Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:11]2=[O:22])[S:5][C:6]=1[C:7]([OH:9])=O.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:11]2=[O:22])[S:5][C:6]=1[C:7]([NH:59][CH2:60][C:61]1[CH:62]=[N:63][CH:64]=[CH:65][CH:66]=1)=[O:9]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ccncc3)C2=O)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CCN(Cc3ccncc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.6 %

Procedure:
To a solution of 4-methyl-2-(2-oxo-3-(pyridin-4-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylic acid (0.67 g, 2.12 mmol) in anhydrous N,N-dimethyl formamide (10 mL) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.94 g, 2.12 mmol), diisopropylethylamine (1.12 mL, 6.35 mmol) and 3-(aminomethyl)pyridine (0.22 mL, 2.12 mmol). The resulting solution was stirred at ambient temperature for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate solution (15 mL) and brine (15 mL). The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with 10-20% methanol in ethyl acetate as an eluent to afford the title compound as a colorless solid (10%, 0.092 g): mp 233-235° C. (dichloromethane/hexanes): 1H NMR (300 MHz, CDCl3) δ 8.57-8.49 (m, 4H), 7.67 (d, J=7.7 Hz, 1H), 7.26-7.17 (m, 3H), 6.36 (br s, 1H), 4.56 (d, J=5.8 Hz, 2H), 4.45 (s, 2H), 4.12-4.07 (m, 2H), 3.50-3.45 (m, 2H), 2.58 (s, 3H): MS (ES+) m/z 409.2 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][NH:27][CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2.[CH2:32](N(CC)CC)[CH3:33].C(I)C>CN(C)C=O.Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[NH:20][C:21]([C:23]1[S:24][C:25]3[CH2:26][N:27]([CH2:32][CH3:33])[CH2:28][CH2:29][C:30]=3[N:31]=1)=[O:22])=[O:13])=[CH:6]2
Reactant: CCN(CC)CC
Reactant: O=C(N[C@@H]1CCC[C@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCc2nc(C(=O)N[C@@H]3CCC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(±)-trans-N1-[(5-Chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclopentanediamine hydrochloride (500 mg) was dissolved in N,N-dimethylformamide (10 ml), and triethylamine (576 μl) and ethyl iodide (329 μl) were added to stir the mixture overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue to collect insoluble matter by filtration. This product was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a pale brown foamy substance. This substance was suspended in 1N hydrochloric acid (2 ml), and the suspension was concentrated under reduced pressure to obtain the title compound (180 mg) as a pale yellow foamy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:19])=O)[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29]([CH3:37])[CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29]([CH3:37])[CH:28]=3)=[O:19])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1C
Reactant: COc1cn(C(C(=O)O)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Product: COC(=O)c1ccc(NC(=O)C(C(C)C)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1C

Procedure:
120 mg (333 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoic acid (racemate) and 60.4 mg (366 μmol, 1.1 eq.) of methyl 4-amino-2-methylbenzoate were reacted according to General Method 5A. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 155 mg (88% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].C(Cl)(=O)C1C=CC=CC=1.[C:26]([C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:38]=1[O:39][CH2:40][O:41][CH3:42])[C:33](Cl)=O)([CH3:29])([CH3:28])[CH3:27]>>[CH2:10]([N:5]1[C:6]2[C:7](=[O:8])[NH:9][C:33]([C:32]3[CH:36]=[C:37]([C:43]([CH3:46])([CH3:44])[CH3:45])[C:38]([O:39][CH2:40][O:41][CH3:42])=[C:30]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:31]=3)=[N:1][C:2]=2[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCOc1c(C(C)(C)C)cc(C(=O)Cl)cc1C(C)(C)C
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Solvent: O=C(Cl)c1ccccc1
Product: COCOc1c(C(C)(C)C)cc(-c2nc3ncn(Cc4ccccc4)c3c(=O)[nH]2)cc1C(C)(C)C
Yield: 45 %

