Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=2[CH3:25])=[CH:12][CH:11]=1>CS(C)=O.O>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=2[CH3:25])=[CH:14][C:15]=1[Br:8]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cc2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(N)c(Br)c2)s1

Procedure:
NBS (2.52 g, 14.7 mmol) is added to a stirred solution of N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) (3.5 g, 14.7 mmol) in dry dimethylsulphoxide (50 ml) at 10° C. After 10 minutes the solution is diluted with water (200 ml) and the resulting precipitate is removed by filtration. Crystallisation from ethyl acetate-methanol affords the title compound. MH+ (TOF, MS ES+): 325.9, 328.9
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[C:14]([O:1][CH2:2][C:3]1[NH:7][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1cnc(-c2ccccc2)[nH]1
Solvent: Cc1ccccc1
Product: CC(=O)OCc1cnc(-c2ccccc2)[nH]1
Temperature: 52.5 °C

Procedure:
Mix 5-hydroxymethyl-2-phenyl-1H-imidazole (1.3 Kg) and toluene (10.4 L) at 20-25° C., and then heat the mixture with stirring to 50-55° C. Add acetic anhydride (780 ml, 1.1 equivalents) slowly and continue heating at 50-55° C. until the reaction is complete (typically 3-4 hours). Cool the reaction mixture to -5-0° C., filter off the product, wash it with toluene (3×700 ml) and then dry it under vacuum at 50-55° C. to constant weight.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=[N:6][C:7]=1S(C)(=O)=O.[CH3:28][O-:29].[Na+].O>CO.CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:5]([C:12]2[CH:13]=[CH:14][C:15](=[O:21])[N:16]([CH:18]([CH3:20])[CH3:19])[N:17]=2)=[N:6][C:7]=1[O:29][CH3:28]
Reactant: CC(C)n1nc(-c2nc(S(C)(=O)=O)c(N)nc2-c2ccccc2)ccc1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: COc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Yield: 85.8 %

Procedure:
A suspension of 6-[5-amino-6-(methylsulfonyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (205 mg) and sodium methoxide (57.7 mg) in MeOH (0.6 m) was refluxed for 24 hours. Water (3 ml) was added to the reaction mixture to give a precipitate. The precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-(5-amino-6-methoxy-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (154 mg).
Reaction SMILES: [I-].C[N+:3]([CH2:6][C:7]1[N:11]2[C:12]([C:16]([O:18]CC)=O)=[CH:13][CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1)([CH3:5])C.[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32]CN)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>>[C:21]([O:25][C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:5][N:3]1[C:16](=[O:18])[C:12]2[N:11]3[C:7](=[CH:8][N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=2)[CH2:6]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: CCOC(=O)c1cccc2ncc(C[N+](C)(C)C)n12
Agent: [I-]
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCCN1Cc2cnc3cccc(n23)C1=O
Yield: 54.8 %

Procedure:
A solution of 7.78 g (20 mmol) of 3-[(trimethylammonio)methyl]-5-ethoxycarbonylimidazo[1,2-a]pyridine iodide, 6.07 g (30 mmol) of 5-tert-butoxycarbonylamino-1-pentylamine and 5.58 ml (40 mmol) of triethylamine was heated for 64 hours under reflux. The solvent was distilled off. To the residue was added methylene chloride, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 3.93 g of the desired compound (54.9%, a pale yellow solid).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)=[O:6].C1C2C(=O)N[C:30]3C=CC=C[C:29]=3[NH:28][C:27]=2[CH:26]=CC=1.BrCCCC(Cl)=O>C1(C)C=CC=CC=1>[CH2:27]([N:28]([CH2:29][CH3:30])[CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11](=[O:18])[NH:10][C:9]2[CH:19]=[CH:20][CH:21]=[CH:22][C:8]1=2)=[O:6])[CH3:26]
Reactant: O=C1Nc2ccccc2N(C(=O)CCCBr)c2ccccc21
Reactant: O=C1Nc2ccccc2Nc2ccccc21
Agent: O=C(Cl)CCCBr
Solvent: Cc1ccccc1
Product: CCN(CC)CCCC(=O)N1c2ccccc2NC(=O)c2ccccc21

