Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:31]([NH:35][NH2:36])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:31]([NH:35][NH:36][C:13]1[CH:14]=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:12]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][N:7]\1[CH2:24][C@H:25]1[CH2:29][CH2:28][CH2:27][O:26]1)=[O:23])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)NN
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NNc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Yield: 20.1 %

Procedure:
A mixture of Example 1A (300 mg, 0.7 mmol), tert-butylhydrazine hydrochloride (261 mg, 2.1 mmol) and potassium carbonate (385 mg, 2.8 mmol) in DMF (15 mL) was stirred at 40° C. for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The acetate extract was washed with water, brine, dried with MgSO4, and concentrated under reduced pressure. Purification by chromatography (SiO2) afforded 70 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.08 (s, 9 H), 1.30-1.35 (m, 9H), 1.63-2.04 (m, 4 H), 3.68 (t, J=6.7 Hz, 1 H), 3.76-3.88 (m, 1 H), 4.18-4.39 (m, 3 H), 4.62 (s, 1 H), 7.28-7.32 (m, 1 H), 7.46-7.60 (m, 2 H), 8.51 (d, J=1.6 Hz, 1 H), 9.90 (s, 1 H). MS (DCI/NH3) m/z 499 (M+H)+. Anal. calculated for C24H33F3N4O2S: C, 57.81H, 6.67 N, 11.24. Found: C, 58.22H, 6.72 N, 10.98.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][C@@H:12]1[C@@H:20]([O:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C@H:19]([CH3:27])[O:18][C:17](=[O:28])[C@@H:16]([NH:29][C:30](=[O:40])[C:31]2[C:36]([OH:37])=[C:35]([O:38][CH3:39])[CH:34]=[CH:33][N:32]=2)[CH2:15][O:14][C:13]1=[O:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-].[C:50]([O:55][CH2:56]Cl)(=[O:54])[CH:51]([CH3:53])[CH3:52]>CC(C)=O>[C:1]([O:9][CH2:10][CH2:11][C@@H:12]1[C@@H:20]([O:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[C@H:19]([CH3:27])[O:18][C:17](=[O:28])[C@@H:16]([NH:29][C:30](=[O:40])[C:31]2[C:36]([O:37][CH2:56][O:55][C:50](=[O:54])[CH:51]([CH3:53])[CH3:52])=[C:35]([O:38][CH3:39])[CH:34]=[CH:33][N:32]=2)[CH2:15][O:14][C:13]1=[O:41])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CCOC(=O)c3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1O
Reactant: CC(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccnc(C(=O)N[C@H]2COC(=O)[C@H](CCOC(=O)c3ccccc3)[C@@H](OC(=O)C(C)C)[C@H](C)OC2=O)c1OCOC(=O)C(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a mixture of 2-((3S,7R,8R,9S)-3-(3-hydroxy-4-methoxypicolinamido)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)ethyl benzoate (50 mg, 0.087 mmol), Na2CO3 (15 mg, 0.14 mmol) and NaI (3.09 mg, 0.021 mmol) in acetone (0.6 mL) was added chloromethyl isobutyrate (15.4 mg, 0.114 mmol) slowly at room temperature (about 22° C.). The resulting reaction mixture was warmed to 50° C. and stirred at 50° C. overnight. The solvent was evaporated and the crude residue was purified via flash chromatography (SiO2, hexanes/EtOAc gradient) to afford the title compound (35 mg, 76%) as an off-white solid: mp 48-50° C.; 1H NMR (300 MHz, CDCl3) δ 8.55 (d, J=7.9 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 8.04-7.87 (m, 2H), 7.55 (t, J=7.4 Hz, 1H), 7.43 (t, J=7.5 Hz, 2H), 6.95 (d, J=5.4 Hz, 1H), 5.85-5.62 (m, 2H), 5.41 (s, 1H), 5.26-5.06 (m, 2H), 4.94 (dd, J=9.8, 6.3 Hz, 1H), 4.42-4.19 (m, 2H), 3.92 (d, J=14.3 Hz, 3H), 3.65 (s, 1H), 2.76 (t, J=9.5 Hz, 1H), 2.62 (dt, J=10.8, 5.5 Hz, 1H), 2.58-2.47 (m, 1H), 2.30 (s, 1H), 1.82 (s, 1H), 1.29 (d, J=6.3 Hz, 3H), 1.21 (dd, J=7.0, 0.9 Hz, 6H), 1.13 (d, J=7.0 Hz, 6H); ESIMS m/z 673 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:16][CH2:17][N:18]([CH3:20])[CH3:19]>CN(C=O)C>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:6]1[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]1
Reactant: O=[N+]([O-])c1cc[nH]c1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN(C)CCn1ccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
A mixture of 3-nitropyrrole (500 mg, 4.46 mmol), cesium carbonate (3.63 g, 11.2 mmol, 2.5 equiv), 1-chloro-2-dimethylaminoethane (835 mg, 5.8 mmol, 1.3 equiv) and DMF (5 mL) was stirred for 16 h at rt. The reaction mixture was quenched by addition of a saturated aqueous solution of NaHCO3 and extracted with DCM/MeOH (9:1, v/v). The organic phase was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM→DCM/MeOH, 97:3) to afford 656 mg of the title compound as a yellow oil. Title compound: ESI-MS: 184.1 [M+H]+; TLC: Rf=0.38 (DCM/MeOH, 9:1).
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]=1[OH:25])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].C(=O)([O-])[O-].[K+].[K+].CC(C)=O>C(O)C>[C:14]([C:13]1[CH:22]=[CH:23][C:24]2[O:25][CH2:8][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[O:10][C:11]=2[CH:12]=1)(=[O:15])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: O=C(c1ccccc1)c1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C1COc2ccc(C(=O)c3ccccc3)cc2O1
Reaction time: 8 h