Procedure:
An amidation reaction was performed following the same conditions as in Example 1 using 2.2 g (10 mmol) of 4-amino-1-benzyl-5-imidazole carboxamide obtained in Reference Example 2 and using, instead of benzoyl chloride, 3,5-di-t-butyl-4-methoxymethoxybenzoyl chloride which was separately prepared by a conventional method. After a post-treatment, a crude amide product was obtained. The crude amide was subjected to a cyclization reaction for 12 hours according to the same conditions as in Example 1. 2.17 g of 7-benzyl-2-(3,5-di-t-butyl-4-methoxymethoxyphenyl)hypoxanthine was obtained after a post-treatment. Yield 45% (2 steps).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8](F)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:22]([O:25][C:26]([N:28]1[CH2:32][CH2:31][CH:30]([C:33]([OH:35])=[O:34])[NH:29]1)=[O:27])[CH:23]=[CH2:24].CCN(C(C)C)C(C)C>CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:20]=[O:21])[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:8]([N:29]2[CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32][N:28]2[C:26]([O:25][CH2:22][CH:23]=[CH2:24])=[O:27])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OC1CCCCO1
Reactant: C=CCOC(=O)N1CCC(C(=O)O)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1CCC(C(=O)O)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
(2R)-3-Cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl fluoride (784 mg, 2.6 mmol) was added into the solution of 1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidine carboxylic acid (677 mg, 3.38 mmol) and Hunig's base (1811 μl, 10.40 mmol) in N,N-dimethylformamide (DMF) (11.1 ml). The reaction was stirred for 5 hrs at ambient temperature. The reaction was purified by RP-HPLC to give 2-((2R)-3-cyclopentyl-2-{[formyl(tetrahydro-2H-pyran-2-yloxy)amino]methyl}propanoyl)-1-[(2-propen-1-yloxy)carbonyl]-3-pyrazolidinecarboxylic acid (428 mg, 0.889 mmol, 34% yield). MS (ES+) m/z 482.0 (MH+).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-]C(C)C)[CH3:4].[CH3:9][CH:10]([CH3:34])[CH2:11][C:12]1([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25].C(Br)C=C>C1COCC1>[CH3:9][CH:10]([CH3:34])[CH2:11][C:12]1([CH:26]([C:3]([CH3:4])=[CH2:2])[C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25]
Reactant: CC(C)CC1(CC(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=C(C)C(C(=O)OC(C)(C)C)C1(CC(C)C)CCN(CCc2ccccc2)C1=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 85.9 %

Procedure:
LDA (2.0M, 7.7 mL, 16 mmol) is added to a solution of tert-butyl 3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (EXAMPLE 1, step 3; 4.62 g, 12.9 mmol) and THF (45 mL) at -78° C. The solution is stirred at -78° C. for 45 minutes and allyl bromide (1.3 mL, 16 mmol) is added. The solution is allowed to warm to 0° C. over 2 hours, and is allowed to stir overnight at room temperature. After quenching with saturated aqueous ammonium chloride, aqueous workup (EtOAc, MgSO4) and purification by column chromatography (2:1:17 v/v EtOAc:CH2Cl2 :hexane) gives 4.43 g (86%) of the title compound as yellow oil which solidified upon standing (mp 54.5°-56° C.).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][N:42]=5)=[O:58])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)cc2)CCCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)cc2)CCCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]thio]phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide (0.70 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloro-perbenzoic acid (70%, 0.38 g) in dichloromethane (10 ml) and the mixture was stirred at −78° C. for 1 hour. To the reaction system was added an aqueous sodium thiosulfate solution, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The resultant was concentrated under reduced pressure, the residue was separated and purified with column chromatography (basic silica gel, ethyl acetate→ethanol:ethyl acetate 1:19), followed by recrystallization (ethyl acetate-diisopropyl ether) to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(4-propyl-4H-1,2,4-triazol-3-yl)methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzazocin-5-carboxamide (490.1 mg) as yellow crystals (Compound 47).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5]Cl.[Mg].C(Br)CBr.[CH2:13]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:21](=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][C:21]1([OH:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]1=2
Reactant: CN(C)CCCCl
Reactant: O=C1c2ccccc2CCc2ccccc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CN(C)CCCC1(O)c2ccccc2CCc2ccccc21
Yield: 72.6 %

Procedure:
3-(Dimethylamino)propyl chloride (110 g) is dissolved in 600 ml of tetrahydrofuran. About 10% of this solution is added to the reaction flask containing 26.4 g of magnesium and 50 ml of tetrahydrofuran. The mixture is heated to reflux and reaction is initiated with ethylene dibromide. The remaining halide is added slowly (over about 30 minutes) to control the rate of reflux. The mixture is then heated under reflux for an additional 30 minutes. After cooling in an ice bath, 100 g of dibenzosuberone in 200 ml of tetrahydrofuran is added slowly (over about 30 minutes). The mixture is heated under reflux for 1.5 hours. After cooling in an ice bath, the mixture is decomposed by dropwise addition of saturated ammonium chloride solution (1 liter added in 2 hours). The mixture is stirred for an additional hour, the layers are separated and the aqueous layer is reextracted with ether. The combined organic layers are dried over magnesium sulfate, filtered and the solvent is removed in vacuo. The residue is dissolved in ether and extracted with 10% hydrochloric acid. The aqueous layer is basified with sodium hydroxide and extracted twice with ether. The ether extracts are dried, filtered, and the solvent is removed in vacuo leaving 103 g of a solid.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[O:12])[CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:4]>C1COCC1.[OH-].[Li+].CO>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:21]=[CH:22][C:13]=2[C:11]([NH:10][C:5]2([C:3]([OH:4])=[O:2])[CH2:6][CH:7]=[CH:8][CH2:9]2)=[O:12])=[CH:30][CH:29]=1
Reactant: COC(=O)C1(NC(=O)c2ccc3ccccc3c2OCc2ccc(C(F)(F)F)cc2)CC=CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NC1(C(=O)O)CC=CC1)c1ccc2ccccc2c1OCc1ccc(C(F)(F)F)cc1
Yield: 65.2 %