Procedure:
The 5-(4-bromobutyryl)-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one, starting material, was synthesized similarly to the starting material described in Example 1, from 5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one and 4-bromobutyryl chloride. The yield is 74.3% of the theoretical yield and the melting point is 159°-161° C. (toluene).
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C@@H:7]([NH:16][CH2:17][C@@H:18]([OH:46])[C@@H:19]([NH:29][C:30](=[O:45])[C@@H:31]([N:35]2[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH2:42][CH3:43])[C:36]2=[O:44])[CH2:32][CH:33]=C)[CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH2:6]1)[CH:2]=C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:40]([C@H:37]1[CH2:38][CH2:39][N:35]([C@H:31]2[CH2:32][CH:33]=[CH:2][CH2:1][O:4][C@@H:5]3[CH2:6][C@@H:7]([C:8]4[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=43)[NH:16][CH2:17][C@@H:18]([OH:46])[C@H:19]([CH2:20][C:21]3[CH:22]=[C:23]([F:28])[CH:24]=[C:25]([F:27])[CH:26]=3)[NH:29][C:30]2=[O:45])[C:36]1=[O:44])[CH2:41][CH2:42][CH3:43]
Reactant: C=CCO[C@@H]1C[C@H](NC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)[C@H](CC=C)N2CC[C@H](CCCC)C2=O)c2cc(OC)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC[C@H]1CCN([C@H]2CC=CCO[C@@H]3C[C@H](NC[C@@H](O)[C@H](Cc4cc(F)cc(F)c4)NC2=O)c2cc(OC)ccc23)C1=O
Reaction time: 72 h
Yield: 54.7 %

Procedure:
Step J (2): Hoveyda-Grubb's catalyst [(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(O-isoproproxylphenylmethylene)ruthenium] (6.6 mg, 7.8 μmol, Aldrich) was added to flask charge with a solution of (S)—N-((2S,3R)-4-((1S,3R)-3-(allyloxy)-6-methoxy-2,3-dihydro-1H-inden-1-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl)-2-((S)-3-butyl-2-oxopyrrolidin-1-yl)pent-4-enamide (59 mg, 0.0783 mmol, TFA salt) from stepH(1) in CH2Cl2 at room temperature. The mixture was stirred for 3 days. The resulting solution was evaporated to dryness, dissolved in MeOH, and filtered through Celite. Purified using reverse phase preparatory HPLC to give 26.2 mg (46% yield) of the title compound as a TFA salt: LC-MS (M+H)+=612.51; 1H NMR (500 MHz, CDCl3) δ 7.35 (d, J=8.55 Hz, 1H), 7.14 (s, 1H), 6.92-7.10 (m, 2H), 6.41-6.80 (m, 3H), 5.59-5.74 (m, 1H), 5.43-5.57 (m, 1H), 4.78-5.16 (m, 4H), 4.72 (d, J=5.49 Hz, 1H), 4.40 (d, J=9.77 Hz, 1H), 3.98-4.16 (m, 2H), 3.66-3.98 (m, 4H), 3.07-3.39 (m, 3H), 2.47-2.85 (m, 3H), 2.24-2.50 (m, 2H), 1.93-2.20 (m, 2H), 1.68-1.88 (m, 1H), 1.05-1.53 (m, 6H), 0.74-0.94 (m, 3H).
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1([CH2:21]O)[CH2:20][CH2:19][CH2:18][CH2:17]1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl.O1CCOCC1>[NH2:15][C:16]1([CH2:21][O:14][CH:1]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1(CO)CCCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(COC(c2ccccc2)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzhydrol (1.6 g) was added in one portion to a solution of 1-aminocyclopentane-1-methanol (1.0 g) and trifluoroacetic acid (3.5 ml) in methylene chloride (10 ml) and the mixture was stirred at room temperature for 3 hours and then treated with dioxane (10 ml) and 4M aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 30 minutes and evaporated. The residue was partitioned between water and ether and the organic layer was extracted into 2M hydrochloric acid. The acidic extract was washed with ether/hexane (1:1), basified with solid sodium carbonate and extracted into ether. The organic extracts were dried over magnesium sulphate and evaporated to give the title compound as a pale yellow oil which was characterised as containing 0.25 molar equivalents of water (710 mg, 30%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:7]([NH2:8])=[CH:6][NH:5][N:4]=1.O1CCCC1.C(=O)(O)[O-].[Na+].[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>C(OCC)(=O)C.O>[Cl:19][CH2:20][CH2:21][C:22]([NH:8][C:7]1[C:3]([Cl:2])=[N:4][NH:5][CH:6]=1)=[O:23]
Reactant: Nc1c[nH]nc1Cl
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCCl)Nc1c[nH]nc1Cl
Temperature: 5 °C

