Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[Br:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([O:18][CH3:17])=[O:28])=[C:21]([Br:27])[CH:22]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(N)cc1Br
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2C[C@@H](F)CN2C(=O)OC(C)(C)C)cc1Br
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (355 mg, 1.52 mmol), and 4-amino-2-bromo-benzoic acid methyl ester (prepared as described in Part C) (350 mg, 1.52 mmol), HBTU (865 mg, 2.282 mmol) and DIPEA (0.531 mL, 3.04 mmol) in CH2Cl2 (15 mL) was stirred at RT for 60 h. Additional aliquots of (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (180 mg), HBTU (580 mg) and DIPEA (0.265 mL) were added to the mixture, and stirring was continued at RT for 20 h and subsequently at 40° C. for 24 h. The reaction mixture was diluted with CH2Cl2 and the organic layer was washed with water, 1N aqueous HCl (3×), aqueous NaHCO3 solution (2×) and brine, dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: EtOAc/c-hexane gradient 1:3 to 1:2) to afford the title compound as a white foam. TLC Rf (EtOAc/c-hexane 1:2)=0.24; MS (LC/MS): 468 [M+Na]+, 388/390 [MH−tBu]+, 345/347 [MH−Boc]+; tR (HPLC conditions b): 4.36 min.
Reaction SMILES: Cl[C:2]1[C:7]2=[N:8][O:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[C:16]([CH:23]=1)[C:17]([NH:19][CH2:20][CH2:21][F:22])=[O:18]>>[N:10]1[O:9][N:8]=[C:7]2[CH:2]=[C:3]([C:23]3[C:16]([C:17]([NH:19][CH2:20][CH2:21][F:22])=[O:18])=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:4]=[CH:5][C:6]=12
Reactant: Clc1cccc2nonc12
Reactant: O=C(NCCF)c1cncc(Br)c1
Product: O=C(NCCF)c1cnccc1-c1ccc2nonc2c1

Procedure:
Starting from 4-chloro-benzo[1,2,5]oxadiazole and 5-bromo-N-(2-fluoro-ethyl)-nicotinamide. Beige powder. MS(ES−): 285 (M−1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:9][C:8]2[CH:7]=[C:6]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:5]=[CH:4][C:3]1=2.Cl.[CH3:25][CH2:26][CH2:27][CH2:28][CH:29](O)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.C(Cl)CCl>[CH3:25][CH2:26][CH2:27][CH2:28][CH:29]([O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[N:2]([CH3:1])[C:3]2[CH:4]=[CH:5][C:6]([N:17]([CH2:18][CH2:19][Cl:20])[CH2:21][CH2:22][Cl:23])=[CH:7][C:8]=2[N:9]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: Cn1c(CCCC(=O)O)nc2cc(N(CCCl)CCCl)ccc21
Reactant: CCCCCC(O)CCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Product: CCCCCC(CCCC)OC(=O)CCCc1nc2cc(N(CCCl)CCCl)ccc2n1C
Temperature: 75 °C
Reaction time: 120 h
Yield: 104.7 %

Procedure:
A 250 mL three neck round bottom flask was equipped with an overhead stirrer, thermocouple, temperature controller and nitrogen sweep then charged with 3.0 g (7.6 mmol) of bendamustine hydrochloride, 1.21 g (7.7 mmol, 1.01 eq) of 5-decanol, 1.59 g (7.7 mmol, 1.01 eq) of dicyclohexylcarbodiimide (DCC), 30 mL of 1,2-ethylene dichloride (EDC) and 0.1 g (0.76 mmol, 0.1 eq) of DMAP. The reaction was stirred at 75° C. for five days until an in process analysis indicated the reaction was complete. Solids were removed by vacuum filtration and washed with 5 mL of EDC. The filtrate was washed with 4% aqueous sodium bicarbonate solution (1×50 mL) before drying over sodium sulfate, filtering and concentrating to dryness in vacuo. The residue was combined with the residue from a 10 g batch run carried out under the same conditions and the combined batches were chromatographed. The chromatography was carried out using 100 g of silica gel 60, 230-400 mesh, eluting with first 2 L of heptanes, then 1 L of 3:1 heptane/EtOAc and 1 L of 2:1 heptane/EtOAc collecting 100 mL fractions. Product containing fractions were combined and concentrated to dryness in vacuo to yield 3.97 g (7.96 mmol, 24.2%) of the product as a clear yellow oil with an HPLC purity of 99.4A %. 1H NMR (400 MHz, DMSO-d6) δ 7.31 (d, J=8.76 Hz, 1H), 6.93 (d, J=2.28 Hz, 1H), 6.78 (dd, J=2.40, 8.80 Hz, 1H), 4.8 (m, 1H), 3.7 (s, 8H), 3.65 (s, 3H), 2.83 (t, J=7.4 Hz, 2H), 2.44 (t, J=7.36 Hz, 2H), 2.02 (m, 2H), 1.48 (m, 4H), 1.25 (s, b, 10H), 0.84 (m, 6H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:19]([O:23][C:24](=[O:35])[CH2:25][CH2:26][C:27]1[O:31][CH:30]=[N:29][C:28]=1[C:32](O)=[O:33])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CC#N>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:32]([C:28]2[N:29]=[CH:30][O:31][C:27]=2[CH2:26][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:35])=[O:33])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CCc1ocnc1C(=O)O
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1ocnc1C(=O)N1CCN(c2ccccc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.9 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride (Reference Example 1, 2.18 g, 7.50 mmol), 5-(3-tert-butoxy-3-oxopropyl)-1,3-oxazole-4-carboxylic acid (Reference Example 22, 1.90 g, 7.88 mmol), triethylamine (1.52 g, 7.88 mmol), EDCI (1.51 g, 7.88 mmol) and HOBt (1.21 g, 7.88 mmol) in MeCN (40 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with 10% NaHCO3, saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel, 9:1-2:3 hexane/ethyl acetate) to give the title compound (2.81 g) as a light yellow oil.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:3])[CH3:2].[H-].[Na+].Cl[S:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C=O)C>[C:16]([O:15][C:14]([N:13]([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]2[C:4]=1[CH:1]([CH3:3])[CH3:2])[S:24]([C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=1)(=[O:26])=[O:25])=[O:20])([CH3:18])([CH3:17])[CH3:19]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1c(NC(=O)OC(C)(C)C)nc2ccccn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3ccccn3c2C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 51.2 %

Procedure:
To a suspension of compound 4-E (0.267 g, 0.97 mmol) in DMF (10 mL), cooled to 0° C., was added 60% NaH (0.043 g, 1.08 mmol) and the reaction mixture was stirred at 0° C. for 40 min. Methyl 4-(chlorosulfonyl)benzoate (0.341 g, 1.46 mmol) was added in one-portion and the reaction mixture was stirred at ambient temperature for 2 h. Ice water was added to the reaction solution and the product was extracted into EtOAc, washed with H2O (2×), then brine, and dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude product. The crude material was purified by flash column chromatography (SiO2) eluting with a gradient of EtOAc (20-60%) in heptanes to afford compound 4-F as a colorless glass (0.235 g, 51%). 1H-NMR (CDCl3): δ 8.4 (d, J=8.7 Hz, 2H), 8.24 (d, J=8.7 Hz, 2H), 8.05 (d, J=7.1 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.19-7.24 (m, 1H), 6.86-6.90 (m, 1H), 3.98 (s, 3H), 3.37-3.50 (m, 2H), 1.50-1.59 (m, 6H under H2O peak), 1.32 (s, 9H); MS: m/z 474.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]=[O:11])=[CH:5][N:4]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:10]=[O:11])[Si:13]([CH3:15])([CH3:14])[CH3:12])=[CH:5][N:4]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(NC=O)cn1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(N(C=O)[Si](C)(C)C)cn1
Temperature: 10 °C
Yield: 87 %