Procedure:
11.63 ml of ethyl 2,3-dibromopropionate was added drop-by-drop over a 15-minute period to a mixture of 15.9 g of 5B, 58.5 g of anhydrous potassium carbonate and 250 ml of acetone. The stirred mixture was refluxed for 7 hours and stored overnight. The mixture was filtered and the solvent was evaporated from the filtrate under reduced pressure (40° C.). The residue was suspended in 600 ml of ether and the mixture was washed with water, then with sodium bicarbonate solution, then dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed over silica gel using chloroform as eluent. Workup with ether and removal of the solvent gave a residue which was suspended in ethanol and placed in a freezer overnight. The solid was collected, washed with ethanol and dried to give 5, mp: 70°-71° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10](Cl)=[C:11]([C:16]#[N:17])[CH:12]=[N:13]2)=[CH:8][C:7]=1[O:19][CH3:20].C(=O)([O-])OC.[Cl:26][C:27]1[C:33]([OH:34])=[CH:32][C:30]([NH2:31])=[C:29]([F:35])[CH:28]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:26][C:27]1[C:33]([OH:34])=[CH:32][C:30]([NH:31][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[C:7]([O:19][CH3:20])[CH:8]=3)[N:13]=[CH:12][C:11]=2[C:16]#[N:17])=[C:29]([F:35])[CH:28]=1
Reactant: Nc1cc(O)c(Cl)cc1F
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Agent: COC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3cc(O)c(Cl)cc3F)c(C#N)cnc2cc1OCCCCl

Procedure:
By using the above method, starting with 3 g of 7-(3-chloro-propoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 2.35 g of the methyl carbonate of 4chloro-2-fluoro-5-hydroxy-aniline, and 1.1 g of pyridine hydrochloride in 30 ml of 2-ethoxyethanol, 1.7 g of the title compound was obtained as a crystalline solid: mass spectrum (electrospray, m/e) M+H 435.8, 437.8.
Reaction SMILES: [CH:1]1[NH:2][C:3]2[N:9]=[C:8]([NH2:10])[N:7]=[C:6](Cl)[C:4]=2[N:5]=1.C(N(CC)CC)C.CC1C=C(C)C(S)=CC=1.[OH2:28]>CO>[NH:7]1[C:6](=[O:28])[C:4]2[NH:5][CH:1]=[N:2][C:3]=2[N:9]=[C:8]1[NH2:10]
Reactant: O
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: Cc1ccc(S)c(C)c1
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc2nc[nH]c2c(=O)[nH]1