Procedure:
316 mg 1-{[1-(4-trifluoromethyl-benzyloxy)-naphthalene-2-carbonyl]-amino}-cyclopent-3-enecarboxylic acid methyl ester in 9 ml THF, 1.6 ml of 2 M lithium hydroxide and 18 ml methanol were reacted at room temperature for 8 h. The organic solvents were then removed in vacuo, and the residue was acidified with 2 M hydrochloric acid and extracted with ethyl acetate twice. The combined organic layers were dried over magnesium sulphate, and concentrated to yield 200 mg of 1-{[1-(4-trifluoromethyl-benzyl-oxy)-naphthalene-2-carbonyl]-amino}-cyclopent-3-enecarboxylic acid.
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2>CCO.O>[N+:14]([C:11]1[C:10]2[N:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:1])=[CH:13][CH:12]=1)([O-:16])=[O:15]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c2cccnc12
Temperature: 100 °C
Yield: 67.6 %

Procedure:
KOH (2.69 g, 47.9 mmol) was added to a solution of 5-chloro-8-nitro-quinoline 27 (1.0 g, 4.79 mmol) in EtOH (20 ml) and water (30 ml) and the mixture was heated at 100° C. for 2 h. The reaction mixture was cooled in the fridge for 18 h and the resulting crystals were collected by filtration and dried to give the title compound (616 mg, 68%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].[CH2:13]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[CH2:13]([N:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CNCc2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccccc2)S(=O)(=O)c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-cyanobenzene-1-sulfonyl chloride (600 mg, 3 mmol) was added to a solution of N-benzyl-1-(4-methoxyphenyl)methanamine (example 5-46b, 750 mg, 3.3 mmol) and triethylamine (500 mg, 3.6 mmol) in dichloromethane (15 mL). The reaction was stirred at ambient temperature for 4 hours then concentrated on the rotovap. The crude was purified on silica gel to afford N-benzyl-4-cyano-N-(4-methoxybenzyl)benzene-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.68 (s, 3H), 4.26 (s, 2H), 4.31 (s, 2H), 6.75 (d, J=8.4 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 7.07 (m, 2H), 7.21 (m, 3H), 7.98 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][C@@H:47]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48]1.[C:55](Cl)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:55]([N:49]1[CH2:50][CH2:51][CH2:52][C@@H:47]([CH2:46][C:45]([NH:44][C:36]2[CH:37]=[CH:38][C:39]3[NH:40][C:41]4[N:42]=[C:26]([NH:27][C:28]5[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=5)[CH2:33][CH2:34][C:35]=2[CH:43]=3)[N:25]=[CH:24][C:23]=4[Cl:22])=[O:53])[CH2:48]1)(=[O:62])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(C[C@@H]1CCCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCCN(C(=O)c2ccccc2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 61 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-piperidin-3-yl]acetamide tris(trifluoroacetate) and benzoyl chloride as the starting materials in 61% yield. LCMS for C31H31ClN7O2 (M+H)+: m/z=568.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH2:14].C(O[C:23]1[CH:28]=[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:26]=[CH:25][C:24]=1[CH2:37][C:38](OC1C=CC([N+]([O-])=O)=CC=1)=[O:39])C1C=CC=CC=1>>[CH2:30]([O:29][CH:37]([C:24]1[CH:23]=[CH:28][C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)[C:38]([NH:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2][NH2:1])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCCCNCCCCNCCCN
Reactant: O=C(Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Product: NCCCNCCCCNCCCNC(=O)C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 126.9 %

