Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: CC(C)CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
6-Amino-9-benzyl-2-(isobutylthio)purine (60 mg, 0.19 mmol) and bromine (0.4 ml) were dissolved in 85 ml of methylene chloride and the solution was stirred at room temperature for 2 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (chloroform) to give the subject compound (20 mg, yield 27%).
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1>N1C=CC=CC=1>[O:1]([CH2:8][C:9]([O:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(O)cc[nH]1
Reactant: O=C(Cl)COc1ccccc1
Solvent: c1ccncc1
Product: O=C(COc1ccccc1)Oc1cc[nH]c(=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 23 %

Procedure:
A 1.86 ml quantity of phenoxyacetyl chloride was added to a suspension of 1.00 g of 4-hydroxy-2-pyridone in 30 ml of pyridine, and the mixture was stirred at room temperature for four hours. The reaction mixture was concentrated and the concentrate was washed with ethyl acetate, water and chloroform in this order, thereby producing 500 mg of the title compound in a yield of 23%.
Reaction SMILES: [CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[CH3:7][N+:8]([CH3:22])([CH3:21])[CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][N:13]=1.[H][H]>O.[Pd]>[CH3:1][O:2][S:3]([O-:6])(=[O:5])=[O:4].[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH2:9][N+:8]([CH3:22])([CH3:21])[CH3:7])=[N:13][CH:14]=1
Reactant: [H][H]
Reactant: C[N+](C)(C)CCOc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Agent: COS(=O)(=O)[O-]
Solvent: O
Product: C[N+](C)(C)CCOc1ccc(N)cn1

Procedure:
4.0 g (12 mmol) of the compound from Step 12.2 in 80 mL of water was hydrogenated in the presence of 0.4 g of Pd/C (10%) under 9 bar of hydrogen pressure. After 3 hours the catalyst was filtered off and the water was removed in a rotary evaporator.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][C:18](=[N:23][OH:24])[CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(CCCCCCOCc2ccccc2)CC1
Agent: Cl
Product: ON=C1CCN(CCCCCCOCc2ccccc2)CC1

Procedure:
1-(6-Benzyloxyhexyl)-4-piperidone oxime is prepared from 1-(6-benzyloxyhexyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.S(Cl)([Cl:16])(=O)=O>C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[C:3]=1[Cl:16]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nc2cc(Cl)c(N)cc2o1
Solvent: CCOC(C)=O
Product: Cc1nc2cc(Cl)c(N)c(Cl)c2o1

Procedure:
6-Amino-5-chloro-2-methylbenzoxazole (10 g, 54.76 mMole) was dissolved in ethyl acetate (150 mL). At room temperature and with good stirring, sulfuryl chloride (8.8 mL, 109.52 mMole) was added drop by drop over a 20-minute period. As the addition proceeds, additional ethyl acetate (350 mL) was added to keep the mixture stirring. After 1 hour the precipitate was filtered off, washed with ether and air-dried. Yield 10.5 g.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]([CH3:31])[CH3:30])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:32][CH3:33])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]([CH3:30])[CH3:31])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:32][CH3:33])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N(C)C)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)CC[C@@H]3c2ccccc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-N4,N4-dimethyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 4) was purified using chiral SFC to afford peak A (Example 4A) and peak B (Example 4B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 22 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=5.1 min, tR (peak B) 18.1 min. The absolute stereochemistry of individual enantiomers (Examples 4A and 4B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 4).
Reaction SMILES: [CH2:1]([S:8][C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][CH:11]=[C:12](N(C)C)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([OH:29])C>>[CH2:1]([S:8][C:9]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:10][CH:11]=[C:12]([OH:29])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1ccccc1
Agent: Cl
Product: CCOC(=O)C(O)=CC=C(SCc1ccccc1)C(=O)OCC
Temperature: 20 °C
Reaction time: 0.03 h

Procedure:
The procedure is as in Example 2, starting with diethyl 5-benzylthio-2-dimethylamino-2,4-hexadienedioate (10 g) and 1N aqueous hydrochloric acid solution (41.3 cc) in ethanol (41.3 cc). The mixture is heated to boiling for 2 minutes, and then cooled to a temperature in the region of 20° C. After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (30:70 by volume) as eluent, diethyl 5-benzylthio-2-hydroxy-2,4-hexadienedioate (6.3 g) (m.p. <40° C.) is obtained [Rf=0.6; thin layer chromatography on silica gel; eluent: cyclohexane/ethyl acetate (30:70 by volume)].
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=2[NH:16][C:17](=[O:26])[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])(=[O:3])[CH3:2].[BH4-].[Na+].O>O1CCCC1>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:17]([NH:16][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[N:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[C:13]2[O:14][CH3:15])=[O:26]
Reactant: COc1c(C(C)=O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C(C)O)cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 3-acetyl-8-(2,6-dichlorobenzoylamino)-4-methoxyquinoline (115 mg) in tetrahydrofuran was added sodium borohydride (16.8 mg) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 8-(2,6-dichlorobenzoylamino)-3-(1-hydroxyethyl)-4-methoxyquinoline (85.1 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([OH:16])[OH:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:30][C:31](=[CH2:36])[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([CH2:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH2:30])(=[O:15])[OH:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(NC(=O)OCc1ccccc1)P(O)O
Reactant: C=C(CBr)C(=O)OC
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
To a stirred solution of 2.25 g (9.3 mmol) of 1-(benzyloxycarbonylamino)ethylphosphonous acid in 70 ml of methylene chloride, were added triethylamine (2.87 ml, 20 mmol), trimethylsilyl chloride (2.60 ml, 20 mmol), and methyl 2-bromomethylacrylate (1.66 g, 9.3 mmol) at 0° C. After stirring at room temperature for 20 hours, the reaction mixture was washed with H2O, 2N HCl, and then saturated NaCl solution and dried over anhydrous magnesium sulfate. The mixture obtained by filtration and evaporation was purified by silica gel chromatography (eluted with chloroform followed by 10% methanol-chloroform) to give 2.50 g (yield 79%) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][P:6]([O:11][CH2:12][CH3:13])([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[CH3:17][O:18][C:19]([CH3:27])([CH3:26])[C:20]#[C:21]/[CH:22]=[CH:23]/[CH2:24]Br.C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([P:6]([O:8][CH2:9][CH3:10])([O:11][CH2:12][CH3:13])=[O:7])[CH2:24]/[CH:23]=[CH:22]/[C:21]#[C:20][C:19]([O:18][CH3:17])([CH3:27])[CH3:26])[CH3:2]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COC(C)(C)C#C/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C/C=C/C#CC(C)(C)OC)P(=O)(OCC)OCC
Reaction time: 5 h
Yield: 55.8 %

Procedure:
3.36 g of diethylphosphonoacetic acid ethyl ester is dissolved in 40 ml of ethanol, 0.60 g of 60% oily sodium hydride is added under ice cooling and stirring, 1.09 g of (E)-6-methoxy-6-methyl-2-hepten-4-ynyl bromide is added dropwise, and the mixture is stirred under ice cooling for 1 hour and then at room temperature for 5 hours. 15 ml of acetic acid is added to the reaction solution, the solvent is distilled off under reduced pressure, and the residue is extracted with a system of water and ethyl acetate. The organic layer is post-treated in a conventional manner, and the product is purified by silica gel column chromatography [Wako gel C-200, 100 g; hexane/ethyl acetate=1/2] and medium pressure liquid chromatography [Lobar column, size B, Lichroprep Si 60F (produced by Merck Co.); hexane/ethyl acetate=1/1→1/2] to obtain 1.01 g of (E)-diethylphosphono(6-methoxy-6-methyl-2-hepten-4-ynyl)acetic acid ethyl ester as colorless oil.
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:36]=[C:37](N)[S:38][CH:39]=1)[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.O>O1CCCC1>[C:8]([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:36]=[CH:37][S:38][CH:39]=1)[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(N)n1
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1cscn1
Yield: 45.5 %

Procedure:
A solution of t-butyl nitrite (1.7 g) in tetrahydrofuran (10 ml) was dropwise added to a solution of benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (5 g) in tetrahydrofuran (50 ml) at 50° to 53° C. under stirring and the mixture was stirred at the same temperature at 25 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water and the organic layer was separated. The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was subjected to column chlomatography on silica gel. The elution was carried out with a mixture of benzene and ethyl acetate (19:1) and the eluates containing the object compound were evaporated to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetate (syn isomer) (2.2 g).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[C:12]([OH:13])=[C:11]([CH2:14][CH2:15]O)[C:10]([CH3:17])=[N:9][C:8]=12)(=O)[NH2:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][CH2:15][CH2:14][C:11]1[C:10]([CH3:17])=[N:9][C:8]2[N:7]([CH:6]=[N:5][C:4]=2[C:1]#[N:2])[C:12]=1[OH:13]
Reactant: Cc1nc2c(C(N)=O)ncn2c(O)c1CCO
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(C#N)ncn2c(O)c1CCCl
Reaction time: 0.5 h

Procedure:
0.17 mol of the compound obtained in Stage A of Example 3, dissolved in 200 ml of phosphorus oxychloride, is brought to 85° C. for one hour 30 minutes. The phosphorus oxychloride is then removed by evaporation under vacuum. 100 ml of water are added and the pH is adjusted to 7 using sodium bicarbonate to crystallize the expected compound. The latter is filtered off.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3].CCN(C(C)C)C(C)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[NH4+].[Cl-]>C(Cl)Cl>[O:31]1[CH2:32][CH2:33][N:28]([S:2]([C:5]2[CH:6]=[C:7]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=2)[C:8]([O:10][CH3:11])=[O:9])(=[O:4])=[O:3])[CH2:29][CH2:30]1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)Cl)c1
Reactant: C1COCCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1.3 h

Procedure:
To a solution of methyl 3-(chlorosulfonyl)-5-(trifluoromethyl)benzoate (0.3 g, 991 μmol, Buttpark Ltd.) in CH2Cl2 (1.0 mL) were added DIPEA (192 mg, 260 μL, 1.49 mmol) and morpholine (86.4 mg, 86.4 μL, 991 μmol). The clear light yellow solution was stirred at room temperature for 1.3 hours and then poured on saturated aqueous NH4Cl solution and CH2Cl2. The layers were separated and the aqueous layer was extracted twice with CH2Cl2. The organic layers were dried over MgSO4, filtered, treated with silica gel and evaporated. Light brown solid (0.357 g; 91%). MS (EI): m/z=353 [M].
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH:11]([F:13])[F:12])[N:6]=1)C.Cl>O>[F:13][CH:11]([F:12])[C:7]1[N:6]=[C:5]([CH:4]=[O:3])[N:9]([CH3:10])[N:8]=1
Reactant: CCOC(OCC)c1nc(C(F)F)nn1C
Agent: Cl
Solvent: O
Product: Cn1nc(C(F)F)nc1C=O
Temperature: 57.5 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
Water (190 mL) was added to 5-(diethoxymethyl)-3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole (47.6 g, 0.2024 mol, from Step 2), and the mixture was degassed. Then concentrated HCl (73 mL, 0.81 mol, 11.1 M) was added, and the mixture was stirred at 55-60° C. for 24 h. After this, the reaction mixture was evaporated, and the residue was repeatedly (8-10 times) evaporated with THF until the water and HCl were completely removed. The final residue was distilled under vacuum to give the crude title product (bp 46-50° C. at 0.04 mm Hg), containing, according to LC-MS data, 7% of a dimerization side-product. Further purification on a silica gel (ethyl acetate/hexane 1:3) yielded 18.37 g (56.3%) of 3-(difluoromethyl)-1-methyl-1H-1,2,4-triazole-5-carbaldehyde. Satisfactory C,H,N-analysis was obtained. 1H NMR (400 MHz, CDCl3): δ 4.25 (s, 3H), 6.74 (t, J=56 Hz, 1H), 10.01 (s, 1H). LC/MS (API-ES) calcd for C5H5F2N3O: 161.04, found (M+H+): 162.1; (M+18+H+): 180.1 m/z.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.ClC(Cl)C>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: O=C(Nc1cnc2ccccc2c1Cl)C1CCCCC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a mixture of 3-amino-4-chloroquinoline (8.00 g, 1 eq), cyclohexanecarbonyl chloride (18.2 mL, 3 eq) and anhydrous dichloroethane (150 mL) was heated at 90° C. for 23 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with hexanes to provide a solid. The solid was combined with hexanes, stirred for 30 minutes, isolated by filtration, rinsed with hexanes, and then dried to provide 11.9 g of N-(4-chloroquinolin-3-yl)cyclohexanecarboxamide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCCc1nc2c(N)nc3c(c2n1CCOCCN)CCCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCc1nc2c(N)nc3c(c2n1CCOCCNS(C)(=O)=O)CCCC3
Temperature: 0 °C
Yield: 31.5 %

Procedure:
1-[2-(2-Aminoethoxy)ethyl]-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.00 mmol) was dissolved in 30 mL of anhydrous CH2Cl2 and cooled to 0° C. under N2. To the stirred solution were added Et3N (0.84 mL, 6.00 mmol) and methanesulfonyl chloride (232 μL, 3.00 mmol) and the reaction was allowed to warm to room temperature overnight. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (30 mL). The organic layer was separated and washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure to give a yellow solid. The solid was triturated with Et2O and a few drops of MeOH. The resulting white powder was isolated by filtration and further purified by column chromatography (SiO2, 3% MeOH/CHCl3 saturated with aqueous NH4OH) to give 389 mg of N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide as a white powder. m.p. 151.0-153.0° C.;
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:26])[CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:10])C1C=CC=CC=1.C(OC(N[C@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O)(C)(C)C>>[C:22]([O:21][C:19]([NH:18][CH2:17][C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:26])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
Compound 27 was synthesized from compound 26, following the procedure as described for compound 3a, as a white solid. MS (ESI, EI−) m/z=271 (MIT).
Reaction SMILES: C1(S[CH2:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH3:25])[CH:16]=3)[NH:11][C:10]([CH3:27])([CH3:26])[CH:9]=2)CCCC1.BrCC1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](C3C=CC=CC=3OC)[CH:38]=2)[NH:33]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C1(S)CCCC1>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:26])([CH3:27])[CH:9]=[C:8]2[CH2:7][NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSC1CCCC1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: SC1CCCC1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
4-Cyclopentylsulfanylmethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 69 mg of potassium carbonate, and 48 μL of cyclopentyl mercaptan reacted to give 7 mg of the title compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:22])([CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:22])([C:9]([O:11][CH3:12])=[O:10])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(CCC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(C)(CCC(=O)O)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 101.5 %

Procedure:
Methyl 2-(4-chlorophenyl)propanoate (1.50 g, 7.55 mmol) was dissolved in THF (14 mL) and cooled to 0° C. The solution was treated with KOtBu (85 mg, 0.755 mmol) and allowed to stir for 15 minutes. The solution was cooled to −78° C. and then treated with the acrylate (1.22 mL, 8.31 mmol). The mixture was allowed to stir overnight to room temperature to completion by TLC analysis. The mixture was then quenched with saturated NH4Cl. The THF was removed in vacuo to afford a yellow oil. The residue was partitioned between ethyl acetate and water. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic portion was washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo to afford the crude material as a yellow oil. The material was purified by chromatography (silica gel eluted with 90:10 hexanes:ethyl acetate, Rf=0.35) to afford 5-tert-butyl 1-methyl 2-(4-chlorophenyl)-2-methylpentanedioate as a colorless oil (1.69 g, 69%). This 5-tert-butyl 1-methyl 2-(4-chlorophenyl)-2-methylpentanedioate (1.69 g, 5.17 mmol) was dissolved in TFA (15.9 mL; 207 mmol) at room temperature and allowed to stir for 2 hours to completion by LCMS (neg) analysis. The solution was concentrated in vacuo to afford 4-(4-chlorophenyl)-5-methoxy-4-methyl-5-oxopentanoic acid as a colorless oil (1.42 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(F)cc4)cc3CC[C@@H]12
Yield: 66.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-fluorophenylboronic acid (109 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 140 mg (67%) of the title compound as a white solid. mp 121°-122°. FDMS: m/e=323. α[D]589 =+79.46 (c=0.99, chloroform).