Procedure:
A 250-mL 3-neck flask was charged with 3-chloro-1H-pyrazol-4-amine.hydrochloride (10.0 g, 64.9 mmol), tetrahydrofuran (50 mL), and water (50 mL). The resulting suspension was cooled to 5° C. and sodium bicarbonate (17.6 g, 210 mmol) was added, followed by dropwise addition of 3-chloropropanoyl chloride (7.33 g, 57.7 mmol) at <5° C. The reaction was stirred at <10° C. for 1 hour, at which point thin layer chromatography (TLC) [Eluent: 1:1 ethyl acetate (EtOAc)/hexane]analysis indicated the starting material was consumed and the desired product was formed. It was diluted with water (50 mL) and ethyl acetate (50 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (20 mL) and the combined organic layers were concentrated to dryness to afford a pale brown solid, which was purified by flash column chromatography using ethyl acetate as eluent. The pure fractions were concentrated to afford a white solid (9.20 g, 77%): mp: 138-140° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1 H), 9.68 (s, 1 H), 8.03 (d, J=1.7 Hz, 1 H), 3.85 (t, J=6.3 Hz, 2 H), 2.85 (t, J=6.3 Hz, 2 H); 13C NMR (101 MHz, DMSO-d6) δ 167.52, 130.05, 123.59, 116.48, 40.75, 37.91; EIMS m/z 207 (m+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][N:34]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@H](SC(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C[C@H]1CN)=O)(C)(C)C.[F:71][C:72]1[CH:79]=[CH:78][C:77]([F:80])=[CH:76][C:73]=1[CH:74]=O>>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][NH:34][CH2:74][C:73]1[CH:76]=[C:77]([F:80])[CH:78]=[CH:79][C:72]=1[F:71])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN=[N+]=[N-]
Reactant: O=Cc1cc(F)ccc1F
Agent: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN
Product: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CNCc1cc(F)ccc1F

Procedure:
From (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared via (2S,4R)-2-aminomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester [as light brown foam, MS: 475 (MH+)] and further reaction with 2,5-difluoro benzaldehyde analogously to reductive amination gave (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless oil MS: 601 (MH+) which was treated according to trityl cleavage (method 5) to give (2S,4R)-2-[(2,5-difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid tert-butyl ester as colorless liquid MS: 359 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([CH2:14][OH:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([C:14]([OH:24])=[O:15])([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: OC[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Yield: 62 %