Procedure:
To a solution of spermine (1,4-bis [{(3-amino) propyl}amino]butane, 460 mg) in N,N-dimethylformamide anhydride (5 ml) is added a solution of para-nitrophenyl 2,4-dibenzyloxyphenylacetate (100 mg) in N,N-dimethylformamide anhydride (5 ml). The resulting solution is concentrated to dryness under reduced pressure and thereto are added 5 % aqueous sodium hydrogencarbonate solution (0.1 ml) and then water (30 ml). The resulting precipitate is filtered and washed thoroughly with water, followed by drying, to yield crude 2,4-dibenzyloxyphenylacetylspermine (72 mg, yield 64%). 3) To a solution of crude 2,4-dibenzyloxyphenylacetylspermine (72 mg) in acetic acid (5 ml) is added 10% palladium-carbon (50 mg) and then catalytic reduction is carried out in a hydrogen stream for one and half hours. After the reaction is over, the catalyst is removed by filtration and the filtrate is concentrated to dryness under reduced pressure. The residue is subjected to separation and purification by high-performance liquid chromatography (reversed-phase partition column TSK gel ODS-120T manufactured by Toyo Soda Mfg., CO., Ltd.; inner diameter of the column: 7.8 mm, length: 30 mm; resin diameter; 3 μm; column temperature: 40° C.; eluent: water/acetonitrile mixed solvent (98/2, V/V) to which trifluoroacetic acid has been added to final concentration of 0.05% by volume). The solvent is distilled off to yield 2,4-dihydroxyphenylacetyl-spermine trifluoroacetic acid salt (3.0 mg, yield 4.2%).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][C:9]([NH2:11])=[S:10])(=[O:4])=[O:3].Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCO>[CH2:18]([O:17][C:15]([C:14]1[N:11]=[C:9]([CH2:8][CH2:7][CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[S:10][CH:13]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CS(=O)(=O)NCCCC(N)=S
Solvent: CCO
Product: CCOC(=O)c1csc(CCCNS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 89.3 %

Procedure:
A solution of 4-methanesulfonylamino-thiobutyramide (0.35 g, 1.8 mmol) and ethyl bromopyruvate (0.37 g, 1.9 mmol) in EtOH (50 mL) was stirred at room temperature for 17 h. Additional ethyl bromopyruvate (0.05 g, 0.26 mmol) was added and the reaction mixture was stirred at room temperature for 5.5 h. The reaction mixture was concentrated and was purified by flash chromatography (79:1 to 19:1 EtOAc:MeOH) to afford the title compound (0.47 g). 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 4.40 (q, 2H), 3.24 (t, 2H), 3.17 (t, 2H), 2.96 (s, 3H), 2.10 (t, 2H), 1.39 (t, 3H); MS 293 (M+30 1).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=1.CN1CCOCC1.[CH3:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>C(Cl)Cl>[CH3:25][C:26]1[CH:27]=[C:28]([S:32]([NH:1][C:2]2[C:3](=[O:17])[N:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][CH:7]=2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cccc(S(=O)(=O)Nc2ccc(C)n(CC(=O)OC(C)(C)C)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 3-amino-6-methyl-1-(tert-butoxycarbonylmethyl)-2-pyridinone (1.42 g, 5.88 mmol), as prepared in step 3 of Example 1, and N-methylmorpholine (1.29 mL, 11.76 mmol) in methylene chloride (40 mL) was added 3-methylbenzenesulfonyl chloride (1.12 g, 5.88 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight. Additional methylene chloride (60 mL) was added. The resulting methylene chloride solution was washed with saturated NaHCO3 (2×50 mL), 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (5 to 10% ethyl acetate in methylene chloride) to give the title compound as a white solid (2.1 g, 91%). 1H-NMR (300 MHz, CDCl3) δ7.63 (m, 2H), 7.55 (br s, 1H), 7.42 (d, 1H, J=8 Hz), 7.32 (m, 2H), 6.01 (d, 1H, J=8 Hz), 4.64 (s, 2H), 2.37 (s, 3H), 2.20 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:23]=[N:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=2)[CH2:16][CH:17]2C[CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.[CH:33]1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(NC(=O)C)=NC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:29]([NH:28][C:25]1[N:24]=[CH:23][C:22]([N:15]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:13](=[O:14])[N:12]([CH3:33])[C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:32])=[CH:8][N:9]=2)=[CH:27][CH:26]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(NC(C)=O)nc2)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CC(=O)Nc1ccc(NCC2CCCC2)cn1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC(=O)Nc1ccc(N(C(=O)N(C)c2ncc(SCC(=O)O)s2)C2CCCC2)cn1

Procedure:
The title compound was prepared via {2-[3-(6-acetylamino-pyridin-3-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-[5-(cyclopentylmethyl-amino)-pyridin-2-yl]-acetamide and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester