Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([O:14][C:15]2[C:20]([F:21])=[C:19]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][C@@H:24]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:11][C@H:10]1[CH2:34][OH:35])(C(C)(C)C)(C)C.C(N(CC)CC)C.C1(N(C2C=CC=CC=2)C([NH:52][S:53](Cl)(=[O:55])=[O:54])=O)C=CC=CC=1.Cl>C1COCC1>[S:53](=[O:55])(=[O:54])([O:35][CH2:34][C@@H:10]1[CH2:11][C@@H:12]([O:14][C:15]2[C:20]([F:21])=[C:19]([NH:22][C@@H:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25][C@@H:24]3[O:32][CH3:33])[N:18]=[CH:17][N:16]=2)[CH2:13][C@@H:9]1[OH:8])[NH2:52]
Reactant: O=C(NS(=O)(=O)Cl)N(c1ccccc1)c1ccccc1
Reactant: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(O[C@@H]2C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)C2)c1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1ncnc(O[C@@H]2C[C@@H](COS(N)(=O)=O)[C@@H](O)C2)c1F
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of {(1S,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-[(5-fluoro-6-{[(1R,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)-oxy]cyclopentyl}methanol (190 mg, 0.36 mmol) in THF (5.40 mL) was added triethylamine (0.08 mL, 0.54 mmol) and [(diphenylamino)carbonyl]sulfamoyl chloride (186 mg, 0.54 mmol) at 0° C. under an atmosphere of Argon, and the mixture was stirred for 30 min. The reaction mixture was added 1.00 M Hydrochloric acid in (5.40 mL) at 23° C., and the resulting mixture was stirred for 16 h. The reaction mixture was quenched by addition of saturated NaHCO3 solution (80.0 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 0 to 10% methanol in DCM to afford the title compound (91.0 mg, 51%). 1H-NMR (400 MHz, CD3OD) δ: 8.01 (s, 1H), 7.25-7.13 (m, 4H), 5.72 (d, 1H, 1=6.5 Hz), 5.65-5.58 (m, 1H), 4.43-4.38 (m, 1H), 4.33 (dd, 1H, J=9.7, 7.6 Hz), 4.22 (dt, 1H, J=5.0, 2.4 Hz), 4.16 (dd, 1H, J=9.7, 7.3 Hz), 3.35 (s, 3H), 3.14 (dd, 1H, J=16.6, 2.4 Hz), 3.02 (dd, 1H, J=16.6, 5.0 Hz), 2.60-2.49 (m, 1H), 2.31 (ddd, 1H, d=14.8, 6.8, 2.3 Hz), 2.12 (ddd, 1H, J=14.8, 5.0, 4.7), 2.08-1.95 (m, 2H). LC/MS: Rt=6.76, ES+ 469.3 (FA long).
Reaction SMILES: CO.[NH2:3][OH:4].[CH2:5]([O:7][CH:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=O)[C:19]([NH:21][CH3:22])=[O:20])[CH3:9])[CH3:6]>O>[CH2:5]([O:7][CH:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18](=[N:3][OH:4])[C:19]([NH:21][CH3:22])=[O:20])[CH3:9])[CH3:6]
Reactant: NO
Reactant: CCOC(C)OCc1ccccc1C(=O)C(=O)NC
Solvent: O
Solvent: CO
Product: CCOC(C)OCc1ccccc1C(=NO)C(=O)NC
Yield: 37.5 %

Procedure:
Methanol (4 ml) and 50% aqueous hydroxylamine solution (0.4 g, 0.006 mol) were added to 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-N-methyl-2-oxoacetamide (0.53 g, 0.002 mol). The mixture was stirred under reflux for 5 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-hydroxyimino-N-methylacetamide (Isomer A: 0.21 g (Yield: 37.5%), colorless oil; Isomer B: 0.14 g (Yield: 25.0%), colorless crystals).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[CH:17][C:16]([CH3:19])=[N:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][C:16]1[CH:17]=[CH:18][C:10]2[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH:20]=[CH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)=[N:14][CH:13]=[N:12][C:11]=2[N:15]=1
Reactant: Cc1ccc2c(Nc3cccc(Br)c3)ncnc2n1
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c(Nc3cccc(C=Cc4ccccc4)c3)ncnc2n1
Temperature: 120 °C
Yield: 17.4 %