Procedure:
To a stirred solution of racemic Intermediate 38, one enantiomer being ((1S,2S)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hex-1-yl)-methanol (0.69 g, 2.5 mmol) in acetone (20 mL) was added Jones Reagent (3 mL) dropwise with stirring. Additional acetone (50 mL) was added and the material was triturated then filtered to remove the solid. The filtrate was concentrated and partitioned between water of pH=6 and methylene chloride. The organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound (0.45 g, 62% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH2:23][NH:24][CH3:25])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=1)[CH2:23][N:24]([CH3:25])[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: CNCc1cccc(OC)c1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(CN(C)CC(=O)c2ccc3ccccc3c2)c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of α-bromo-2′-acetonaphthone (386.2 g, 1.57 mol) in dichloromethane (2.5 L) at 0° C. was added Compound 3 (249.1 g, 1.65 mol) in 30 min, followed by the addition of triethylamine (220.7 mL, 1.57 mmol) in 45 min. After stirring at 0° C. for 40 min, the reaction mixture was warmed to room temperature and stirred overnight. The reaction solution was then washed with water (2×) and the aqueous layer was re-extracted with dichloromethane (2×). The combined organic extract was dried over sodium sulfate and concentrated in vacuo. The ketone, Compound 4, was obtained as a reddish oil (513.3 g, quantitative), was used in the next step without further purification: 1H NMR (CDCl3, 500 MHz) δ 8.50 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.92 (d, 8.0 Hz, 1H), 7.88-7.85 (m, 2H), 7.60-7.54 (m, 2H), 7.26-7.23 (m, 1H), 6.97-6.94 (m, 2H), 6.82 (dd, J=8.0, 2.5 Hz, 1H), 3.88 (s, 2H), 3.75 (s, 3H), 3.69 (s, 2H), 2.42 (s, 3H); ESI MS m/z 320 [M+H]+.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]([C:19]4[C:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:21][O:22][C:23]=4[CH3:24])=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.N1CC[O:34][CH2:33]C1>>[CH3:24][C:23]1[O:22][N:21]=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]=1[C:16]1[O:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]([N:1]3[CH2:2][CH2:33][O:34][CH2:4][CH2:5]3)=[O:7])=[CH:9][CH:10]=2)=[N:18][N:17]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)n3ccnc3)cc2)o1
Reactant: C1COCCN1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(=O)N3CCOCC3)cc2)o1
Yield: 94 %

Procedure:
As described for example 78c, imidazol-1-yl-{4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenyl}-methanone (200 mg, 0.50 mmol) was converted using morpholine instead of cyclopropylamine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 196 mg, 94%) which was obtained as a colorless foam. MS: m/e=417.3 [M+H]+.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)CC)C.Cl.Cl.[CH3:30][N:31]1[C:35]2[NH:36][CH2:37][CH2:38][S:39][CH:40]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[C:34]=2[C:33]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)=[N:32]1>C1COCC1.C(OCC)(=O)C>[CH3:20][C:15]1[C:14]([NH:13][C:5]([N:44]2[CH2:45][CH2:46][CH:41]([CH:40]3[S:39][CH2:38][CH2:37][NH:36][C:35]4[N:31]([CH3:30])[N:32]=[C:33]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=5)[C:34]3=4)[CH2:42][CH2:43]2)=[O:11])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: Cc1ncccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2C1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ncccc1NC(=O)N1CCC(C2SCCNc3c2c(-c2ccccn2)nn3C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 116.1 %

Procedure:
To a mixture of triphosgene (0.017 g, 0.056 mmol) and 3-amino-2-methylpyridine (0.018 g, 0.17 mmol) in anhydrous THF (5 mL) was added dropwise triethylamine (0.14 mL, 1 mmol), at about 0° C. After stirring for about 5 min at about 0° C., 1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride (0.07 g, 0.17 mmol, Preparation #4) was added at about 0° C. Subsequently, the mixture was stirred for about 1 h and allowed to come to rt. Then the mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, DCM/methanol/ammonium hydroxide 92:7.5:0.5) to give N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]piperidine-1-carboxamide (0.03 g, 0.065 mmol, 26%) as an off white solid: LC-MS (Table 1, Method b) Rt=2.00 min; m/z 464 (M+H)+.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-:20].[K+].[CH4:22]>C1(C)C=CC=CC=1>[CH2:1]([O:20][CH2:22][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: C
Reactant: [OH-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Distearyl ether was synthesized by reacting stearyl bromide (Sigma) with PEG-900 in the presence of potassium hydroxide. Stearyl bromide (4.168 g in 10 ml toluene) was slowly added with stirring to 4.64 g of PEG-900 in 10 ml of toluene at 45° C. The mixture was then stirred at 60° C. for 30 min. and refluxed for 6 hrs. The final product was treated with charcoal, filtered and isolated from toluene.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[CH2:22]([S:24](Cl)(=[O:26])=[O:25])[CH3:23].C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:24]([CH2:22][CH3:23])(=[O:26])=[O:25])[CH:2]([CH3:4])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)CC(C)C

