Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[C:6]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=4)[N:21]=[CH:20][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[OH-].[Na+:39]>C(O)C.O>[Cl:1][C:2]1[CH:37]=[CH:36][C:5]2[C:6]3[N:23]=[C:22]([NH:24][C:25]4[CH:33]=[CH:32][C:28]([C:29]([O-:31])=[O:30])=[C:27]([O:34][CH3:35])[CH:26]=4)[N:21]=[CH:20][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[F:19])[C:4]=2[CH:3]=1.[Na+:39]
Reactant: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)[O-]
Reaction time: 1 h
Yield: 86.8 %

Procedure:
To a stirred suspension of Compound Formula (II) (98.0 g, 190 mmol) in ethanol (2.0 L) was added 1.044 M Sodium hydroxide in water (199 mL). The resultant homogeneous solution was stirred for 1 hour, during which time a thick precipitate formed. The product was collected by filtration, and washed with ethanol (0.5 L) and diethyl ether (1.0 L). The resultant solid was dried in vacuo at 60-70° C. for 4 days to provide 88.6 g (86.8%) of compound Formula (I) as a light tan solid, mp 225° C. (decomp). 1H NMR (DMSO-d6) δ 9.86 (s, 1H), 8.60 (s, 1H), 8.29 (d, 1H), 7.79 (dd, 1H), 7.60 (br s, 1H), 7.40 (dd, 1H), 7.29 (d, 1H), 7.25-7.15 (m, 2H), 6.9 (br s, 2H), 4.9 (br s, 1H), 3.8 (br s, 1H), 3.70 (s, 3H), 3.35 (br s, 3H); MS m/z 519 (M+−Na+H, 100%); CHN Anal. Calcd. for C27H19ClFN4NaO40.33 EtOH1.3H2O: C, 57.33; H, 4.10; N, 9.67. Found C, 57.14; H, 3.99; N, 9.65.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:34][O:35][CH2:36][C:37](Cl)=[O:38]>>[CH3:34][O:35][CH2:36][C:37]([N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:38]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A138) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][CH2:5]2.C([Li])CCC.CCCCCC.CN([CH:26]=[O:27])C.[Cl-].[NH4+]>C1COCC1>[S:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:26]=[O:27])=[CH:11][CH:10]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: Brc1ccc2c(c1)CCCS2
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCCS2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-thiochromane (1.00 g) was dissolved in THF (15.0 mL), added dropwise with 2.69 mol/L n-butyl lithium/hexane solution (3.24 mL) at −78° C., and stirred for 1 hour at the same temperature. After adding DMF (0.71 mL) at the same temperature, it was stirred for 16 hours while raising the temperature to room temperature. A saturated aqueous solution of ammonium chloride was added, and after extraction with ethyl acetate, the organic layer was washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and the residues were purified by silica gel column chromatography (2 to 15% ethyl acetate/hexane) to obtain the title compound (342 mg) as a colorless oil.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH2:4][CH2:3]1.[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][CH:2]2[CH2:7][CH2:6][N:5]([C@H:8]([CH3:12])[CH2:9][C:10]#[N:11])[CH2:4][CH2:3]2)=[CH:17][CH:16]=1
Reactant: C[C@H](CC#N)N1CCC(=O)CC1
Reactant: CSc1ccc(N)cc1
Product: CSc1ccc(NC2CCN([C@H](C)CC#N)CC2)cc1
Yield: 89 %

Procedure:
Using general procedure A, (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (1.00 g, 6.00 mmol) and 4-(methylthio)aniline afforded (R)-3-[4-(4-methylsulfanyl-phenylamino)-piperidin-1-yl]-butyronitrile as a brown oil (1.55 g, 89%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([F:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[C:13]=1[F:20].[CH2:21]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C@H:31]2[CH2:36][CH2:35][C@H:34]([CH2:37]I)[CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[CH2:22][CH2:23][CH3:24].Cl>CN(C=O)C>[Cl:3][C:4]1[C:9]([F:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:37][C@H:34]2[CH2:35][CH2:36][C@H:31]([C@H:28]3[CH2:29][CH2:30][C@H:25]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]3)[CH2:32][CH2:33]2)=[C:14]([F:19])[C:13]=1[F:20]
Reactant: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CI)CC2)CC1
Reactant: Cc1ccc(-c2ccc(O)c(F)c2F)c(Cl)c1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(-c4ccc(C)c(F)c4Cl)c(F)c3F)CC2)CC1
Reaction time: 1 h

Procedure:
In a mixture of 0.7 g (60% oiliness, corresponding to 17.6 mmol) of sodium hydride and 5 ml of DMF was added by drops a solution of 4.0 g (14.7 mmol) of the 2′-chloro-2,3,3′-trifluoro-4-hydroxy-4′-methylbiphenyl in 20 ml of DMF at room temperature and stirred at the same temperature for 1 hour. Subsequently, a solution of 8.0 g (22.0 mmol) of trans-4-(trans-4-butylcyclohexyl)-1-iodomethylcyclohexane in 20 ml of DMF was added by drops to the reaction solution at room temperature, stirred at the same temperature for 1 hour, and then refluxed for 3 hours. After termination of the reaction, the reaction solution was poured into 50 ml of a diluted hydrochloric acid and extracted with 150 ml of toluene. The organic layer thus obtained was washed with a diluted aqueous sodium hydroxide solution thrice and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: heptane/toluene=7/3) to obtain 4.6 g of a crude 2′-chloro-2,3,3′-trifluoro-4′-methyl-4-((trans-4-(trans-4-butylcyclohexyl)cyclohexyl)methoxy)biphenyl. This product was recrystallized from a mixed solvent of ethanol/ethyl acetate to obtain 3.3 g of the subject compound. (Yield: 44.6%)
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[OH:11][C@H:12]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@:18]3([OH:36])[CH2:19][CH2:20][C@@H:21]2/[CH:22]=[C:23](\[CH3:26])/[CH:24]=O)[CH2:13]1>O.O1CCOCC1>[NH:6](/[N:5]=[CH:24]/[C:23](/[CH3:26])=[CH:22]/[C@H:21]1[CH2:20][CH2:19][C@:18]2([OH:36])[C@H:17]3[C@H:30]([CH2:29][CH2:28][C@:27]12[CH3:35])[C@:31]1([CH3:34])[C@@H:14]([CH2:13][C@@H:12]([OH:11])[CH2:33][CH2:32]1)[CH2:15][CH2:16]3)[C:7]([NH2:9])=[NH:8]
Reactant: C/C(C=O)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(/C=N/NC(=N)N)=C\[C@H]1CC[C@]2(O)[C@@H]3CC[C@@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.50 g of aminoguanidine hydrogencarbonate in 10 ml of water and 30 ml of dioxane was made acid to pH 3 with 3N HCl. A solution of 0.95 g of (E)-3β,14β-dihydroxy-21-methyl-5β-pregn-20-ene-21-carboxaldehyde (Prepn. 1) in 10 ml of dioxane was added at room temperature. After 3 days the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (SiO2) using chloroform/methanol/28% ammonium hydroxide 80/20/3 as the eluant: the fractions containing the title compound were collected and evaporated to dryness. The residue was ground with diethyl ether and ethanol to give 0.75 g of the title compound (I-aa) as a white solid.
Reaction SMILES: [C:1]([CH:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4](=[O:10])[C:5]([O:7]CC)=O)#[N:2].[C:17]1([CH2:23][C:24]#[N:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[O-]CC.[Na+].[Na]>C(O)(=O)C.O>[C:17]1([CH:23]([C:5](=[O:7])[C:4](=[O:10])[CH:3]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:1]#[N:2])[C:24]#[N:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(=O)C(C#N)c1ccccc1
Reactant: N#CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(C(=O)C(=O)C(C#N)c1ccccc1)c1ccccc1

Procedure:
Ethyl 3-cyano-3-phenylpyruvate (50.0 g., 0.23 mol.) and 41.0 g. (0.35 mol.) of phenylacetonitrile were added to an alcoholic solution of sodium ethoxide [prepared from 13.4 g. (0.58 g. -atom) of sodium and 360 ml. of absolute ethanol] and the resulting yellow solution was refluxed for 1.75 hours. The cooled solution was diluted with 700 ml. of water and acidified by slow addition of acetic acid. After further cooling in ice, the suspension was filtered and the solid was washed with water and dried to give 2,5-diphenyl-3,4-dioxoadiponitrile, m.p. 284°-286° (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10](OS(C)(=O)=O)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(Cl)Cl>[N:25]([CH:10]([CH2:11][NH:12][C:13]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:19])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N+:26]=[N-:27]
Reactant: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(CNC(=O)OC(C)(C)C)N=[N+]=[N-]
Temperature: 60 °C

Procedure:
To a solution of tert-butyl N-(3-{[(tert-butoxy)carbonyl]amino}-2-(methanesulfonyloxy)propyl)carbamate XL (2.31 g, 6.6 mmol) in DMF was added NaN3. The mixture was heated overnight at 60° C., diluted with DCM and washed with 10% Na2S2O3 (5×), 5% NaHCO3, brine and dried over MgSO4. The solvent was evaporated under vacuum to give crude product (1.75 g). The product was purified on a silica gel column (1:10 EtOAc:hexane) to give the pure tert-butyl N-(2-azido-3-{[(tert-butoxy)carbonyl]amino}propyl)carbamate XLI as white crystals (1.33 g, 4.2 mmol, 67% yield). 1H NMR (CDCl3) 1.47 (s, 18H), 3.07-3.26 (m, 2H), 3.27-3.53 (m, 2H), 3.59-3.75 (m, 1H), 5.06 (brs, 2H); ESIMS found for C13H25N5O4 m/z 316 (M+H).
Reaction SMILES: C([O:8][C:9]1[CH:38]=[C:37]([Cl:39])[C:12]([CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])[CH2:21][CH2:20]3)[C:15]2=[O:36])=[C:11]([Cl:40])[CH:10]=1)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[Cl:39][C:37]1[CH:38]=[C:9]([OH:8])[CH:10]=[C:11]([Cl:40])[C:12]=1[CH2:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C@H:19]2[CH2:20][CH2:21][C@H:22]([O:25][Si:26]([CH:27]([CH3:28])[CH3:29])([CH:33]([CH3:34])[CH3:35])[CH:30]([CH3:31])[CH3:32])[CH2:23][CH2:24]2)[C:15]1=[O:36]
Reactant: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)[Si](O[C@H]1CC[C@H](N2CC[C@@H](Cc3c(Cl)cc(O)cc3Cl)C2=O)CC1)(C(C)C)C(C)C

Procedure:
Stir (R)-3-(4-Benzyloxy-2,6-dichloro-benzyl)-trans-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-2-one (Preparation 17) (1.83 g, 3.03 mmol) and palladium hydroxide (20% on carbon) (0.200 g, 10% by weight) in 100 ml of Ethyl Acetate. Bubble hydrogen gas through the solution while stirring at room temperature for 5 minutes. Stir the mixture under the hydrogen gas atmosphere for 5 hours. Filter through celite and strip the solvent to receive 1.42 g of the title compound (91%). Mass spectrum (apci) m/z=514 (M+H).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[CH:8][C:7]=1[N+:23]([O-:25])=[O:24])([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O.C(OCC)(=O)C>[N+:23]([C:7]1[CH:8]=[C:9]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([O:18][CH2:12][C:9]2[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=2)=[O:17])=[O:13])[CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:1](=[O:3])[O:2][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O-:25])=[O:24]
Reactant: BrCc1ccccc1
Reactant: O=C(O)CNc1ccc(C(=O)c2ccccc2C(=O)O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(C(=O)c2ccccc2C(=O)OCc2ccccc2)cc1[N+](=O)[O-])OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 165.6 %

Procedure:
To a solution of 2-({4-[(carboxymethyl)amino]-3-nitrophenyl}carbonyl)benzoic acid (0.26 g, 0.76 mmol) in N,N-dimethyl formamide (5.0 mL), potassium carbonate (0.52 g, 3.80 mmol) was added, followed by the addition of benzyl bromide (0.22 mL, 1.82 mmol). The reaction mixture was stirred for 15 hours at room temperature. It was poured into ice water and diluted with ethyl acetate (50 mL). The organic layer was separated and it was washed with water, 2M aqueous hydrochloric acid and brine. It was dried over anhydrous sodium sulfate. Evaporating the solvent, followed by purification of the crude product by silica gel flash chromatography (hexane:ethyl acetate 4:1 to 3:2 eluent) resulted in phenylmethyl 2-{[3-nitro-4-({2-oxo-2-[(phenylmethyl)oxy]ethyl}amino)phenyl]carbonyl}benzoate (0.33 g, 82% yield) as an amorphous residue. MS (EI) for C30H24N2O7: 524 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[OH:31].C([O-])(O)=O.[Na+].CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[OH:31])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Reactant: CC(=O)c1ccc(OCCCCl)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)c1ccc(OCCCN2CCC(c3nsc4cc(F)ccc34)CC2)c(O)c1
Yield: 97 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (2.4 g, 10.1 mmol), 1-[4-(3-chloropropoxy)-3-hydroxyphenyl] ethanone (2.5 g, 11.1 mmol), NaHCO3, (0.94 g, 11.1 mmol), KI (100 mg) and CH3CN (100 ml) was stirred at reflux under N2 for 65 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed with H2O (1×) and brine (3×) and after drying with MgSO4 the solvent was evaporated to give 4.2 g of a dark solid. Three consecutive recrystallizations from EtOH provided 2.1 g (48%) of glittery beige crystals m.p.=135-137° C.
Reaction SMILES: N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N1CCC[C@H]1C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NCC([NH:73][C@H:74]([C:79](N[C@H](C(N)=O)CCSC)=[O:80])[CH2:75][CH:76]([CH3:78])[CH3:77])=O)=O)CC1C=CC=CC=1)=O)CC1C=CC=CC=1)=O)CCC(=O)N)=O)CCC(=O)N)=O)=O)CCCCN)=O)=O)CCCNC(=N)N.P([O-])([O-])([O-])=[O:97]>>[NH2:73][C@H:74]([C:79]([OH:80])=[O:97])[CH2:75][CH:76]([CH3:77])[CH3:78]
Reactant: O=P([O-])([O-])[O-]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCN)NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCCNC(=N)N)C(N)=O
Product: CC(C)C[C@H](N)C(=O)O
Reaction time: 0 h

Procedure:
The degradation of H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SEQ ID NO: 112) (˜7.4×10−5 M) in 50 mM phosphate buffer solutions of pH 7.4 containing carboxypeptidase A (1 U/ml) was studied as described above. The pseudo first-order rate constant for the degradation was estimated to 2.0×10−2 min−1 and the corresponding half-life calculated to 35 min as previously described.
Reaction SMILES: [CH3:1][C:2]1[NH:3][NH:4][C:5](=[O:7])[CH:6]=1.[Mg].Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1.Cl>C1COCC1.CCOCC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:2]3([CH3:1])[CH2:6][C:5](=[O:7])[NH:4][NH:3]3)=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(=O)[nH][nH]1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 9.8 g of 3-methyl-pyrazolin-5-one in 100 ml of THF is added dropwise with stirring and cooling, to a Grignard solution prepared from 4.8 g of magnesium and 20.3 g of 4-bromo-4'-fluoro-biphenyl in 800 ml of absolute ether. After stirring for 2 hours at 10°-25°, the mixture is decomposed with ice and dilute hydrochloric acid and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH:18]=[O:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][OH:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3F)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc2cc(CO)c(-c3ccccc3F)nc12

Procedure:
Prepared according to Procedure B using 2-(2-fluorophenyl)-8-methylquinoline-3-carbaldehyde (0.725 g, 2.73 mmol), and sodium borohydride (0.155 g, 4.1 mmol, 1.5 eq) in THF (15 mL). (2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanol was obtained as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.46 (1 H, s), 7.90 (1 H, d, J=7.9 Hz), 7.63 (1 H, d, J=6.7 Hz), 7.50-7.60 (3 H, m), 7.38 (1 H, d, J=7.9 Hz), 7.35-7.37 (1 H, m), 5.42 (1 H, t, J=5.5 Hz), 4.50 (2 H, d, J=5.5 Hz), 2.69 (3 H, s) Mass Spectrum (ESI) m/e=268.1 (M+1)
Reaction SMILES: [C:1]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(N(CC)CC)C>[S:15]([O:11][CH2:10][C:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([CH3:13])[CH3:12])(=[O:17])(=[O:16])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
N-Boc-2-Amino-2-methylpropanol is dissolved in triethylamine under argon at 0° C. Methanesulfonyl chloride is added and the mixture is stirred overnight. The solution is poured into 10% aqueous citric acid and extracted with ethyl acetate. The organic layer is dried over MgSO4, filtered and evaporated to give N-Boc-2-amino-2-methyl-1-propyl mesylate.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([OH:13])[CH2:11][NH2:12].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](=O)[CH3:30])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CO>ClCCl>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:28][CH:29]([NH:12][CH2:11][CH:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)[OH:13])[CH3:30])=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NCC(O)c1cc2ccccc2o1
Reactant: CC(=O)Cc1ccc(OCc2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(Cc1ccc(OCc2ccccc2)cc1)NCC(O)c1cc2ccccc2o1

Procedure:
This was prepared in an identical manner to the compound described in Example 2 using 2-(2-benzofuranyl)-2-hydroxyethanamine (3.51 g) and 1-(4-benzyloxyphenyl)propan-2-one (4.75 g). Chromatography of the residual oily solid on Kieselgel 60 (4% methanol in dichloromethane) gave the title compound, m.p. 111°-122°, as a 20:80 mixture of diastereoisomers.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[CH2:11][N:12]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[S:24]([CH3:23])(=[O:26])=[O:25])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2cccc(CNCc3ccncc3)c2)n1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N(Cc1ccncc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 14 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 389.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4([NH2:26])[CH2:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=3)=[N:6][N:5]2[C:27]=1[CH:28]=[CH2:29].C(O)C>C(OCC)(=O)C.[Pd]>[CH2:28]([C:27]1[N:5]2[N:6]=[C:7]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4([NH2:26])[CH2:23][CH2:24][CH2:25]4)=[CH:20][CH:21]=3)[C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:9][C:4]2=[N:3][C:2]=1[CH3:1])[CH3:29]
Reactant: C=Cc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1c(C)nc2cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nn12
Reaction time: 3 h

Procedure:
14.3 mg (0.04 mmol) 1-[4-(2-Methyl-7-phenyl-3-vinyl-imidazo[1,2-b]pyridazin-6-yl)-phenyl]-cyclobutylamine, example 12, were given in five mL ethyl acetate (no complete dissolution). After addition of a catalytic amount of palladium/charcoal (10%) the reaction mixture was stirred under a hydrogen atmosphere for three hours. Due to an incomplete reaction one mL ethanol was added and stirring was continued over night. The catalyst was sucked off via a glass fibre filter and washed with ethanol. After evaporation of the solvents 11.9 mg (66.2%) of the title compound were obtained which were slightly contaminated.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[C@H:11](CC([O-])=O)[C@H:10](CC([O-])=O)[C@H:9](CC([O-])=O)[C@@H:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)=[CH:34][CH:33]=3)[CH:25]=2)[O:7]1)(=[O:3])[CH3:2].[C:49]([OH:52])(=[O:51])[CH3:50]>C1COCC1.O>[C:49]([O:52][C@H:11]1[C@H:10]([O:51][C:49](=[O:52])[CH3:50])[C@@H:9]([O:4][C:1](=[O:3])[CH3:2])[C@H:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][OH:41])=[CH:34][CH:33]=3)[CH:25]=2)[O:7][C@@H:6]1[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:51])[CH3:50]
Reactant: CC(=O)OC[C@@H]1O[C@H](c2ccc(Cl)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@@H](CC(=O)[O-])[C@@H](CC(=O)[O-])[C@H]1CC(=O)[O-]
Reactant: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (2.59 g, 3.66 mmol) in THF:Water (1:1, 36 mL) was added acetic acid (54 mL) at 0° C. The reaction mixture was stirred at r.t. for 24 h. After completion of reaction, as confirmed by TLC, the reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 4:6 Ethyl acetate:Pet. Ether) to afford title compound (1.8 g, 82%).