Procedure:
A mixture of the product from Example 240A (0.063 g, 0.20 mmol), styrene (0.0412 g, 0.40 mmol, 2.0 eq), palladium(II) acetate (0.9 mg, 0.004 mmol, 0.02 eq), tri-o-tolylphosphine (2.4 mg, 0.008 mmol, 0.04 eq), and triethylamine (0.0607 g, 0.60 mmol, 3.0 eq) in dimethylformamide (2 mL) was heated in a 120° C. oil bath for 4 hours. The mixture was then cooled to room temperature and the solvent evaporated under a stream of nitrogen gas. The residue was partitioned between ethyl acetate and water and the aqueous layer further extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was recrystallized from methanol and dried to provide the title compound as yellow crystals (11.8 mg, 17%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.01 (s, 1H), 8.89 (d, J=8.46 Hz, 1H), 8.72 (s, 1H), 8.03 (s, 1H), 7.72-7.85 (m, J=6.07, 2.76 Hz, 1H), 7.64 (d, J=6.99 Hz, 2H), 7.57 (d, J=8.82 Hz, 1H), 7.35-7.49 (m, 4H), 7.24-7.35 (m, 3H), 2.63-2.74 (m, 3H); MS (ESI+) m/z 339.1 (M+H)+, (ESI−) m/z 337.1 (M−H)−.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.C(N(C(C)C)C(C)C)C.[NH:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20].[NH:32]([CH3:52])[C@H:33]([C:38]([NH:40][C@H:41]([C:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44])[CH3:42])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36]>C(Cl)(Cl)Cl>[NH:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:18]([C:22]([N:32]([CH3:52])[C@H:33]([C:38]([NH:40][C@H:41]([C:43]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44])[CH3:42])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:24])[CH:19]([CH3:20])[CH3:21]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)Cc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 2 h

Procedure:
12.9 ml (12.7 g=106 mMol) pivaloyl chloride and 23 g (212 mMol) N-ethyl-diisopropylamine are added to a solution of 23.2 g (106 mMol) BOC-L-Val-OH in 400 ml chloroform and the mixture stirred for 2 hrs. at room temperature under a nitrogen atmosphere. 27.37 g (89 mMol) H-MeLeu-Ala-Bzl dissolved in 100 ml chloroform are then added and the reaction mixture stirred for a further 18 hrs. at 60° C. again under a nitrogen atmosphere. The obtained solution is washed with 300 ml 1N HCl, the aqueous phase extracted with 200 ml methylene chloride and the combined organic phases washed 2× with 200 ml saturated potassium carbonate solution. The aqueous phases are extracted with 200 ml methylene chloride, the combined organic phases dried over potassium carbonate, filtered and concentrated. The residue is chromatographed on 2 kg silica gel 60 (0.065-0.2 mm) with 1% methanol in methylene chloride as eluant to yield the title compound as a colourless oil: rotation [α]D25 =-97.2 (c=1.0 in chloroform).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[C:24]([NH2:31])=[N:23]1.O.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[C:8]([C:6]1[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[N:3]=[C:2]([NH:31][C:24]2[C:25]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[NH:22][N:23]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(Cl)nc(-c2ccccc2C(F)(F)F)n1
Reactant: Nc1n[nH]c2ncccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc(Nc2n[nH]c3ncccc23)nc(-c2ccccc2C(F)(F)F)n1
Temperature: 165 °C
Yield: 5.3 %

Procedure:
A mixture of 4-chloro-6-tert-butyl-2-(2-trifluoromethylphenyl)-pyrimidine (0.10 g, 0.32 mmol) and 1H-pyrazolo[3,4-b]pyridin-3-ylamine (0.064 g, 0.48 mmol) was heated neat at 160-170° C. for 16 hours. The resulting residue was cooled, dissolved in N-methyl-pyrrolidinone (2 mL), then poured into water (20 mL) and sodium bicarbonate (5 mL) and extracted twice with ethyl acetate. The combined organic layers were washed four times with water, once with brine, then dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC to provide the title compound (0.007 g, 4% yield) as a yellow solid. 1H-NMR (500 MHz, DMSO-d) δ 13.2 (br s, 1H), 10.6 (br s, 1H), 8.49 (m, 2H), 7.84 (d, J=7.8 Hz, 2H), 7.76 (m, 2H), 7.68 (m, 1H), 7.12 (m, 1H), 1.32 (s, 9H) ppm; LC-MS 413.08 (M+H); Rt (Method A) 3.112 minutes.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[O:35]1[CH2:40][CH2:39][CH:38]([C:41](Cl)=[O:42])[CH2:37][CH2:36]1>C1COCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([N:23]([CH3:24])[C:41]([CH:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)=[O:42])=[CH:21][CH:22]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C1CCOCC1
Reactant: CNc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)C1CCOCC1)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
[1-(4-Methylamino-benzenesulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.13 g, 0.35 mmol) was dissolved in THF (5 ml). To this was added diisopropylethylamine (0.18 ml, 0.7 mmol) in one portion followed by the drop wise addition of tetrahydro-2H-pyran-4-carbonyl chloride (0.06 ml, 0.38 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was concentrated, diluted with DCM (200 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered and concentrated to give the title compound (0.17 g, 98% yield) as a white powder which was taken on without further purification. Tr=1.89 min m/z (ES+) (M+Na+) 504.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[C:23]1([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]3)=[CH:4][CH:3]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)ccc12
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(-c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
Ethyl 6-bromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (0.185 g, 0.500 mmol), phenylboronic acid (0.76 g, 0.625 mmol, 1.2 equiv.) and potassium phosphate trihydrate (0.200 g, 0.750 mmol, 1.5 equiv.) were mixed together in a 10 ml microwave vial. The vial was purged with Argon and trans-dichlorobis(triphenylphosphine)-palladium (II) (0.0105 g, 0.015 mmol, 3 mol %) and 5 ml of dry dioxane were added to the mixture. The microwave vial was capped and irradiated at 100 watt, 150° C., under pressure up to 10 bars. Then it was allowed to cool down to rt, and toluene was removed under reduced pressure and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using 20% of ethyl acetate/cyclohexane as eluent to yield a light-beige-colored solid in 70-80%. 1H-NMR (DMSO-d6) δ 1.11, 1.35 (each t, 3H, 3J=7.1 Hz, CH3); 2.60 (m, 2H, 2′-H); 3.31 (m, 2H, 1′-H); 3.99, 4.35 (each q, 2H, 4J=7.1 Hz, CH2); 7.35 (m, 2H, 4-H, 5-H); 7.46 (m, 2H, 2″-H, 6″-H); 7.62 (dd, 1H, 4″-H); 7.65 (m, 2H, 3″-H, 5″-H); 7.75 (dd, 1H, 7-H); 11.63 (s, 1H, NH). 13C-NMR (DMSO-d6) δ 14.9, 15.1 (2CH3, each C═OOCH2CH3); 20.90 (C-2′); 35.9 (C-1′); 60.7, 61.2 (2CH2, each C═OOCH2CH3); 111.0 (C-7); 120.1 (C-4); 121.8 (C-3); 122.3 (C-3a), 124.8 (C-5) 127.2 (C-2″, C-6″); 127.7 (C-4″); 128.0 (C-3″, C-5″); 129.8 (C-2); 137.7 (C-7a); 138.2 (C-6); 141.9 (C-1″); 162.3 (2′-CO2Et); 173.1 (2-CO2Et). LC-MS (m/z): 383 [M-NH4+]+, 366 [M]+, 364 [M]−. Purity LC-MS: 96%.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:27][CH2:26][CH2:25][C@H:6]1[C:7]([N:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])(O)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[C:43]1([CH:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[C:43]1([CH:49]2[CH2:50][CH2:51][N:52]([C:1](=[O:2])[CH2:4][N:5]3[CH2:27][CH2:26][CH2:25][C@H:6]3[C:7]([N:9]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:10](=[O:17])[C@H:11]([C@H:13]([CH2:15][CH3:16])[CH3:14])[NH2:12])=[O:8])[CH2:53][CH2:54]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)N1CCC(c2ccccc2)CC1
Yield: 59 %

Procedure:
Using the procedure described above, a solution of L-isoleucine, N-[1-(carboxymethyl)-L-prolyl] benzylamide (0.124 g, 0.33 mmol, 1.0 eq), and N-methylmorpholine (43 uL, 40 mg, 0.40 mmol, 1.20 eq), in acetonitrile (3 mL) was treated with isobutyl chloroformate (45 uL, 47 mg, 0.35 mmol, 1.05 eq) followed by 4-phenylpiperidine (69 mg, 0.43 mmol, 1.3 eq). Workup as above provided 101 mg (59%) of L-isoleucine, N-[1-(2-(4-phenylpiperidyl)-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].[Br:20][CH2:21]/[CH:22]=[CH:23]/[CH2:24]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Br:20][CH2:21]/[CH:22]=[CH:23]/[CH2:24][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[S:10]1(=[O:18])=[O:19]
Reactant: BrC/C=C/CBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccc(F)cc1F
Yield: 66.8 %

Procedure:
In an analogous manner to general procedure IV, 1-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (3.37 g, 11.9 mmol) was treated with (E)-1,4-dibromobut-2-ene (8.9 g, 41.7 mmol) and cesium carbonate (3.9 g, 11.9 mmol) to give 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (3.3 g, 67%) as a clear oil.
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[CH2:11][O:10][C:9](=[O:13])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:14]=[CH2:15])[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>C(Cl)Cl>[CH:1]1([C:4]2[C:12]3[CH2:11][O:10][C:9](=[O:13])[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:14]2[CH2:15][O:24]2)[CH2:3][CH2:2]1
Reactant: C=Cc1ccc2c(c1C1CC1)COC2=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C1OCc2c1ccc(C1CO1)c2C1CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-cyclopropyl-5-vinyl-2-benzofuran-1(3H)-one (440 mg, 2.2 mmol) in 50 mL of DCM was slowly added mCPBA (1.14 g, 6.6 mmol) in 50 mL of DCM at 0° C. After warming to room temperature, the mixture was stirred for 12 hours. The mixture was washed with aqueous Na2SO3 until KI paper didn't change color. The organic layers were combined, washed with brine and then concentrated. The residue was purified via prep-TLC to give the title compound. 1H-NMR (400 MHz, CDCl3) δ ppm 7.77 (d, J=8.6 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 5.39 (s, 2H), 4.43-4.45 (m, 1H), 3.26-3.28 (m, 1H), 2.68-2.70 (m, 1H), 1.94-2.01 (m, 1H), 1.08-1.12 (m, 2H), 0.65-0.75 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:11][C:10]2[C:5](=[C:6]([Cl:15])[C:7]([Cl:14])=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=[O:16])[CH3:2].[H-].[Na+].[CH2:19](I)[CH2:20][CH3:21]>COCCOC>[CH2:1]([C:3]1([CH2:19][CH2:20][CH3:21])[CH2:11][C:10]2[C:5](=[C:6]([Cl:15])[C:7]([Cl:14])=[C:8]([O:12][CH3:13])[CH:9]=2)[C:4]1=[O:16])[CH3:2]
Reactant: CCCI
Reactant: CCC1Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCC1(CC)Cc2cc(OC)c(Cl)c(Cl)c2C1=O

Procedure:
2-Ethyl-2-n-propyl-5-methoxy-6,7-dichloro-1-indanone is prepared following substantially the same procedure described in Example 5, Step E, using the following substances: 2-ethyl-5-methoxy-6,7-dichloro-1-indanone (13 g., 0.05 mole), sodium hydride (1.3 g., 0.055 mole), 1,2-dimethoxyethane (500 ml.) and n-propyliodide (6 ml.). The above procedure gives 6.0 g. of 2-ethyl-2-n-propyl-5-methoxy-6,7-dichloro-1-indanone which after recrystallization from ethanol melts at 92° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>O=[Pt]=O.CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:12][C@H:11]2[C:13]([OH:15])=[O:14])=[CH:8][CH:9]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc([N+](=O)[O-])cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A Fischer-Porter bottle containing racemic-(trans)-2-(4-nitrophenyl)cyclopropanecarboxylic acid (V-2) (4.60 g, 22.22 mmol), PtO2 (0.16 g, 0.70 mmol), ethyl acetate (70 mL) and MeOH (50 mL) was purged with N2 (3x's) then charged with 40 psig H2 at RT. After 1 h, the bottle was carefully vented and the suspension was filtered through Celite. The solution was concentrated to give the title compound as a white powder (4.01 g, ˜100%). 1H NMR (400 MHz, DMSO) δ 6.79 (d, J=8.6 Hz, 2H), 6.47 (d, J=8.6, 2H), 5.02 (bs, 2H), 2.21-2.16 (m, 1H), 1.61-1.56 (m, 1H), 1.31-1.28 (m, 1H), 1.19-1.14 (m, 1H). ES-MS m/z 176.3 (MH−).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:19])=[C:13]([C:15]([O:17]C)=[O:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[OH-]>C(O)C.O>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([CH3:19])=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)c1nc(CNC(=O)OC(C)(C)C)sc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1sc(CNC(=O)OC(C)(C)C)nc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-(N-Boc-aminomethyl)-5-methylthiazole-4-carboxylate (22.0 g, 77 mmol) was dissolved in ethanol (100 ml), and a solution of LiOH (2.2 g, 92 mmol) in water (50 ml) was added. After the mixture had been stirred for 30 minutes at room temperature, the ethanol was removed on a rotary evaporator and the solution which remained was diluted with water (70 ml). The aqueous phase was washed with ethyl acetate (3×) and brought to pH 2 with 20% strength NaHSO4 solution, during which process a pale brown oil separated out. The aqueous phase was extracted with dichloromethane and the combined organic extracts were dried (MgSO4) and concentrated in vacuo. The pale brown residue was extracted by stirring in diisopropyl ether. The colorless precipitate which remained was filtered off with suction and washed with diisopropyl ether. Yield: 6.9 g (25.4 mmol, 33%, colorless solid).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:15])[CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13]O.S([O-])(=O)(=O)C.[CH2:21]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][OH:40])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:21]([O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][OH:15])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCCOCCOCCOCCOCc1ccccc1
Reactant: OCCOCCOCCOCCO
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Reaction time: 1 h
Yield: 34.5 %

Procedure:
To a solution of tetrahydrofuran (140 mL) containing sodium hydride (0.43 g, 18 mmol) was added dropwise a solution of monodispersed tetraethylene glycol (3.5 g, 18 mmol) in tetrahydrofuran (10 mL) and the reaction mixture was stirred for 1 h. Then mesylate of monodispersed tetraethylene glycol monobenzylether 24 (6.0 g, 16.5 mmol) dissolved in tetrahydrofuran (10 mL) was added dropwise and the reaction mixture was stirred overnight. The crude reaction mixture was filtered through Celite (washed; CH2Cl2, 250 mL) and the filtrate was washed H2O, dried MgSO4, and evaporated to dryness. The resultant oil was chromatographed (silica, ethyl acetate/methanol, 10:1) and chromatographed (silica, chloroform/methanol, 25:1) to afford the monodispersed compound 25 as a clear oil (2.62 g, 34% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]([NH:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:18](OC(OCC)OCC)C>C(O)C>[Cl:1][C:2]1[C:11]2[N:12]=[CH:18][N:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CC(C)CNc1c(N)c(Cl)nc2ccccc12
Solvent: CCO
Product: CC(C)Cn1cnc2c(Cl)nc3ccccc3c21
Temperature: 25 °C
Yield: 92 %

Procedure:
A suspension of 2-chloro-N4 -(2-methylpropyl)-3,4-quinolinediamine (35 g) and triethylorthoformate (52.3 g, 2.5 eq) was heated at 145° C. for 10 h, during which time ethanol was removed by distillation. The resulting mixture was cooled to room temperature and the solid was removed by filtration. The solid was dissolved in hydrochloric acid (100 mL, 4N). The resulting solution was added to a solution of sodium hydroxide. The precipitate was filtered and washed with water to afford the product 4-chloro-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline in 92% yield.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[N:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=[O:8])[CH3:3].Cl>>[ClH:1].[CH2:13]([NH:12][C:5]([CH2:6][C:7]([OH:9])=[O:8])=[N:4][CH2:2][CH3:3])[CH3:14]
Reactant: CCN=C(CC(=O)OCC)NCC
Agent: Cl
Product: CCN=C(CC(=O)O)NCC

Procedure:
A solution of 2.2 g. (0.01 mole) of N,N'-diethyl-carboethoxyacetamidine hydrochloride in 60 ml. of 12N-hydrochloric acid is converted to the free acid in a manner similar to the procedure of Preparation A-1c.