Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[CH2:6][CH2:7][O:8][CH2:9][C:4]=2[S:3][C:2]=1[NH2:10].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](O)=[O:18].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>O1CCCC1.CN(C)C=O.CCOC(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16]([CH:20]=1)[C:17](/[N:10]=[C:2]1\[S:3][C:4]2[CH2:9][O:8][CH2:7][CH2:6][C:5]=2[NH:1]\1)=[O:18]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: Nc1nc2c(s1)COCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)/N=c1/[nH]c2c(s1)COCC2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a solution of commercially available 6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine (1.73 g, 11.1 mmol, JW-Pharmalab) in tetrahydrofuran/N,N-dimethylformamide (5:1, 60 mL) were added 5-chloro-2-methoxybenzoic acid (2.27 g, 12.2 mmol, Aldrich), 1-hydroxybenzotriazole (1.9 g, 12.2 mmol, Aldrich), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (2.3 g, 12.2 mmol, Aldrich) and triethylamine (4.6 ml, 33.2 mmol). After stirring at 60° C. for 16 h, the reaction mixture was cooled, diluted with EtOAc (50 mL) and quenched with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-5% methanol in methylene chloride). MS (ESI+) m/z 325 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([OH:19])[CH:13]2[OH:20])[CH2:11][C:10]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:12]2([CH:17]=[CH:16][C:15](=[O:18])[CH:14]([O:19][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:13]2[OH:20])[CH2:11][C:10]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC2(CC(=O)N2OCc2ccccc2)C(O)C1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1C(=O)C=CC2(CC(=O)N2OCc2ccccc2)C1O
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a solution of rac-(4R,5S,6S)-1-benzyloxy-5,6-dihydroxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (2) (123 mg, 0.425 mmol) and imidazole (35 mg, 0.510 mmol) in DMF (0.6 ml) was added at 0° C. a solution of tert-butyldimethylsilyl chloride (77 mg, 0.510 mmol) in DMF (1.2 ml). After 12 h at room temperature, the reaction was quenched with H2O (3 ml) and the mixture extracted with AcOEt (3×5 ml). The combined extracts were washed with saturated aqueous CuSO4 solution (2×10 ml) and brine (2×10 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-AcOEt, 5:2) to give rac-(4R,5S,6S)-1-benzyloxy-6-tert-butyldimethylsilyloxy-5-hydroxy-1-azaspiro[3.5]nona-8-ene-2,7-dione (3) as a white solid (133 mg, 78%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[CH2:17]([C:19]1[NH:23][C:22]([C:24](O)=[O:25])=[N:21][C:20]=1[I:27])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:17]([C:19]1[NH:23][C:22]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])=[N:21][C:20]=1[I:27])[CH3:18]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1I
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1I
Yield: 86 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (130 mg, 0.56 mmol), 5-ethyl-4-iodo-1H-imidazole-2-carboxylic acid obtained in Example (58b) (95 mg, 0.36 mmol), WSC hydrochloride (220 mg, 1.15 mmol) and HOBT (46 mg, 0.34 mmol), to obtain 146.2 mg of the title compound as a white solid (86%).
Reaction SMILES: 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][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[C-]#[C-].[Li+].[CH2:27](N(CC)CCN)[CH3:28].[Li+].[Cl-].[K+]>CS(C)=O>[C:20]([Si:17]([O: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][C:27]#[CH:28])([CH3:19])[CH3:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCN(CC)CCN
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCCCCCCCCCBr
Agent: [C-]#[C-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: C#CCCCCCCCCCCCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
The solution of (14-bromo-tetradecyloxy)-tert-butyl-dimethylsilane (8.9 g, 21.4 mmol, 1 eq) in DMSO (10 mL) was added dropwise to the solution of N,N-diethylethane-1,2-diamine lithium acetylide (3.1 g, 33.2 mmol, 1.5 eq) in DMSO (15 mL) at 0° C. This solution was stirred at room temperature for 6 hours, poured into saturated aqueous solution of potassium chloride (100 mL), and extracted three times with hexane (100 mL). The extract was washed with aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated. The resulting concentrate was subjected to silica gel flush column chromatography (eluate: hexane-CH2Cl2=80-20) to obtain the colorless liquid of the title compound (6.12 g, yield 81%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]1([CH3:63])[CH:45]=[CH:44][C:43]([S:46]([O:49][CH2:50][CH2:51]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:48])=[O:47])=[CH:42][CH:41]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:51][CH2:50][O:49][S:46]([C:43]2[CH:44]=[CH:45][C:40]([CH3:63])=[CH:41][CH:42]=2)(=[O:48])=[O:47])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(O)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
To a solution of 150 mg di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-[(5-hydroxypyridin-2-yl)methyl]-L-glutamate (0.32 mmol) in N,N-dimethylformamide (8 mL) was added 126 mg of cesium carbonate (0.39 mmol), followed by 143 mg of 1,2-ethanediol di-p-toluenesulfonate (0.39 mmol). The mixture was stirred for 5 h at room temperature. Water was added, the mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The crude product was purified by preparative HPLC (method A) to give 86 mg (40% yield) of the title compound.
Reaction SMILES: [N:1]([C@:4]1([CH2:43][OH:44])[O:8][C@@H:7]([N:9]2[C:40]3[N:39]=[C:16]([NH:17]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC(OC)=CC=4)[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[C@H:6]([F:41])[C@@H:5]1[OH:42])=[N+:2]=[N-:3]>C(O)=O>[N:1]([C@:4]1([CH2:43][OH:44])[O:8][C@@H:7]([N:9]2[C:40]3[N:39]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[C@H:6]([F:41])[C@@H:5]1[OH:42])=[N+:2]=[N-:3]
Reactant: COc1ccc(C(Nc2nc3c(ncn3[C@@H]3O[C@@](CO)(N=[N+]=[N-])[C@@H](O)[C@H]3F)c(=O)[nH]2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=CO
Product: [N-]=[N+]=N[C@]1(CO)O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)[C@H](F)[C@@H]1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
Compound (27)—A solution of compound 50-8 (580 mg, 0.72 mmol) in 7N NH3 in CH3OH (30 mL) was stirred at R.T. overnight. The solvent was evaporated in vacuo, and the residue was purified on silica gel column using DCM/MeOH (95:5 to 90:10) to give 4′-azido-2′-fluoro-N2-(4-methoxytrityl)-2′-deoxyguanosine (332 mg, 77%). 4′-Azido-2′-fluoro-N2-(4-methoxytrityl)-2′-deoxyguanosine (80 mg, 0.13 mmol) was dissolved in 80% HCOOH (3 mL), stirred at R.T. for 3 hours. The solvent was evaporated at R.T. and co-evaporated with MeOH/toluene (3 times). Purification using RP-HPLC (water: acetonitrile) gave (27) (26.0 mg, 61%) as a white foam after lyophilization. 1H NMR (DMSO-d6) δ 3.55-3.67 (m, 2H), 4.69-4.77 (m, 1H), 5.37 (dd, J=2.4, 4.8 Hz, 1H), 5.51 (t, J=2.8 Hz, 1H), 5.65 (t, J=6.0 Hz, 1H), 6.13 (d, J=7.6 Hz, 1H), 6.30 (dd, J=2.4, 18.4 Hz, 1H), 6.60 (br s, 1H), 7.91 (s, 1H), 10.74 (br s, 1H); 19F NMR δ (−199.0 to −199.25, m); ESI-LCMS m/z=325.3 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH2:6].[N+]([O-])(O)=O.CC1C=C(C)[N:18]([C:22](N)=[NH:23])N=1>C(O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[CH2:5][NH:6][C:22]([NH2:23])=[NH:18]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: NCc1ccc(N)c(I)c1
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)NCc1ccc(N)c(I)c1

Procedure:
An ethanol (5 ml) solution of 3-iodo-4-aminobenzylamine (0.220 g, 0.887 mmol) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.179 g, 0.087 mmol) was heated at reflux temperature for 3 hr. under argon. The solvent was evaporated in vacuo and the residue washed with ether and dichloromethane to remove 3,5-dimethylpyrazole and unreacted amine. The crude product was recrystallized from methanol/ether to give fine, pale-yellow needles (0.163 g, 72.5%), mp 135°-137° C.; PMR (DMSO-d6) γ6.62-7.66 (m, 9H), 4.1 (s, 2H); IR (Nujol) 1660, 1620 cm-1 (C=N); Anal. Calcd. for C18H11IN4. HNO3.0.5H2O): C, 27.20; H, 3.42, N, 19.08. Found C, 26.70; H, 3.33; N, 19.08.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([C:13](=[CH2:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1>C(OCC)(=O)C.[C].[Pd]>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH:13]([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: C=C(C(=O)OCC)C1OB(O)c2cc(O)cc(C)c21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)C1OB(O)c2cc(O)cc(C)c21
Temperature: 35 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acrylate (1 g, 3.44 mmol, 1.00 equiv, 90%) and Palladium carbon (10%, 300 mg) in ethyl acetate (50 mL) was stirred for 1 h at 35° C. under a hydrogen atmosphere. The solid was filtered out and washed with 2×10 mL of THF. The filtrate was concentrated under vacuum. This resulted in 0.8 g (71%) of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)propanoate as a light-brown oil.
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[F:23][C:24]1[CH:45]=[CH:44][C:27]([CH2:28][N:29]2[CH2:33][CH2:32][N:31]([C:34]3[S:35][C:36]([C:40](O)=[O:41])=[C:37]([CH3:39])[N:38]=3)[C:30]2=[O:43])=[CH:26][CH:25]=1.[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1>>[F:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:40]([C:36]2[S:35][C:34]([N:31]3[CH2:32][CH2:33][N:29]([CH2:28][C:27]4[CH:26]=[CH:25][C:24]([F:23])=[CH:45][CH:44]=4)[C:30]3=[O:43])=[N:38][C:37]=2[CH3:39])=[O:41])=[CH:49][CH:48]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(F)cc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 38 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 4-fluorobenzylamine in place of benzylamine, the title compound was obtained as a white powder in 38% yield: mp 177-178° C.; 1H NMR (300 MHz, CDCl3) δ 7.29-7.21 (m, 4H), 7.04-6.96 (m, 4H), 5.98 (s, 1H), 4.50 (d, J=5.7 Hz, 2H), 4.41 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.42 (t, J=8.1 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.1, 162.4, 160.8, 155.3, 153.2, 133.8, 131.3, 129.9, 129.5, 117.2, 115.7, 115.4, 47.2, 43.2, 42.0, 41.6, 17.2; MS (ES+) m/z 443.2 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]=[O:28])[CH2:23][C:22]1=[O:29])=[O:6])[CH:2]=[CH2:3].O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH:27]=[O:28])[CH2:23][C:22]1=[O:29])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CN1CCN(C=O)CC1=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CN1CCN(C=O)CC1=O
Yield: 132.5 %

Procedure:
To a solution of (2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-(4-formyl-2-oxopiperazin-1-yl) methylpyrrolidine (11.74 g) in tetrahydrofuran (100 ml) was added n-tetrabutylammonium fluoride under ice cooing with stirring, and the mixture was stirred at the same temperature for 1 hour. Water was added to the mixture, and the mixture was evaporated in vacuo. Ethanol was added to the residue, and the mixture was stirred at 60° C. for 20 minutes. The mixture was filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of chloroform and methanol (9:1 v/v) to give (2S,4R)-1-allyloxycarbonyl-2-(4-formyl-2-oxo-piperazin-1-yl) methyl-4-hydroxypyrrolidine (11.38 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[Se]=[O:13].[BH4-].[Na+]>O1CCOCC1>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([CH2:1][OH:13])[CH:7]=1
Reactant: O=[Se]
Reactant: Cc1cc(C)c([N+](=O)[O-])cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(CO)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the mixture of 2,4-dimethyl-5-nitropyridine (3.0 g, 20 mmol) in 30 ml of dioxane, was selenium oxide (2.8 g, 25 mmol) added at an ambient temperature. The reaction was refluxed for 10 hrs. The reaction was cooled to room temperature and concentrated under vacuum. The residue was poured into water and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated under vacuum. The crude mixture of the aldehyde was diluted in methanol (30 mL) and sodium borohydride (0.74 g, 20 mmol) was added portionwise at 0° C. After stirred for 1 hr, the reaction was quenched with water (20 mL) and concentrated under vacuum. The reaction was extracted with ethyl acetate and dried over MgSO4. The ethyl acetate was dried under vacuum and purified under SiO2 with 50% ethyl acetate in hexane to afford (4-methyl-5-nitropyridin-2-yl)methanol in 83% (2.7 g). 1HNMR (CDCl3, 400 MHz) δ 2.65 (s, 1H), 4.60 (d, J=8.1, 2H), 5.81 (t, J=8.1, 1H), 7.67 (s, 1H), 9.21 (s, 1H).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:23][O:24][CH:25]([O:33][CH3:34])[CH2:26][NH:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([N:27]([CH2:26][CH:25]([O:33][CH3:34])[O:24][CH3:23])[C:17](=[O:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12][C:11]2[CH:20]=[CH:21][CH:22]=[C:9]([C:7]3[CH:6]=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH:8]=3)[CH:10]=2)[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: COC(CNC1CCCC1)OC
Reactant: CC(C)n1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Product: COC(CN(C(=O)CCOCCc1cccc(-c2cnn(C(C)C)c2)c1)C1CCCC1)OC

Procedure:
The subtitled compound (140 mg) was prepared from 3-(3-(1-isopropyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 20 Step iii)] and N-(2,2-dimethoxyethyl)cyclopentanamine [Preparation 9] using a similar method to that described in Example 18, Step iii). MS [M+H-MeOH]+=426 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 8.01 and 8.00 (2×s, 1H), 7.79 (s, 1H), 7.40 (s, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.23 (t, J=7.6 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 4.56 and 4.37 (2×t, J=5.1 Hz, 1H), 4.53 (septet, J=6.8 Hz, 1H), 4.26-4.16 (m, 1H), 3.76-3.64 (m, 4H), 3.35 and 3.22 (2×d, J=5.1 Hz, 2H), 3.34 (s, 3H), 3.32 (s, 3H), 2.84 (t, J=6.7 Hz, 2H), 2.65 (t, J=6.2 Hz, 2H), 1.82-1.45 (m, 8H), 1.51 (d, J=6.8 Hz, 6H); a ˜2:1 mixture of rotamers is observed.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[NH:41][C:40]2[N:39]=[CH:38][C:37](/[CH:42]=[CH:43]/[C:44](O)=[O:45])=[CH:36][C:35]=2[CH2:34][CH2:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)[C:44](=[O:45])/[CH:43]=[CH:42]/[C:37]1[CH:38]=[N:39][C:40]2[NH:41][C:32](=[O:31])[CH2:33][CH2:34][C:35]=2[CH:36]=1
Reactant: CNCc1cccc2ncccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cccc2ncccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2

Procedure:
According to the procedure of Example 1, except substituting methyl-quinolin-5-ylmethyl-amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.387 g, quantitative) was prepared as a tan solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.69-10.63 (m, 1H), 9.26-9.13 (m, 2H), 8.39-8.25 (m, 2H), 8.11-7.93 (m, 3H), 7.77-7.45 (m, 2H), 7.30-7.17 (m, 1H), 5.50-5.22 (m, 2H), 3.15-3.01 (m, 3H), 2.94-2.78 (m, 2H), 2.56-2.44 (m, 2H); MS (ESI) m/e 373 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C(N(CC)CC)C.[F:40][C:41]([F:49])([F:48])[CH2:42][CH2:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:27]=[CH:28][C:29]([O:32][S:44]([CH2:43][CH2:42][C:41]([F:49])([F:48])[F:40])(=[O:46])=[O:45])=[CH:30][CH:31]=1
Reactant: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c2c(n(-c3ccc(Cl)cc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one (0.40 g, 0.85 mmol) in dichloromethane (20 ml) at 0° C. was added triethylamine (0.14 ml, 1.02 mmol) followed by 3,3,3-trifluoropropanesulfonyl chloride (0.20 g, 1.02 mmol). The reaction mixture was subsequently stirred at room temperature for two hours. Concentration and purification by flash chromatography (heptane:EtOAc gradient) afforded 200 mg (37%) of the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30](O)=[O:31].C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[O:31])=[CH:17][CH:16]=3)=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:23])[CH:3]=1
Reactant: Cc1cc(N)c2cc(C(=O)Nc3ccc(CN)cc3)ccc2n1
Reactant: O=C(O)c1ccccn1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(N)c2cc(C(=O)Nc3ccc(CNC(=O)c4ccccn4)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a solution of 27 mg (0.05 mmol) 4-amino-N-[4-(aminomethyl)phenyl]-2-methyl-6-quinolinecarboxamide, 7 mg (0.1 mmol) 2-pyridinecarboxylic acid, and 0.028 ml (0.2 mmol) triethylamine in 2 ml DMF was added 36 mg (0.75 mmol) PyBrop and stirred at room temperature for 1 d. After evaporation of the solvent the residue was purified by HPLC and lyophilized to yield 7.4 mg (23%) of the title compound. MS 412.3 (M+1)+, 1H-NMR (DMSO-d6) δ 2.60 (s, 3H), 4.47 (d, 2H), 6.64 (s, 1H), 7.33 (d, 2H), 7.60 (m, 1H), 7.70 (d, 2H), 7.86 (d, 1H), 8.00 (t, 1H), 8.04 (t, 1H), 8.35 (d, 1H), 8.65 (m, 1H), 8.94 (s, 1H), 8.98 (br. 2H), 9.32 (t, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC[Si](C)(C)C)=[O:25])[CH:15]=[CH:14][CH:13]=2)=[N:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>CN(C)C=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: C[Si](C)(C)CCOC(=O)CCCCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
2-(Trimethylsilyl)ethyl 7-[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]heptanoate (0.50 g, 1.1 mmol) was dissolved in N,N-dimethylformamide (4 ml), and 1.0 M tetrabutylammonium fluoride solution in tetrahydrofuran (2.6 ml, 2.6 mmol) was added thereto. The reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. Trifluoroacetic acid (5 ml) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was subjected to a silica gel (40 g) column chromatography. The fractions eluted with hexane-ethyl acetate (1:1, v/v) were collected and concentrated. The residue was recrystallized from ethanol-hexane to give the titled compound (0.24 g, 61%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SC1C=CC2C(=CC=CC=2)C=1.BrCC1[C:44]2[C:39](=[CH:40][CH:41]=[C:42](C3C=CC=CC=3OC)[CH:43]=2)[NH:38]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C1C2C(=CC=CC=2)C=CC=1S>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1ccc3ccccc3c1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: Sc1ccc2ccccc2c1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-(naphthalen-2-ylsulfanylmethyl)-1,2-dihydroquinoline 100 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 80 mg of potassium carbonate, and 42 mg of 2-naphthalenethiol reacted to give 8 mg of the title compound as an oil.