Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[CH:5]=[O:6].ClC1C=C(C=CC=1OCC)C=[O:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH3:13])[C:5]([OH:19])=[O:6]
Reactant: CCCOc1ccc(C=O)cc1Cl
Reactant: CCOc1ccc(C=O)cc1Cl
Product: CCCOc1ccc(C(=O)O)cc1Cl
Yield: 95 %

Procedure:
When the product of Step B was substituted for 3-chloro-4-ethoxybenzaldehyde in Example 49, Step A the identical process afforded the title compound in 95% yield, as a colourless solid. 1H-NMR (CDCl3) 1.00 (tr, 3H, J=7.38 Hz); 1.73-1.87 (m, 2H); 3.98 (tr, 2H, J=6.47 Hz); 6.85 (d, 1H, J=8.65 Hz); 7.84 (dd, 1H, J=2.09, 8.68 Hz); 7.98 (d, 1H, J=2.07 Hz).
Reaction SMILES: [C:1]1(=[O:11])[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Br[C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:26][C:20]([N:8]1[CH2:9][CH2:10][C:5]2([C:1](=[O:11])[NH:2][CH2:3][CH2:4]2)[CH2:6][CH2:7]1)([CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: O=C1NCCC12CCNCC2
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C)(C)N1CCC2(CCNC2=O)CC1
Temperature: 80 °C

Procedure:
A mixture of 2,8-diazaspiro[4.5]decan-1-one (3.03 g, 19.65 mmol), triethylamine (5.48 ml, 39.3 mmol) and ethyl 2-bromo-2-methylpropanoate (5.77 ml, 39.3 mmol) was heated at 80° C. overnight. The reaction mixture was partitioned between methylene chloride (200 mL) and saturated sodium bicarbonate, the alkaline phase was extracted with methylene chloride (3×100 mL). The combined organic phase was dried over magnesium sulfate, concentrated and the residue was purified on silica gel using methanol/methylene chloride to give the title compound. LC/MS (M+1)+: 269.4
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][O:15][CH:16]=[CH2:17]>>[CH:16]([O:15][CH2:14][CH2:13][NH:12][CH:9]([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH2:17]
Reactant: CC(=O)Cc1ccc(Cl)cc1
Reactant: C=COCCN
Product: C=COCCNC(C)Cc1ccc(Cl)cc1

Procedure:
N-(2-vinyloxyethyl)-α-methyl-β-(4-chlorophenyl) ethyl amine was prepared from 4-chlorophenylacetone and 2-aminoethylvinyl ether according to the method of Example 1 to yield the product (58% yield) as a colorless oil, b.p. 103°-104°/0.4 mm; ND25 1.5199.
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: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: Cn1c(-c2ccc(OCCCN3CCCCC3)cc2O)nc2cc(Br)ccc2c1=O
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: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.C(O)(=O)C>[Zn].O>[ClH:1].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(N[C@@H]1CN2CCC1CC2)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc2sc(C(=O)N[C@@H]3CN4CCC3CC4)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
422 mg (1.15 mmol) of N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-5-nitro-1-benzo-thiophene-2-carboxamide hydrochloride are suspended in 10 ml of a 1:1 mixture of acetic acid and water. 300.0 mg (4.59 mmol) of zinc are added, the mixture is then stirred at RT for 1 h. The reaction mixture is filtered through kieselguhr, and the filter cake is washed with methanol. The filtrate is concentrated under reduced pressure and the residue is purified by preparative HPLC. The product fraction is dissolved in 4M of HCl in dioxane, concentrated under reduced pressure and recrystallized from acetonitrile. 203 mg (47.3% of theory) of the title compound are obtained. The analytical data correspond to those of the enantiomeric compound from example 62.
Reaction SMILES: C([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.COC(=O)[CH2:22][NH2:23]>CO.[Pd]>[CH:13]([C@@H:12]1[NH:11][C:9](=[O:8])[CH2:22][NH:23][C:16]1=[O:18])([CH3:15])[CH3:14]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)CN
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H]1NC(=O)CNC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.2 %

Procedure:
A solution of 27.14 g (84.19 mmol) N-Benzyloxycarbonyl-valine-glycine-methylester (82) in 600 ml dry methanol was hydrogenated by adding Pd/C-catalyst and stirring the resulting mixture under H2 at r.t. for 4 h. After that the mixture was filtered through celite and the remaining solution was refluxed for 24 h. Evaporation of the solvent yielded 13.17 g (84.33 mmol, 100%) 6-(S)-Isopropyl-piperazine-2,5-dione (83) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:14])/[C:11]([OH:13])=O)=[CH:5][CH:4]=1.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH2:25][NH:26][CH3:27].C1C=CC2N(O)N=NC=2C=1.O.CCN(CC)CC.C(Cl)CCl>CN(C=O)C.C(Cl)Cl>[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH3:14])/[C:11]([N:26]([CH3:27])[CH2:25][C:17]2[N:16]([CH3:15])[C:24]3[C:19]([CH:18]=2)=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:13])=[CH:5][CH:4]=1
Reactant: C/C(=C\c1ccc(N)nc1)C(=O)O
Reactant: CNCc1cc2ccccc2n1C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C/C(=C\c1ccc(N)nc1)C(=O)N(C)Cc1cc2ccccc2n1C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
To a stirred solution of (E)-3-(6-aminopyridin-3-yl)-2-methylacrylic acid HCl salt (0.5 g, 2.3 mmole) in dry 1:1 DMF/CH2Cl2 (30 mL) at RT was added 1-methyl-2-(methylaminomethyl)indole (0.42 g, 2.4 mmole), HOBt.H2O (0.32 g, 2.4 mmole), Et3N (0.66 mL, 4.7 mmole), and EDC (0.46 g, 2.4 mmole). After stirring for 24 hr the reaction was concentrated to dryness. The residue was taken up in ethyl acetate and the solution was washed with H2O, dried (Na2SO4), and concentrated under vacuum. Flash chromatography on silica gel (4% methanol/CHCl3) followed by trituration with ethyl acetate/hexane gave the title compound (0.55 g, 75%) as an off-white solid: LCMS (ES) m/e 335.2 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.96 (s, 1H), 732 (d, J=7.8 Hz, 1H), 7.48 (dd, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.14 (t, 1H), 7.03 (t, 1H), 6.46 (d, J=8.7 Hz, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 6.17 (br s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][O:12][C:11]2=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][O:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: O=C1OCCCN1c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(N2CCCOC2=O)cc1

Procedure:
A mixture of 3-(4-nitrophenyl)-1,3-oxazinan-2-one (0.10 g, 0.00045 mol) in 5 mL of methanol was hydrogenated, in the presence of 10% Pd/C, under balloon pressure of hydrogen, overnight. After filtering off the catalyst, the filtrate was evaporated to dryness and used directly in next step. LCMS (M+H) 193.0.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.CC([O-])(C)C.[K+].O.OS(O)(=O)=O>C1COCC1>[CH2:16]([CH:13]([CH2:14][CH3:15])[CH2:12][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:17]
Reactant: CCOC(=O)C1(CC(CC)CC)CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 54 °C
Reaction time: 20 h
Yield: 98.9 %

Procedure:
1-(2-Ethyl-butyl)-cyclohexanecarboxylic acid ethyl ester (2.0 g, 8.32 mmol) was added dropwise under stirring to a solution of KOtBu (3.735 g, 33.3 mmol) in THF (15 mL) containing a small amount of water (225 mg, 12.5 mmol). The mixture was stirred 20 h at 54° C., cooled to room temperature, slowly poured onto a mixture of ice and 4N H2SO4 and extracted with DCM (2×150 mL) after adjusting to pH 1. The organic phases were washed with diluted aq. NaCl (100 mL), combined, dried over sodium sulfate and concentrated to afford 1.748 g (99%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, purity 95.2% (GC with internal standard).
Reaction SMILES: CO.C(O)(=O)C.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:44][O:45][CH3:46])[C:14]([NH:16][CH:17]2[C:42](=[O:43])[N:19]3[CH:20]([C:29]([O:31]CC4C=CC([N+]([O-])=O)=CC=4)=[O:30])[C:21](=[CH:24][O:25][C:26](=[O:28])[CH3:27])[CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1.O>O1CCCC1.[C].[Pd]>[NH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:44][O:45][CH3:46])[C:14]([NH:16][CH:17]2[C:42](=[O:43])[N:19]3[CH:20]([C:29]([OH:31])=[O:30])[C:21](=[CH:24][O:25][C:26](=[O:28])[CH3:27])[CH2:22][S:23][C@H:18]23)=[O:15])[N:12]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=COC(C)=O)CS[C@H]12)c1csc(N)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(=COC(C)=O)CS[C@H]12)c1csc(N)n1
Reaction time: 3 h
Yield: 14 %

Procedure:
Methanol (10 ml) and acetic acid (3 ml.) were added to a solution of 4-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethylenecepham-4-carboxylate (syn isomer, 2.5 g.) in tetrahydrofuran (60 ml.). 10% palladium-carbon (0.5 g.) containing water (2 ml.) was added to a solution and the mixture was subjected to catalytic reduction under ordinary pressure for 3 hours. After removing the insoluble substance from the resultant mixture by filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate and an aqueous solution of sodium bicarbonate were added to the solution and adjusted to pH 7.5. The insoluble substance was removed from the mixture. The aqueous layer was separated, adjusted to pH 5.0 and washed with ethyl acetate. The solution was adjusted to pH 3.0 and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and treated with activated charcoal. After concentrating the solution under reduced pressure, the residue was pulverized with diisopropyl ether and collected by filtration to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetoxymethylenecepham-4-carboxylic acid (syn isomer, 0.27 g.).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>CCOCC.C1COCC1>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]([OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCCCCCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
In a 100 ml round bottom flask with a Y-adapter, condensor, and a 10 ml addition funnel was added 0.38 g (15.63 mmol) of Mg turnings which had been ground with a mortar and pestle. The apparatus was then flushed with argon and flamed dried. After allowing the apparatus to cool under argon, 4 ml of anhydrous diethyl ether was added to the Mg. While vigorously stirring the Mg in the ether, 2.52 g (13.05 mmol) of 1-bromooctane in 3 ml of diethyl ether was added dropwise. After 5 drops, the Grignard reaction started and the addition was continued at a rate sufficient to maintain a steady reflux. After addition was complete, 4 ml of dry THF was added to the Grignard reagent and it was stirred at R.T. for an additional 1/2 hour. A warm water bath was then placed under the flask, and refluxing was continued for 15 minutes. Afterwards, the reaction was cooled to 0° C. with an ice bath and 2.00 g (16.81 mmol) of p-bromobenzaldehyde in 4 ml of THF was added. The reaction was stirred at R.T. for 1.5 hr., whereupon the Grignard was quenched with saturated NH4Cl. The organic layer was washed with H2O and brine, then dried (MgSO4). Rotary evaporation of the solvent under reduced pressure produced 2.96 g of a crude yellow oil. The oil was dissolved in a diethyl ether and loaded onto a silica gel column. Elution with diethyl ether/hexane yielded 2.22 g of the titled product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9](Cl)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O-:20].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:20][CH3:19])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[O-]
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)c2ncn(Cc3ccccc3)c2n1
Reaction time: 30 h
Yield: 76.8 %

Procedure:
6-Amino-9-benzyl-2-chloropurine (200 mg, 0.77 mmol) and sodium methylate (208 mg, 3.85 mmol) were dissolved in methanol (20 ml) and then the solution was refluxed on heating under stirring for 30 hours. The reaction mixture was evaporated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on sodium sulfate and evaporated in vacuo to dryness. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (151 mg, yield 77%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[O:17][CH:16]2C([O-])=O)=[CH:11][CH:10]=1.[Na+].C1(C)C=CC=CC=1.O.C(O)(=O)C>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]=[O:17])=[CH:11][CH:10]=1
Reactant: O=C([O-])C1OC1c1ccc(COc2ccccn2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=CCc1ccc(COc2ccccn2)cc1
Temperature: 73 °C
Reaction time: 1.5 h

Procedure:
A mixture of sodium 3-(4-(pyridin-2-yloxymethyl)-phenyl)-oxiran-2-carboxylate described in Preparation Example 2-1-2 (9.95 g), toluene (200 mL), water (120 mL) and acetic acid (16 mL) was stirred at 73° C for 90 minutes. The reaction mixture was allowed to room temperature, to the reaction mixture was added ethyl acetate, and extracted, and then the organic layer was separated, washed with saturated sodium chloride water, and dried over anhydrous magnesium sulfate. The solvent thereof was evaporated under a reduced pressure to obtain the title compound (6.82 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28]([C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])=[CH:27][C:26](=O)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:37]=[CH:36][CH:35]=[C:32]([C:33]#[N:34])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(N)cc1-n1cccc1
Product: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1-n1cccc1

Procedure:
The title compound was prepared from (2-amino-5-methoxy-4-pyrrol-1-yl-phenyl)-carbamic acid tert.-butyl ester (Example J4) (303 mg, 1.0 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example L1) (252 mg, 1.1 mmol) according to the general procedure M. Obtained as an off-white solid (257 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.O=S(Cl)Cl.[CH3:20][O:21][C:22]([C:24]1[NH:25][CH:26]=[CH:27][CH:28]=1)=[O:23]>ClC(Cl)C>[CH3:20][O:21][C:22]([C:24]1[NH:25][CH:26]=[C:27]([C:13]([C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[O:15])[CH:28]=1)=[O:23]
Reactant: COC(=O)c1ccc[nH]1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C(=O)c2c(-c3ccccc3)noc2C)c[nH]1
Temperature: 25 °C

Procedure:
A mixture of 406 mg (2 mmol) 5-methyl-3-phenyl-isoxazole-4-carboxylic acid (commercially available) and 4 mL SOCl2 was heated to reflux for 3 h. After evaporation of all volatiles the residue was added to a mixture of 206 mg (2 mmol) 1H-pyrrole-2-carboxylic acid methyl ester (commercially available) and 440 mg (3 mmol) AMCl3 in 25 mL dichloroethane and heated to reflux for 3 h. After cooling to room temperature the precipitate was collected and washed with dichloromethane. The residue was purified on silica eluting with a gradient of ethyl acetate and heptane affording 210 mg (37%) of the title compound as white foam. (m/e): 311.0 (MH+; 100%).
Reaction SMILES: N(CCCC(OC)=O)=[N+]=[N-].C(C1C=CC(OC)=CC=1)#C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[N:31][N:32]([CH2:34][CH2:35][C:36]([OH:38])=O)[CH:33]=2)=[CH:25][CH:24]=1.[NH2:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47](=[O:54])[NH:46][N:45]=1.C(Cl)CCl.C(N(CC)CC)C>O1CCOCC1.CN(C=O)C>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:30]=[N:31][N:32]([CH2:34][CH2:35][C:36]([NH:39][CH2:40][CH2:41][CH2:42][NH:43][C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:47](=[O:54])[NH:46][N:45]=3)=[O:38])[CH:33]=2)=[CH:27][CH:28]=1
Reactant: NCCCNc1n[nH]c(=O)c2ccccc12
Reactant: COc1ccc(-c2cn(CCC(=O)O)nn2)cc1
Agent: C#Cc1ccc(OC)cc1
Agent: COC(=O)CCCN=[N+]=[N-]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cn(CCC(=O)NCCCNc3n[nH]c(=O)c4ccccc34)nn2)cc1
Temperature: 175 °C
Reaction time: 5 h

Procedure:
Methyl 4-azidobutyrate (200 mg, 1.40 mmol) and 1-ethynyl-4-methoxybenzene (277 mg, 210 mmol) were dissolved in dioxane (3 mL) and heated in a microwave reactor for 5 min at 175° C. The reaction mixture was filtered and the filtrate was concentrated under vacuum. Compound 3-[4-(4-methoxy-phenyl)-[1,2,3]triazol-1-yl]-propionic acid methyl ester was treated with aqueous 2M NaOH (5 mL) in THF (3 mL) and stirred at RT for 5 h. The methanol was removed under vacuum and the residue was dissolved in dioxane (5 mL) and treated with concentrated HCl dropwise until a precipitate formed. The resulting acid was collected by filtration and the purity was measured by RPLC (78%). Compound 3-[4-(4-methoxy-phenyl)-[1,2,3]triazol-1-yl]-propionic acid (125 mg, 0.50 mmol) and 4-(3-amino-propylamino)-2H-phthalazin-1-one (100 mg, 0.46 mmol) were dissolved in DMF (2 mL) and treated with EDC (95 mg, 0.50 mmol) and triethylamine (76 mg, 0.75 mmol). 3-[4-(4-Methoxy-phenyl)-[1,2,3]triazol-1-yl]-N-[3-(4-oxo-3,4-dihydro-phthalazin-1-ylamino)-propyl]-propionamide was isolated by preparative RPLC.
Reaction SMILES: [Cl-].[NH2:2][C:3]1([CH2:33][CH2:34][OH:35])[CH2:7][CH2:6][C@@H:5]([C:8]([NH:10][C@H:11]([CH:30]([CH3:32])[CH3:31])[C:12]([N:14]2[CH2:19][CH2:18][C@@:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)([OH:20])[C:16]([CH3:29])([CH3:28])[CH2:15]2)=[O:13])=[O:9])[CH2:4]1.[C:36](C1NC=CN=1)(C1NC=CN=1)=[O:37].C(N(CC)CC)C>C1COCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C@@:17]2([OH:20])[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C@H:11]([NH:10][C:8]([C@@H:5]3[CH2:6][CH2:7][C:3]4([CH2:33][CH2:34][O:35][C:36](=[O:37])[NH:2]4)[CH2:4]3)=[O:9])[CH:30]([CH3:32])[CH3:31])[CH2:15][C:16]2([CH3:29])[CH3:28])=[CH:22][CH:23]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: CC(C)[C@@H](NC(=O)[C@@H]1CCC(N)(CCO)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](NC(=O)[C@@H]1CCC2(CCOC(=O)N2)C1)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.33 %

Procedure:
To a solution of (1R)-3-amino-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)-3-(2-hydroxyethyl)cyclopentanecarboxamide (from step F, 30 mg, 0.061 mmol) in THF (1 mL) was added carbonyl diimidazole (14.77 mg, 0.091 mmol) and triethylamine (0.021 mL, 0.152 mmol). The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and subjected preparative HPLC(Shimadzu VP-ODS 20×100 mm, 8 min. gradient, Solvent A: 10% MeOH, 90% H2O, 0.1% TFA; Solvent B: 90% MeOH, 10% H2O, 0.1% TFA; wavelength: 220 nM) to yield the desired product as a diastereomer mixture. The diastereomer mixture was subjected to chiral preparative HPLC (Column: ChiralPak ASH, 250×3 cm, 5 μm; Flow rate: 120 mL/min; Mobile Phase: CO2/MeOH=80/20; Inj. Vol.=2.0 mL, Wavelength=220 nM; isomer 1, retention time=5.75 min; isomer 2, retention time=9.10 min) to yield the individual diasteromers (2 mg for each isomer, 3.85 μmol, 6.33% yield) as a solid.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cn1ccnc1S
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nccn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 2-mercapto-1-methylimidazole was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.48-1.65 (m, 8H) 1.86 (m, 2H) 3.72 (s, 3H) 3.80 (s, 3H) 7.04 (m, 2H) 7.19 (d, J=1.7 Hz, 1H) 7.46 (s, 1H) 7.58 (s, 1H). MS (APCI) calcd for C23H27ClN2O4S: 462.99; found 463.1.