Procedure:
6-Chloroguanine derivative prepared in Preparation 6 (4.86 g) was dissolved in 85 ml of methanol and 1.4 g of triethylamine and 2.9 g of 4-methylthiocresol were added. The reaction mixture was reacted under reflux condition for 24 hours. The reaction was stopped by adding 20 ml of water, and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified by silica gel column to give a compound wherein 6-position of guanine was substituted by 4-methylphenylthio group.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([Cl:24])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(-n2nccn2)c(C(=O)Cl)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a suspension of 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (4.00 g, 19.7 mmol) in CH2Cl2 (90 mL) cooled at 0° C. was added DMF (76 μL, 0.98 mmol) and oxalyl chloride (2.15 mL, 24.6 mmol). The reaction was allowed to warm to ambient temperature and stirred for 3.5 h. The solution was concentrated in vacuo to provide 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl chloride as a yellow-orange oil which gave a mass ion (ES+) of 218.2. 1H NMR δ (ppm) (CDCl3): 7.89 (2H, s), 7.76 (1H, d, J=8.2 Hz), 7.59-7.60 (1H, m), 7.48-7.50 (1 H, m), 2.48 (3H, s).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.Cl.[N:45]1[CH:50]=[CH:49][C:48]([CH2:51][C:52](O)=[O:53])=[CH:47][CH:46]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:52](=[O:53])[CH2:51][C:48]3[CH:49]=[CH:50][N:45]=[CH:46][CH:47]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1ccncc1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (1.2 g, 7.8 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 4-pyridylacetic acid hydrochloride (0.4 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: CH3OH: CH2Cl2 3:97) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-pyridin-4-yl-acetamide (0.4 g, 50%) as white solid: mp 294-296° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=0.87 min. (98%); 1H NMR (DMSO-d6) δ 2.02-2.07 (m, 1H), 2.52-2.96 (m, 2H), 2.84-2.96 (m, 1H), 3.59 (s, 2H), 5.12-5.18 (dd, J=5.2 and 12.7 Hz, 1H), 7.31 (d, J=5.5 Hz, 2H), 7.64-7.70 (m, 1H), 7.79-7.84 (m, 2H), 8.50 (d, J=5.6 Hz, 2H), 8.77 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 37.91, 41.27, 48.83, 121.96, 124.54, 127.17, 131.53, 133.30, 134.71, 138.88, 144.92, 149.37, 166.88, 167.41, 169.33, 169.78, 172.73; Anal. Calcd. for C21H18N4O5: C, 62.07; H, 4.46; N, 13.79. Found: C, 61.77; H, 4.39; N, 13.59.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.[OH-].[Na+].Br[CH2:15][CH2:16][CH2:17][Cl:18]>CC(C)=O>[Cl:18][CH2:17][CH2:16][CH2:15][N:9]1[CH2:10][CH2:11][CH:6]([CH2:5][CH2:4][O:3][CH3:2])[CH2:7][CH2:8]1
Reactant: COCCC1CCNCC1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COCCC1CCN(CCCCl)CC1
Yield: 86.7 %

Procedure:
4-(2-Methoxy-ethyl)-piperidine hydrochloride (1.5 g, 8.4 mmol), acetone (30 ml, 20 vol), 5M NaOH solution (6.03 ml, 3.6 eq.) and 1-bromo-3-chloropropane (3.96 g, 25.1 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.6 g, 88%) as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.N1C(C)=CC=CC=1C.O([Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Si:28]([O:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C(O)[C@H]1CC[C@H](CO)CC1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of trans-4-(1-hydroxymethyl)-cyclohexanecarboxylic acid (1.00 g, 6.32 mmol) and 2,6-lutidine (2.95 mL, 25.29 mmol) in DCM (61 mL) was added drop wise tert-butyldimethylsilyl triflate (4.36 mL, 18.96 mmol). The reaction mixture was stirred at RT for 1.5 hours. The reaction mixture was quenched with water and the organic phase removed. The aqueous phase was extracted with further DCM (×2). The combined organic extracts were combined and washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was dissolved in THF (30 mL) and methanol (90 mL) and 10% aqueous potassium carbonate (30 mL) added. The reaction mixture was stirred at RT for 2 hours. The solvent was evaporated at reduced pressure and the residue partitioned between water and ether. The organic phase was discarded. The aqueous phase was washed with further ether (×2). The pH of the aqueous extract was adjusted to 5 and extracted with ethyl acetate (×3). The combined ethyl acetate extracts were washed with brine, dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (1.59 g, 93%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[CH2:14](SSCC)C.BrC1C(C2C=NC=CC=2)=NNC=1>>[CH2:1]([S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1)[CH3:14]
Reactant: CSc1c[nH]nc1-c1cccnc1
Reactant: CCSSCC
Agent: Brc1c[nH]nc1-c1cccnc1
Product: CCSc1c[nH]nc1-c1cccnc1
Yield: 76 %

Procedure:
Compound 21D was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using ethyldisulfanyl-ethane as the disulfide and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.O[C@H]1CCNC1=O.Cl[CH2:31][C:32]1[NH:33][C:34](=[O:42])[C:35]2[CH2:41][O:40][CH2:39][CH2:38][C:36]=2[N:37]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([C@@H:15]3[CH2:19][CH2:18][N:17]([CH2:31][C:32]4[NH:33][C:34](=[O:42])[C:35]5[CH2:41][O:40][CH2:39][CH2:38][C:36]=5[N:37]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: O=c1[nH]c(CCl)nc2c1COCC2
Reactant: COc1ccc(C(=O)C2CCN([C@@H]3CCNC3=O)CC2)cc1
Agent: O=C1NCC[C@@H]1O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN([C@@H]3CCN(Cc4nc5c(c(=O)[nH]4)COCC5)C3=O)CC2)cc1
Temperature: 0 °C
Yield: 26 %

Procedure:
To a solution of (R)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg), which was prepared in a similar manner as (R)-3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one from (S)-3-hydroxypyrrolidin-2-one and 2-chloromethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (0.165 mmol, 33.2 mg) in THF (5 mL) was added 1 M solution of potassium hexamethyldisilylamide in THF (0.331 mmol, 0.331 mL) at −78° C. for 2 hours. The reaction was allowed to warm to 0° C. for 16 hours and evaporated under vacuum. The remaining residue was purified by flash column chromatography (silica) eluting over a gradient of 0-50% MeOH/ethyl acetate provided the title compound as an off-white solid (20 mg, 25.9% yield). HRMS calculated for C25H30N4O5 466.5417. found (ESI, [M+H]′) 467.2296. 1H NMR (400 MHz, MeOD) 8 ppm 1.69-1.91 (m, 4H) 2.10-2.33 (m, 2H) 2.49-2.59 (m, 1H) 2.59-2.67 (m, 2H) 2.76-2.89 (m, 1H) 2.91-3.01 (m, 1H) 3.11-3.22 (m, 1H) 3.32-3.44 (m, 2H) 3.46-3.58 (m, 2H) 3.59-3.71 (t, J=8.78 Hz, 1H) 3.88-3.96 (m, 2H) 4.04-4.14 (d, J=15.56 Hz, 2H) 4.36-4.42 (m, 2H) 4.44-4.51 (m, 2H) 6.97 (d, J=9.03 Hz, 2H) 7.92 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=4.02 min.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:26])[CH2:24][NH2:25])[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:27])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>C(Cl)Cl>[C:28]([NH:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:27])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)[CH3:22])=[O:26])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8-[2,6-dichloro-3-(N-glycyl-N-methylamino)benzyloxy]-2-methylquinoline (100 mg), acetic anhydride (35 ml), pyridine (60 μl) and methylene chloride (2 ml) was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated and the residue was purified by preparative thin-layer chromatography (ethyl acetate-methanol) to give 8-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline (138 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:11])=[O:10])=[C:4]([CH3:12])[C:3]=1[Cl:13].[Cu](C#N)[C:15]#[N:16].O>CN(C=O)C>[Cl:13][C:3]1[C:4]([CH3:12])=[C:5]([CH2:8][C:9]([NH2:11])=[O:10])[CH:6]=[CH:7][C:2]=1[C:15]#[N:16]
Reactant: Cc1c(CC(N)=O)ccc(Br)c1Cl
Reactant: N#C[Cu]C#N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(CC(N)=O)ccc(C#N)c1Cl
Temperature: 150 °C
Yield: 67 %

Procedure:
A suspension of bromide 23B (2.70 g, 10.3 mmol) and copper cyanide (0.92 g, 10.3 mmol) in DMF (30 mL) was heated to 150° C. for 4 h. The suspension was cooled, poured into water with stirring, and the solid was filtered and dried to give 1.44 g (67%) of the desired nitrile. 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 2.29 (s, 3H), 7.72 (d, J=8.8, 1H), 7.75 (d, J=8.2, 1H), 9.73 (s, 1H); 13C NMR (DMSO-d6) δ 15.3, 23.5, 107.7, 116.5, 123.0, 130.1, 131.5, 135.7, 142.3, 168.8; HPLC a) column: Phenomenex ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.23 min retention time; HPLC b) column: Shimadzu Shim-Pack VP-ODS C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold, 4 mL/min, UV detection at 220 nm, 2.13 min retention time (95%); MS (ES) m/z 209 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[C:12]([C:13](OC3C=CC=CC=3)=[O:14])=[CH:11][C:10]([OH:22])=[CH:9][C:5]=12.[C:23]([C:28]1[CH:38]=[C:37]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])[CH:36]=[CH:35][C:29]=1[O:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH2:26][CH3:27])([CH3:25])[CH3:24]>>[OH:1][CH:2]1[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4]1[C:12]([C:13](=[O:14])[NH:34][CH2:33][CH2:32][CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:37]([C:39]([CH2:42][CH3:43])([CH3:41])[CH3:40])=[CH:38][C:28]=3[C:23]([CH2:26][CH3:27])([CH3:24])[CH3:25])=[CH:11][C:10]([OH:22])=[CH:9][C:5]=12
Reactant: CCC(C)(C)c1ccc(OCCCN)c(C(C)(C)CC)c1
Reactant: O=C(Oc1ccccc1)c1cc(O)cc2c1C1CCC2C1O
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(O)cc3c2C2CCC3C2O)c(C(C)(C)CC)c1

Procedure:
The phenyl ester (14.8 g) synthesized in (2) above was mixed with 3-(2,4-di-t-pentylphenoxy)propylamine (14.6 g), and the mixture was reacted at 140° C. under a reduced pressure of 20 mmHg for 4 hours. After cooling, the reaction product was crystallized from n-hexane to obtain 3,6-dihydroxy-4-[3-(2,4-di-t-pentylphenoxy)propylcarbamoyl]benzonorbornene. (Yield: 15.1 g (61.2 %), m.p.: 142° C.)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1I)[C:5]#[N:6].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[Sn](CCCC)(CCCC)CCCC>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[OH:1]
Reactant: N#Cc1ccc(I)c(O)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2ccco2)c(O)c1
Temperature: 100 °C

Procedure:
3-Hydroxy-4-iodo-benzonitrile (120 mg, 0.49 mmol) and PdCl2(PPh3)2 (35 mg, 0.049 mmol) and 2-furyltributyltin (200 g, 0.56 mmol) in N,N-dimethylformamide (DMF) (5 mL) is degassed and heated at 100° C. for 30 minutes (min). After the mixture cooled to room temperature, an aqueous work up is performed and the product is isolated from chromatography (80 mg, 88%).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:58]=[CH:57][C:29]3=[N:30][N:31]([C:33]4[CH:38]=[C:37]([C:39]([CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:47]([C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)([CH3:49])[CH3:48])[C:34]=4[OH:56])[N:32]=[C:28]3[CH:27]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[CH3:10][C:3]1([CH3:11])[CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[N:2]1[O:1][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:58]=[CH:57][C:29]3=[N:30][N:31]([C:33]4[CH:38]=[C:37]([C:39]([CH2:42][C:43]([CH3:44])([CH3:45])[CH3:46])([CH3:41])[CH3:40])[CH:36]=[C:35]([C:47]([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)([CH3:48])[CH3:49])[C:34]=4[OH:56])[N:32]=[C:28]3[CH:27]=2)=[CH:24][CH:25]=1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccc(N)cc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Agent: CC(C)(C)ON=O
Solvent: c1ccncc1
Product: CC(C)(C)CC(C)(C)c1cc(-n2nc3ccc(-c4ccc(ON5C(C)(C)CCCC5(C)C)cc4)cc3n2)c(O)c(C(C)(C)c2ccccc2)c1
Yield: 87.3 %

Procedure:
The title compound is prepared reacting 0.59 g (3.75 mmol) of 1-oxyl-2,2,6,6-tetra-methylpiperidine, 1.0 g (10 mmol) of tert-butyl nitrite, 2.3 mg (0.0037 mmol) of (S,S)-(+)-N,N-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II), 120 mL of pyridine and 24.0 g (75 mmol) of 5-(4-aminophenyl)-2-(2-hydroxy-3-α-cumyl-5-tert-octylphenyl)-2H-benzotriazole, prepared in Example 17, in 10 mL of pyridine at 70° C. The crude product obtained is purified by vacuum flash chromatography (2% ethyl acetate/heptane) to give 2.20 g of the title compound as a colorless oil in 87.3% yield. M/S [M+1] 673
Reaction SMILES: [CH2:1]([NH:3][CH2:4]C)C.[F:6][C:7]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:8]=1[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14]Br>O1CCCC1.C(Cl)Cl>[CH3:1][N:3]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][CH2:9][C:8]1[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:7]=1[F:6])[CH3:4]
Reactant: CCNCC
Reactant: Fc1ccc(Br)cc1COCCCCBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)CCCCOCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Diethylamine (17.6 ml, 35.3 mmol) was added to a solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (1.2 g, 3.53 mmol) in tetrahydrofuran (18 ml). The resulting mixture was stirred at ambient temperature for about 18 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate. The aqueous fraction was back extracted with methylene chloride. The organic fractions were combined and dried over sodium sulfate. The solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography.