Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])=[O:4].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>>[CH2:6]([N:5]([CH2:8][CH3:9])[C:3](=[O:4])[CH2:2][N:10]([S:27]([C:21]1[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:20]=1[O:19][CH3:18])(=[O:29])=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[CH3:7]
Reactant: CCN(CC)C(=O)CBr
Reactant: COc1cc(C)ccc1S(=O)(=O)Cl
Reactant: Cc1ccc(N)cc1
Product: CCN(CC)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1OC

Procedure:
prepared by reaction of 2-bromo-N,N-diethylacetamide with p-toluidine and 2-methoxy-4-methyl-benzenesulfonyl chloride
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[S:11](Cl)([CH3:14])(=[O:13])=[O:12].C(N(CC)CC)C>O1CCCC1>[CH3:14][S:11]([O:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@@H]1C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of trans-ethyl 2-hydroxymethyl-1-cyclopropanecarboxylate (1.136 g, 7.88 mmol) in dry tetrahydrofuran (20 ml) was cooled to 0° C. (ice bath), treated dropwise with mesyl chloride (0.675 ml, 8.66 mmol) and then treated immediately with triethylamine (1.32 ml, 9.52 mmol). This solution was stirred at 0° C. for 1.5 h (tlc indicated no substrate left). After dilution with ether (200 ml), the solution was washed with water, saturated ammonium chloride (10 ml), brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a clear oil, 1.690 g (97%) which was used as such for the next step without purification. ir (film) νmax : 1720 cm-1 (C=O); 1Hmr (CDCl3) δ: 4.13 (2H, q, J=7, CH2 --CH3, 3.05 (2H, s, CH2 --OMs), 2.0~0.6 (4H, m, cyclopropyl), 1.27 ppm (3H, t, J=7, CH3 --CH2).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([Cl:15])=[N:10][CH:11]=[CH:12][C:13]=1I)(C)(C)C.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:15][C:9]1[C:8]([NH2:7])=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:12]=[CH:11][N:10]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1c(I)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Nc1c(-c2ccccc2)ccnc1Cl

Procedure:
(2-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester a (4.20 g, 11.8 mmol), phenyl boronic acid (1.90 g, 15.6 mmol), potassium carbonate (2.42 g, 17.5 mmol) and tetrakistriphenylphosphine palladium(0) (0.68 g, 0.59 mmol) were weighed into a 20 ml microwave vial. The vial was evacuated, then purged with nitrogen gas 3 times. 16.7 ml dry DMF was added, then 3.3 ml of water, which had been degassed by bubbling nitrogen through it overnight. The vial was then capped and microwaved at 130° C. for 40 minutes. The resulting solution was poured into 250 ml water and extracted with EtOAc (3×50 ml). The combined organics were dried with MgSO4, filtered and concentrated. The resulting oil was adsorbed onto silica gel and purified by flash chromatography (150 g SiO2, 0% to 40% EtOAc in hexanes) to give 2-chloro-3-amino-4-phenyl pyridine b (0.84 g, 4.1 mmol, 35%) and the Boc-protected 2-chloro-3-amino-4-phenyl pyridine c (1.74 g, 5.7 mmol, 48%) as yellow and white solids, respectively.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][C:19](O)=[O:20])[CH:15]=3)[N:10]([C:22](=[O:30])[NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][C:19]([N:32]4[CH2:35][CH2:34][CH2:33]4)=[O:20])[CH:15]=3)[N:10]([C:22]([NH:23][C:24]3[S:25][C:26]([Cl:29])=[CH:27][N:28]=3)=[O:30])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCC(=O)O)cc12
Reactant: C1CNC1
Agent: Cl
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CCC(=O)N3CCC3)cc12

Procedure:
(3-(1′-Acetyl-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-5-yl)propanoic acid and azetidine hydrochloride
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Mg]I.O>O1CCCC1>[CH2:11]([C:9]1[N:8]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])=[O:23])=[CH:17][CH:18]=2)[C:7]2[CH:35]=[CH:36][C:4]([C:1]([OH:3])([CH3:37])[CH3:2])=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: C[Mg]I
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2cc(C(C)(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of N-[({2-[4-(5-acetyl-2-ethyl-1H-benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78, 100 mg, 0.19 mmol) in tetrahydrofurane (15 ml) was added MeMgI (1.2 ml, 0.99 mmol) dropwise under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 h and then was stirred at rt for 30 min. The mixture was added water (10 ml) and extracted with CH2Cl2(50 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2:methanol (30:1/20:1/10:1) to afford 100 mg (97%) of the title compound as white solids.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6](O)=O)[CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][NH:43][C:44]1[C:45]([NH2:50])=[CH:46][CH:47]=[CH:48][CH:49]=1>C1COCC1>[CH3:42][N:43]1[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[N:50]=[C:6]1[CH:4]1[CH2:5][C:2](=[O:1])[CH2:3]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: CNc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C2CC(=O)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-oxocyclobutanecarboxylic acid (0.5 g, 4.4 mmol) and DIPEA (2.2 mL, 13.2 mmol) in dry THF (10 mL) under N2 was added HATU (2.0 g, 5.3 mmol) and N′-methylbenzene-1,2-diamine (0.8 g, 6.6 mmol) in one portion. The reaction mixture was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. AcOH (5 mL) was added and the mixture was stirred at room temperature for 2 h. The solvent was removed and the residue was partitioned between EtOAc and a 5% NaHCO3 aqueous solution. The aqueous layer was extracted with EtOAc (2×10 mL) and the combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (eluent: 1/1, Pet ether/EtOAc) to give Intermediate 1 as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.75-7.58 (m, 1H), 7.35-7.09 (m, 3H), 3.86-3.61 (m, 4H), 3.60-3.35 (m, 1H), 2.74 (s, 3H). MS: m/z=200.1 (M+).
Reaction SMILES: [NH2:1][CH:2]([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[CH2:3][NH:4]C(=O)OCC1C=CC=CC=1.C1CCCCC=1.[ClH:26]>C(O)C.[Pd].C(OCC)C>[ClH:26].[ClH:26].[CH:17]([O:16][CH2:15][CH:2]([NH2:1])[CH2:3][NH2:4])([CH3:19])[CH3:18]
Reactant: CC(C)OCC(N)CNC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(C)OCC(N)CN

Procedure:
Under argon, 218 mg (0.71 mmol, 87% pure) rac-benzyl (2-amino-3-isopropoxypropyl)carbamate from Example 76A were initially charged in ethanol (5.0 ml), and 76 mg (0.07 mmol) of 10% palladium on activated carbon and 2.2 ml (21.36 mmol) of cyclohexene were added. The reaction mixture was stirred under reflux overnight. The mixture was then filtered through a Millipore® filter, the filter cake was washed with ethanol, 0.7 ml (1.42 mmol) of 2 M hydrogen chloride in diethyl ether were added to the filtrate and the mixture was concentrated and dried under high vacuum. This gave 190 mg (99% of theory, purity 76%) of the target compound.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19](OCC4C=CC=CC=4)=O)[CH2:15][CH2:14]3)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[CH:29](=O)[CH2:30]C.[H][H]>CO.[Pd]>[CH2:19]([N:16]1[CH2:15][CH2:14][CH:13]([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:18][CH2:17]1)[CH2:29][CH3:30]
Reactant: NC(=O)c1cccc2nc(C3CCN(C(=O)OCc4ccccc4)CC3)oc12
Reactant: CCC=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCN1CCC(c2nc3cccc(C(N)=O)c3o2)CC1
Yield: 46.6 %

Procedure:
A mixture of benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)piperidine-1-carboxylate (200 mg, 0.53 mmol), propionaldehyde (40 mg, 0.7 mmol) and 10% Pd/C (20 mg) in methanol (20 mL) was stirred at room temperature over 1 atm hydrogen for 4 hr. The mixture was filtered, and evaporated under reduced pressure. The residue was purified by prep-HPLC to give 2-(1-propylpiperidin-4-yl)benzo[d]oxazole-7-carboxamide (71 mg, yield 46%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.84-0.88 (t, J=7.2 Hz, 1H), 1.43-1.48 (m, 2H), 1.83-1.89 (m, 2H), 2.04-2.12 (m, 2H), 2.24-2.28 (m, 2H), 2.88-2.91 (m, 2H), 2.89-3.02 (m, 1H), 7.39-7.73 (t, J=7.6 Hz, 1H), 7.72-7.77 (m, 3H), 7.84-7.85 (d, J=6.8 Hz, 1H); LCMS (ESI) m/z: 288 (M+1)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH3:9].C1(C)C=CC=CC=1.C([O:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])C.[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:9][N:5]1[CH2:6][CH2:7][CH2:8][CH:4]1[CH2:3][CH2:2][NH:1][C:20](=[O:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CN1CCCC1CCN
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NCCC1CCCN1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.9 %

Procedure:
Toluene (0.7 ml), dried using MS 4A, was mixed with 0.83 ml of a n-hexane solution of 15% Me3Al. With the mixture being cooled in an ice-methanol bath, 0.14 ml (0.98 mmol) of 2-(2-aminoethyl)-1-methylpyrrolidine was added dropwise over about 2 minutes. After stirring for 20 minutes, the temperature was raised to room temperature, and 0.4 ml of a toluene solution of 0.2 g (0.65 mmol) of linoleic acid ethyl ester was added dropwise over 1 minute. After stirring for 2 hours at 70° C., the mixture was cooled with ice, and 10 ml of a 1N NaOH solution was added dropwise (inner temperature 12˜27° C.). The mixture was stirred for 10 minutes, and water and ethyl acetate were added. Then, the mixture was separated into respective layers, and the organic layer was washed twice with 20 ml of a saturated aqueous solution of sodium chloride. After this layer was dried over anhydrous magnesium sulfate, it was concentrated under reduced pressure on a 30° C. water bath to obtain the captioned compound (yield 0.114 g). This compound was subjected to silica gel column chromatography (mobile phase: CHCl3:MeOH (19:1→9:1)) for purification. NMR and mass spectrum confirmed the purified compound to have the following structure:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[CH:8][N:7]=2)[CH2:3]1.[C:15](Cl)(=[O:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl>[C:15](=[O:26])([O:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)[O:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:14]=[CH:13][C:9]([C:10](=[O:11])[NH2:12])=[CH:8][N:7]=2)[CH2:3]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC(=O)c1ccc(N2CC(O)C2)nc1
Solvent: ClCCl
Product: NC(=O)c1ccc(N2CC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)C2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10 %

Procedure:
To a solution of 6-(3-hydroxyazetidin-1-yl)nicotinamide (0.19 g, 1 mmol) in DCM (5 mL) under nitrogen was added 4-nitrophenyl carbonochloridate (0.20 g, 1 mmol). The resulting solution was stirred under N2 at room temperature for 24 h. The reaction mixture was then filtered and the filter cake was washed with DCM. The combined filtrates were concentrated to afford the title compound (36 mg, 10%) as a yellow liquid. [LCMS RtA=1.71 min, [M+H]+=359.0].
Reaction SMILES: Cl.C[CH:3]([C:9]([OH:11])=O)[C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].[NH3:12]>>[OH2:7].[NH2:5][C@H:4]([C:6]([OH:8])=[O:7])[CH2:3][C:9](=[O:11])[NH2:12]
Reactant: N
Reactant: CC(C(=O)O)[C@H](N)C(=O)O
Agent: Cl
Product: NC(=O)C[C@H](N)C(=O)O
Product: O
Temperature: 0 °C

Procedure:
18.3 g of β-methyl-L-aspartate hydrochloride are dissolved in 80 ml of a solution containing 20 g of ammonia. After reaction at ambient temperature for 3 hours, during which the reaction mixture is slowly stirred, the excess ammonia is removed under a partial vacuum of 12 mm Hg. The pH-value is then reduced to pH 5.4 by the addition of 10 g of 32% hydrochloric acid. The L-asparagine is precipitated in monohydrate form. 200 g of methanol are then added to the mixture, followed by cooling to 0°C. The crystals are collected by filtration, washed with 20ml of a saturated (approximately 2%) aqueous solution of L-asparagine and then dried at 70°C. L-asparagine monohydrate is thus obtained in a yield of 12 g (80%). The product has the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([Br:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)(=O)C>[Br-:18].[CH2:11]([N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]=1[CH3:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1nc2ccccc2s1
Reactant: BrCc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1sc2ccccc2[n+]1Cc1ccccc1
Product: [Br-]

Procedure:
A solution of 2-methylbenzothiazole (5.0 g, 0.033 mol) and benzyl bromide (40 mL, 0.33 mol) in 250 mL of ethyl acetate was refluxed under nitrogen for 48 hours. Solid had formed. The mixture was filtered and washed with cold ethyl acetate to give 3-benzyl-2-methylbenzothiazol-3-ium bromide as a light yellow solid, mp 230-231° C.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:35][O:36][CH2:37][CH3:38])[N:23]([CH2:24][C:25]([NH:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])([CH3:27])[CH3:26])[C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH2:46])=[CH:14][C:13]=2[N:12]=1.C(N(CC)CC)C>ClCCl>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:35][O:36][CH2:37][CH3:38])[N:23]([CH2:24][C:25]([NH:28][C:29]([NH:31][CH:32]([CH3:34])[CH3:33])=[O:30])([CH3:26])[CH3:27])[C:19]=2[C:18]2[CH:17]=[CH:16][C:15]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][S:2]([CH3:1])(=[O:5])=[O:3])=[CH:14][C:13]=2[N:12]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCOCc1nc2c(N)nc3cc(OCCCCCCN)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCCCCCCNS(C)(=O)=O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Methanesulfonic anhydride (0.34 g, 1.93 mmol) was added to a stirred solution of N-{2-[4-amino-7-[(6-aminohexyl)oxy]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-N′-isopropylurea (prepared as described in Parts A-H of Example 369, 10.9 g, 1.75 mmol) and triethylamine (0.35 mL, 3.5 mmol) in dichloromethane (50 mL) at 0° C. After approximately 30 minutes, the solution was allowed to warm to room temperature and was stirred overnight. The following morning, the solution was cooled to 0° C. and additional methanesulfonic anhydride (0.13 g) was added. After 30 minutes, the solution was allowed to warm to room temperature. After 2 hours, the solution was transferred to a separatory funnel and washed with water (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 10% methanol in dichloromethane) followed purification by chromatography on a HORIZON HPFC system (an automated, modular high-performance flash purification product available from Biotage, Inc, Charlottesville, Va., USA) (silica gel, gradient elution with 0-40% CMA in chloroform where CMA is a solution of 80:18:2 chloroform/methanol/concentrated ammonium hydroxide) to yield 0.31 g of N-(6-{[4-amino-2-(ethoxymethyl)-1-(2-{[(isopropylamino)carbonyl]amino}-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]oxy}hexyl)methanesulfonamide as an off white solid, mp 190-194° C.
Reaction SMILES: C(=[O:4])CC.[CH3:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][C:14](Cl)=[O:15])[CH:9]([CH:17]([CH3:19])[CH3:18])[CH2:8][CH2:7]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>N1C=CC=CC=1.C1COCC1>[CH3:5][CH:6]1[CH2:11][CH:10]([O:12][CH2:13][C:14]([OH:4])=[O:15])[CH:9]([CH:17]([CH3:19])[CH3:18])[CH2:8][CH2:7]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Reactant: CCC=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CO
Solvent: C1CCOC1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
1-Propenyl L-menthoxyacetate is prepared from propionaldehyde, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and 1-propenyl L-menthoxyacetate (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl L-menthoxyacetyl-L-2-hydroxybutyrate and methyl L-menthoxyacetyl-D-2-hydroxybutyrate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-2-hydroxybutyric acid, methanol, and L-menthoxyacetic acid.
Reaction SMILES: [CH2:1]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([NH:11][NH2:12])=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH:15][CH2:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CN(C=O)C>[OH:22][CH2:21][C:20]1[CH:24]=[CH:25][C:17]([C:16]([NH:12][NH:11][C:9](=[O:10])[C:8]2[CH:13]=[CH:14][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=2)=[O:15])=[CH:18][CH:19]=1
Reactant: CC(C)Cc1ccc(C(=O)NN)cc1
Reactant: O=C(O)c1ccc(CO)cc1
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(=O)NNC(=O)c2ccc(CO)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.5 %

Procedure:
4-Isobutylbenzohydrazide (2.10 g, 10.9 mmol) was added to a stirred solution of 4-hydroxymethylbenzoic acid (1.66 g, 11.2 mmol), HBTU (4.25 g, 11.2 mmol), diisopropylethylamine (1.45 g, 11.2 mmol) and DMF (50 mL) and stirred at room temperature for 12 hours. The reaction was diluted with ethyl acetate (200 mL), washed with 5% NaHCO3 (aq.) and brine, dried (MgSO4), filtered and concentrated in vacuo to give a white solid. The solid was triturated with ethyl acetate and filtered to give the title compound (2.01 g, 56% yield).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.[Br:8][C:9]1[CH:10]=[CH:11][C:12](F)=[C:13]([CH:16]=1)[C:14]#[N:15]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:7][CH2:6][CH:3]2[CH2:5][CH2:4]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OCC1CC1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Sodium hydride, 60% suspension in oil (3.6 g, 0.09 mol), is added to a solution of cyclopropylmethanol (6.49 g, 0.09 mol) in dry DMF (200 ml) at 0° C. under nitrogen. After 30 min at 0° C., 5-bromo-2-fluorobenzonitrile (12.0 g, 0.06 mol) in dry DMF (50 ml) is added, and the reaction is stirred at 50° C. for 16 h. Ice-water (200 ml) is added to the reaction mixture, which is then extracted with ethyl acetate (2×200 ml). The organic phases are washed with water (2×200 ml) and saturated sodium chloride solution (1×200 ml) and dried over sodium sulfate. After removal of the solvent, the crude product is purified by chromatography, giving 14 g of a yellow oil;
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH:23][OH:24])[CH3:22])[C:16]=1[Cl:25].C([O-])(=O)C.[Na+].O1CCOCC1>O>[CH3:5][O:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([N:23]([C:1](=[O:3])[CH3:2])[OH:24])[CH3:22])[C:16]=1[Cl:25]
Reactant: COC(=O)c1ccccc1Nc1cccc(C(C)NO)c1Cl
Reactant: CC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1Nc1cccc(C(C)N(O)C(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Acetyl chloride (0.49 g, 6.2 mmol) is added dropwise to a mixture of 2[[2-chloro-3-[1-(N-hydroxyamino)ethyl]phenyl]amino]benzoic acid methyl ester (2.0 g, 6.2 mmol) and sodium acetate (0.77 g, 9.4 mmol) in 2:1 dioxane:water with ice bath cooling. The reaction mixture is stirred at room temperature overnight. It is then diluted with water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer is washed with water (200 mL) and brine (100 mL), and is dried over magnesium sulfate. Evaporation of the ethyl acetate gives the crude product which is purified by flash chromatography (silica, 50% ethyl acetate/hexane). Recrystallization gives 2-[[3-[1-(acetylhydroxyamino)ethyl]-2-chlorophenyl]amino]benzoic acid methyl ester (0.34 g, 15%). mp=171-172° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1

Procedure:
A solution of 122.2 g (400 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [preparation, see Example 2b)] in 1500 ml of methanol is hydrogenated, at RT and under low pressure, in the presence of 4.0 g of Nishimura catalyst [Rh(III)- and Pt(IV)-oxide monohydrate, Degussa]. Filtering off the catalyst, and evaporating the filtrate, results in the title compound: TLC Rf (D)=0.54; FAB-MS (M+H)+ =312.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>C1C=CC=CC=1>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([Cl:13])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccsc1C(=O)O
Solvent: c1ccccc1
Product: Cc1ccsc1C(=O)Cl
Yield: 100.3 %

Procedure:
In 100 ml of benzene was suspended 3.00 g (21.1 mmol) of 3-methyl-2-thiophenecarboxylic acid, oxalyl chloride [7.36 ml (84.4 mmol)] was added and the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off to obtain 3.40 g of 3-methylthenoyl chloride (yield: quant.). To a solution of 1.50 g (6.23 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.61 ml (18.7 mmol) of triethylamine in 60 ml of methylene chloride, 1.20 ml (7.48 mmol) of the 3-methylthenoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain powder. The powder was washed with ether and dried to obtain 1.54 g of the desired compound (yield: 84.5%, pale yellow powder). mp: 104.0°-105.0° C.