Procedure:
N-(2-Methoxy-5-pyridyl)formamide (30.4 g, 0.2 mol) was added to 200 ml benzene. This was stirred with a mechanical stirrer under argon at 10° C. Trimethylsilyl chloride (25 g, 0.23 mol) was added. While stirring at 10° C., triethylamine (21 g, 0.21 mol) dissolved in 50 ml benzene was added dropwise over 0.5 hour. The slurry was warmed to room temperature and after 0.5 hour filtered. The salt cake was washed with 100 ml benzene and the combined filtrates concentrated on a rotary evaporator at 30° C. under aspirator vacuum. The dark liquid product was distilled under reduced pressure. A clear liquid, 39 g, 87% yield, (b.p. 87° C./0.25 mmHg). The product was stored under argon.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11](OC)[O:12]C)=[C:5]([CH3:16])[CH:4]=1.[Na+].[Cl-]>CCOCC>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]=[O:12])=[C:5]([CH3:16])[CH:4]=1
Reactant: COC(COc1ccc(Br)cc1C)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1cc(Br)ccc1OCC=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 116.6 %

Procedure:
A 5N HCl (15 mL) solution is added to a stirred solution of 4-bromo-1-(2,2-dimethoxy-ethoxy)-2-methyl-benzene (1.40 g, 5.09 mmol) in Et2O (25 mL). The two-layered solution is stirred vigorously at ambient temperature under nitrogen for 2 days. Et2O (50 mL) and saturated aqueous NaCl solution (25 mL) are added to the mixture. The organic layer is separated, washed with a half-saturated aqueous NaCl solution (30 mL) containing saturated NaHCO3 (0.5 mL), dried over MgSO4, filtered and concentrated at ambient temperature to give 1.36 g of the crude (4-bromo-2-methyl-phenoxy)acetaldehyde as oil. The oil is diluted in Et2O to form a stock solution (67 mg/mL), which is used for the subsequent reaction.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][NH:4][C:3]1=[S:18].Br[CH2:20][CH2:21][CH2:22][Cl:23].[H-].[Na+]>C(O)C>[Cl:23][CH2:22][CH2:21][CH2:20][S:18][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:17])=[N:12]3)=[N:5][N:4]=1
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1

Procedure:
To 4-methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (3.6 g, preparation reported in WO 02/40471) in ethanol (60 ml) containing 1-bromo-3-chloropropane (2.0 ml) was carefully added with stirring sodium hydride (0.60 g, 60% in mineral oil). The mixture was heated at reflux for 45 min. Volatiles were evaporated under reduced pressure and the residue submitted to column chromatography (EtOAc—acetone gradient). The material thus obtained was precipitated from hot EtOAc (20 ml) by adding petroleum ether (40-60, 50 ml), cooled and collected by filtration to provide the title compound as colourless crystals (2.1 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][C:4](=O)[CH2:3]1.B.CSC>O1CCCC1>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2(C)C
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: COc1cc2c(cc1[N+](=O)[O-])NCCC2(C)C
Yield: 56.3 %

Procedure:
A solution of 4,4-dimethyl-6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (2.5 g, 10 mmol) in tetrahydrofuran (45 mL) was treated with borane-dimethylsulfide complex (20.5 mL, 41 mmol, 2 M in THF, Acros Organics). The mixture was heated at reflux for 16 h, cooled, quenched carefully via dropwise of excess methanol, concentrated, and purified by column chromatography on SiO2 (0 to 100% ethyl acetate/dichloromethane) to obtain 4,4-dimethyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (1.33 g, 5.63 mmol, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.26 (s, 6 H), 1.58-1.65 (m, 2 H), 3.13-3.21 (m, 2 H), 3.79 (s, 3 H), 5.95 (bs, 1 H), 6.96 (s, 1 H), 7.06 (s, 1 H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4](=[O:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)[CH3:2].CON(C)[C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4](=[O:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:7]=1[C:25](=[O:37])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:21]
Reactant: CCN(CC)C(=O)Oc1ccc(Cc2ccccc2)cc1
Reactant: CON(C)C(=O)CCCCOc1ccccc1
Product: CCN(CC)C(=O)Oc1ccc(Cc2ccccc2)cc1C(=O)CCCCOc1ccccc1

Procedure:
The title compound was prepared from 4-(phenylmethyl)phenyl diethylcarbamate and N-methoxy-N-methyl-5-phenoxypentanamide following the same procedure used in Example F. NMR (CDCl3) δ1.18 (t, 3H), 1.26 (t, 3H), 1.83 (m, 4H), 2.92 (t, 2H), 3.35 (q, 2H), 3.45 (q, 2H) 3.99 (m, 4H), 6.86-7.31 (m, 12H), 7.49 (d, 1H).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26].C(N(CC)CC)C>C(#N)C>[CH2:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:26])[O:27][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)CCCCCCCCCCCCCCO
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCCCCCCCCCCCCCO1
Yield: 84 %

Procedure:
To a refluxing solution of 510 mg (2.0 mmol) of 2-chloro-1-methylpyridinium iodide in 50 ml of acetonitrile, there was added a solution of 134 mg (0.5 mmol) of 15-hydroxypentadecanoic acid and 404 mg (4.0 mmol) of triethylamine in 40 ml of acetonitrile over a period of 8 hours at a continuous and uniform rate, and the reaction mixture was refluxed for an additional 30 minutes after the addition was completed. After evaporation of the solvent, the residue was separated chromatographically on a silica gel column. 1,15-pentadecanolide was obtained in 84% yield.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[O:37][N:36]=[C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:34]=3)[CH2:28][CH2:27]1)[C:18](O)([C:44]([O:46][CH3:47])=[O:45])[CH:17]2[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>C1(C)C=CC=CC=1>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[N:19]([CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[O:37][N:36]=[C:35]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:34]=3)[CH2:28][CH2:27]1)[C:18]([C:44]([O:46][CH3:47])=[O:45])=[C:17]2[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COC(=O)C1(O)C(c2ccccc2)c2cc(Br)ccc2C(=O)N1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.070 g) was added to a suspension of the compound prepared in Example 95 (0.56 g) in toluene (20 mL). The reaction mixture was heated at reflux under Dean-Stark conditions overnight. The reaction mixture was then cooled to room temperature and partitioned between dichloromethane and a saturated aqueous sodium bicarbonate solution. The combined organics were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=3:2) to obtain the title compound (0.35 g) having the following physical data.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Yield: 69 %

Procedure:
Using the general method of Example 245 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) was reacted with p-toluenesulfonyl chloride (1.08 g, 5.55 mmol) to provide 1.57 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-4-methylbenzenesulfonamide as an off white powder, m.p. 197.0-198.5° C. Analysis: Calculated for C24H29N5O2S: %C, 63.83; %H, 6.47; %N, 15.51; Found: %C, 63.68; %H, 6.40; %N, 15.51.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH3:19])[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([Cl:18])(=[O:17])=[O:16])[CH:10]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:19][C:9]1[CH:10]=[C:11]([S:15]([Cl:18])(=[O:16])=[O:17])[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccc(CBr)c1

Procedure:
N-Bromosuccinimide (6.27 g, 0.035 mole), m-toluenesulfonyl chloride (6.72 g, 0.035 mole), and benzoyl peroxide (0.67 g, 0.0019 mole) were combined in CCl4 (40 mL) and heated at reflux 2 h. The reaction mixture was filtered and washed with CCl4. The filtrate was concentrated to give m-bromomethylbenzenesulfonyl chloride, 9.74 g, as a viscous yellow oil.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][C:10]([OH:15])([C:12]([OH:14])=[O:13])[CH2:9]2)C=CC=CC=1.[ClH:22].O1CCOCC1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[ClH:22].[OH:15][C:10]1([C:12]([OH:14])=[O:13])[CH2:11][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: O=C(O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)C1(O)CNC1

Procedure:
1-(Diphenylmethyl)-3-hydroxyazetidine-3-carboxylic acid (assume 3.90 mmol) was suspended in methanol (40 mL) and 4 N hydrochloric acid in dioxane (1 mL, 4 mmol) was added. 20 wt % Palladium hydroxide on carbon (100 mg) was added to the solution and the mixture was treated with hydrogen at 40 psi for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to afford 3-hydroxyazetidine-3-carboxylic acid hydrochloride which was dissolved in tetrahydrofuran (5 mL) and water (5 mL) and treated with potassium carbonate (1.615 g, 11.7 mmol) and di-tert-butyl dicarbonate (935 mg, 4.29 mmol) were added. The mixture was stirred at ambient for 17 h and then the mixture was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate and then was acidified to pH ˜3-4 and extracted twice more with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1-{[(1,1-dimethylethyl)oxy]carbonyl}-3-hydroxyazetidine-3-carboxylic acid which was dissolved in DMF (3 mL). Benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (2.028 g, 3.90 mmol) and N,N-diisopropylethylamine (0.7 mL, 4.03 mmol) were added. The mixture was stirred at ambient for 5 minutes and then allylamine (0.6 mL, 8.03 mmol) was added and the mixture was stirred for 17 h. The mixture was partitioned between ethyl acetate and 5% lithium chloride. The organic portion was washed with 20% citric acid, saturated sodium bicarbonate and brine, then was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, ethyl acetate) gave 1,1-dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol, 78% yield from 1-(diphenylmethyl)-3-hydroxyazetidine-3-carboxamide). 1,1-Dimethylethyl 3-hydroxy-3-[(prop-2-en-1-ylamino)carbonyl]azetidine-1-carboxylate (782 mg, 3.05 mmol) was dissolved in methanol (10 mL) and 4 N hydrochloric acid in dioxane (2 mL, 8 mmol) was added. The mixture was refluxed for 15 minutes and then was concentrated in vacuo to afford 3-hydroxy-N-prop-2-en-1-ylazetidine-3-carboxamide hydrochloride (3.05 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][CH:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4].C(N(C(C)C)C(C)C)C.[CH2:35]([CH:42]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:43](O)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.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>[CH2:46]([CH:42]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:43]([NH:1][C@@H:2]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:3]([NH:5][C@@H:6]([CH2:16][CH:17]([CH3:19])[CH3:18])[C@@H:7]([OH:15])[CH2:8][C@@H:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=[CH2:11])=[O:4])=[O:44])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: C=CC(C[C@H](O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]cn1)C(C)C
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=C[C@@H](C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(Cc1ccccc1)Cc1ccccc1)C(C)C
Yield: 16 %

Procedure:
0.65 g of (S)-α-amino-N-[(1S,2S,4RS)-2-hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamide in 20 ml of acetonitrile were added together with 0.36 ml of ethyldiisopropylamine to a solution of 0.45 g of 2-benzyl-3-phenylpropionic acid (which was prepared according to the method described in J. Am. Chem. Soc. 71 1863 (1949)) and 0.8 g of BOP in 30 ml of acetonitrile and the mixture was stirred at room temperature for 20 hours. Subsequently, the reaction mixture was evaporated under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate and the organic solution was washed twice with 100 ml of water each time, dried over sodium sulfate and evaporated. The residue Was separated by flash chromatography on 100 g of silica gel with a 250:15 mixture of methylene chloride and methanol as the eluting agent, to obtain there was obtained 0.17 g of (S)-α-(2,2-dibenzylacetamido)-N-[(1S,2S,4S)-2 -hydroxy-1-isobutyl-4-isopropyl-5-hexenyl]imidazole-4-propionamide as a white powder, melting point 120°. This compound corresponds to the less polar isomer and has a Rf value of 0.14.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:8][CH:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:29](=[O:40])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>N1C=CC=CC=1>[CH3:3][N:2]([CH2:4][C:5]1[O:6][C:7]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:29](=[O:40])[CH:28]=3)=[CH:21][N:20]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccn(Cc2ccccc2)c(=O)c1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: c1ccncc1
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccn(Cc4ccccc4)c(=O)c3)c(=O)[nH]2)o1
Yield: 83.1 %

Procedure:
2-(2-Dimethylaminomethyl-5-furylmethylthio)ethylamine (2.28 g) and 2-nitroamino-5-(1-benzyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (2.80 g) were refluxed in pyridine (12 ml) for 20 hours. The reaction mixture was evaporated under reduced pressure and the resultant oily residue was washed with hot water. The mixture was allowed to cool and the water was washed twice with cold water and recrystallised from isopropanol to yield 2-[2-(2-dimethylaminomethyl-5-furylmethylthio)ethylamino]-5-(1-benzyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (3.33 g), m.p. 95.5°-98° C.