:39][CH2:40][CH2:41][C:42]=7[CH:43]=[C:35]6[C:34]5=[O:46])[C:6]=4[CH2:5][OH:4])[CH:17]=3)[CH:30]=[C:22]2[CH2:23]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(C)=O)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A mixture of 209e (150 mg, 0.24 mmol) and lithium hydroxide (58 mg, 2.4 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at room temperature for 1 h. The mixture was evaporated in vacuo and diluted with water (4 mL). It was then extracted with ethyl acetate (2×10 mL). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 209 (75 mg, 53%) as a white solid. MS-ESI: [M+H]+ 583.3. 1H NMR (500 MHz, T=80° C., DMSO-d6) δ 8.44 (d, J=8.5 Hz, 1H), 7.93-7.90 (m, 2H), 7.34 (d, J=4.5 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 6.56 (s, 1H), 5.98 (s, 1H), 4.72-4.63 (m, 3H), 4.45-4.43 (m, 2H), 4.16-4.10 (m, 3H), 3.99-3.86 (m, overlap, 5H), 3.58 (s, 3H), 2.62-2.57 (m, 2H), 2.49-2.47 (m, 2H), 2.08 (s, 3H), 1.83-1.77 (m, 2H), 1.72-1.68 (m, 2H).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH3:20])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH:21]1([N:19]([CH3:20])[C:17]2[CH:16]=[N:15][C:13]3[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=3[N:18]=2)[CH2:22][CH2:23][CH2:24]1
Reactant: CN(c1cnc2c(n1)OCCN(Cc1ccccc1)C2)C1CCC1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(c1cnc2c(n1)OCCNC2)C1CCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of 8-benzyl-N-cyclobutyl-N-methyl-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (0.48 g) in methanol (10 mL) was added 20% Pd(OH)2/C (90 mg), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 3 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (10 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (400 μL), and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (257 mg, 65%) as a colorless powder.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccccc2)CC1
Reaction time: 2.5 h
Yield: 98.1 %

Procedure:
To a solution of N-Boc-piperidone (3.0 g, 15.1 mmol) in THF (76 mL) was added benzylamine (1.65 mL, 15.1 mmol), acetic acid (0.86 mL, 15.1 mmol) and sodium triacetoxyborohydride (4.8 g, 22.6 mmol). After stirring 2.5 hours the reaction mixture was concentrated under reduced pressure and CH2Cl2 (50 mL) and saturated aqueous NaHCO3 solution (50 mL) was added. The organic phase was separated, and the aqueous was extracted with CH2Cl2 (2×50 mL). The combined organic phases were then dried (MgSO4), filtered, and concentrated under reduced pressure to afford 4-benzylamino-piperidine-1-carboxylic acid tert-butyl ester (4.30 g, 98%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][CH:15]([O:17]CC3C=CC=CC=3)[CH2:14]2)[CH2:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:14][CH:15]([OH:17])[CH2:16]2)[CH2:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(C2CC(=O)N(Cc3ccccc3)C2)CC(OCc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1(C2CC(=O)N(Cc3ccccc3)C2)CC(O)C1
Reaction time: 1.5 h

Procedure:
A 524 mg (1.29 mmol) portion of 1-benzyl-4-[1-benzyloxy-3-(ethoxycarbonyl)cyclobutan-3-yl]-2-pyrrolidone (Isomer A) was dissolved in 20 ml of ethanol, and the solution was mixed with 530 mg of palladium hydroxide on carbon catalyst and subjected to 1.5 hours of catalytic reduction under a hydrogen pressure of 5 atmospheres and under irradiation of light. After removal of the catalyst by filtration, the solvent was evaporated and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol=95:5) to give 454 mg (quantitative) of the title compound.