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with ethanesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give ethanesulfonic acid isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amide as a light yellow oil. MS: 433.4 ([M+NH4]+)
Reaction SMILES: C([OH:3])C.C(N([CH2:9][CH3:10])CC)C.[CH:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.Cl>C1(C)C=CC=CC=1.O>[CH:11]1([C:17]([O:18][CH2:9][CH3:10])=[O:3])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CCCCC1
Reaction time: 3 h

Procedure:
To a solution of ethanol (45 ml) and triethylamine (78 g) in toluene (120 ml), cyclohexane carbonyl chloride (75 g, 0.51 mol) was added dropwise at 15° C. or lower, and stirring was continued for 3 h at room temperature. The reaction mixture was poured into cold H2O (350 ml), acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic extract was washed thrice with H2O (150 ml), dried over anhydrous Na2SO4 and the solvent was removed in vacuo. The residue (93 g) was distilled under reduced pressure to give the title compound as a colorless oil; yield: 64 g; bp 101°-102° C./35 mmHg (Lit: bp 194° C./~760 torr: G. A. Olah, T. Keumi, D. Meider, Synthesis, 1978, 929.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[K+].[K+]>O1CCCC1.CN(C)C=O.O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CCOC(=O)CC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])nc1
Yield: 35.8 %

Procedure:
To a mixture of 5-bromo-2-nitropyridine (8.66 g, 42.7 mmol) and benzyl ethyl malonate (9.50 g, 42.7 mmol) in tetrahydrofuran (160 ml) and dimethylformamide (40 ml) was added K2CO3 (5.90 g, 42.7 mmol) and stirred under reflux temperature for 20 h. The mixture was diluted with water (11) and extracted with ethyl acetate (3×200 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated to give 5.26 g of title compound as orange oil.
Reaction SMILES: N[CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH:67](=O)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1.[BH3-][C:76]#[N:77].[Na+].Cl>CO>[CH2:67]([N:11]([CH:10]([C@@H:9]([O:8][CH:6]1[C@H:5]([O:64][CH3:65])[C@@H:4]([OH:66])[C@@H:3]([CH2:2][NH:77][CH2:76][C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[O:7]1)[C@@H:49]1[C@@H:53]([OH:54])[C@@H:52]([OH:55])[C@H:51]([N:56]2[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]2=[O:63])[O:50]1)[C:46]([OH:48])=[O:47])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]1[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]1)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Reactant: O=Cc1ccccc1
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CO[C@H]1C(O[C@H](C(C(=O)O)N(CCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)Cc2ccccc2)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CNCc2ccccc2)[C@@H]1O
Reaction time: 0.08 h
Yield: 4.2 %

Procedure:
To a solution of 50 mg (53 μmol) 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) in 0.4 ml of methanol is added 11 mg (2.0 eq., 106 μmol) of benzaldehyde and 3.3 mg (1.0 eq., 53 μmol) of NaBH3CN. After stirring for 5 minutes, 0.04 ml of methanolic hydrochloric acid is added. The reaction mixture is then stirred for 0.5 hour. The reaction is monitored by MS. The solvent is removed under reduced pressure to give a yellow gum. The desired products are separated by preparative HPLC to give 15 mg (26% yield) of Example 20a as a white solid and 2.5 mg (4% yield) of Example 20b as a white solid.