Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[CH2:3](O)[CH3:4].C#C.[CH3:8][C@:9]12[CH2:26][CH:25]=[C:24]3[C@@H:14]([CH2:15][CH2:16][C:17]4[C@:22]3([CH3:23])[CH:21]=[CH:20][C:19](=[O:27])[CH:18]=4)[C@@H:13]1[CH2:12][CH2:11][C:10]2=[O:28]>O1CCCC1.O>[C:3]([C@:10]1([OH:28])[CH2:11][CH2:12][C@H:13]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:8])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=[O:27])[CH:20]=[CH:21]1)[CH2:16][CH2:15]3)#[CH:4]
Reactant: CCO
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C#C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Temperature: 3 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
In a three-necked flask, 95 percent potassium hydroxide (200 g), tetrahydrofuran (1000 ml) and ethanol (120 ml) were stirred at 50° C. for 1 hour under a nitrogen atmosphere and then cooled to 3° C. Into the mixture prepared as above, pure dry acetylene was passed at 3° C. for 2 hours. A solution of 1,4,9(11)-androstatriene-3,17-dione (100 g) in 200 ml of dry tetrahydrofuran was added and stirred for 2 hours. The mixture was acidified with 10 percent aqueous Hcl solution, stirred under reflux for half an hour, and diluted with water. The resulting precipitated product was collected by filtration, washed with water, and dried to give 17α-ethynyl-17β-hydroxyandrosta-1,4-dien-3-one (110.3 g, purity 92.9 percent, yield 96.6 percent).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C)C=O>O>[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCCl)cc1
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCCCCCOc1cccc2ccccc12

Procedure:
A mixture of 1-naphthol (12.9 g), potassium carbonate (23.5 g), 1-chloro-8-(p-toluenesulphonyloxy)octane (23.5 g) and dimethylformamide (200 ml) was stirred at 55° for 2-1/2 days. The solution was then cooled and added to water, and extracted with ether. The extract was dried and evaporated and the residue was chromatographed on silica gel (750 g), eluting with 3:1 hexane: methylene chloride, so as to afford the title compound as an oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([Br:25])=[CH:16][C:17]=1[C:18]2=[N:23]O.C(O)C.C(O)(=O)C>O.[Zn]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:11]=1[C:12]1[CH:13]=[CH:14][C:15]([Br:25])=[CH:16][C:17]=1[CH:18]2[NH2:23]
Reactant: ON=C1c2cc(Br)ccc2-c2c1cccc2-c1nc2ccccc2[nH]1
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NC1c2cc(Br)ccc2-c2c(-c3nc4ccccc4[nH]3)cccc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 224 %

Procedure:
Place 500 mg of 5-(1H-benzimidazol-2-yl)-2-bromo -9H-fluoren-9-one oxime (Z,E) in suspension in a mixture of 3.5 ml of water, 7 ml of ethanol and 3.5 ml of acetic acid. Add 335 mg of powdered zinc and stir at room temperature for 19 hours. The insoluble residues are filtered over sintered glass and rinsed with ethanol. Evaporation of the solvent under reduced pressure is a colourless foam which is taken up in suspension in 100 ml of water. The pH of the supernatant is then brought to 9 by the addition of a 1N aqueous solution of sodium hydroxide, and the persisting precipitate is filtered off, and washed with 3 times 50 ml of water and twice 100 ml of isopropyl ether. After drying at 50° C. in an oven under vacuum, in this way we obtain 1.08 g of 5-(1H-benzimidazol-2-yl)-2-bromo-9H-fluorene-9(R,S)-amine, in the form of a white powder which is used as it is in the following stage.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([OH:29])=O)=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[NH2:30][C:31]1[NH:35][N:34]=[N:33][N:32]=1>>[CH2:1]([C:5]1[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([NH:30][C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[O:29])=[CH:17][CH:16]=2)[C:7]([CH2:11][O:12][CH3:13])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: Nc1nnn[nH]1
Product: CCCCc1nc(Cl)c(COC)n1Cc1ccc(-c2ccccc2C(=O)Nc2nnn[nH]2)cc1

Procedure:
2-n-Butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(methoxymethyl)imidazole (1.0 g) was first converted to the corresponding acid chloride and then coupled to 5-aminotetrazole by the procedure in Example 78, Part C to yield 0.87 g of a yellow glass. Flash chromatography in 100% ethyl acetate over silica gel yielded 77.1 mg of a white solid; m.p. 169°-173°. NMR (200 MHz, CDCl3, DMSO-d6) δ12.0 (br s, 1H); 7.73-7.30 (m, 6H); 7.00 (d, 2H, J=7 Hz); 5.18 (s, 2H); 4.23 (s, 2H); 2.55 (t, 2H, J=7 Hz) 1.63 (t of t, 2H, J=7,7 Hz); 1.31 (t of q, 2H, J=7,7 Hz); 0.84 (t, 3H, J=7 Hz). Anal. Calcd. for C24H26ClN7O2 .(H2O)2 : C, 55.87; H, 5.86. Found: C, 56.01; H, 6.01.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[CH3:29][O:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[C:33]([C:40]([F:43])([F:42])[F:41])[N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:35]1[CH:34]=[C:33]([C:40]([F:42])([F:43])[F:41])[N:32]=[C:31]([O:30][CH3:29])[CH:36]=1
Reactant: COc1cc(B(O)O)cc(C(F)(F)F)n1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc(C(F)(F)F)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 83.9 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (70 mg, 0.16 mmol) were added (2-methoxy-6-(trifluoromethyl)pyridin-4-yl)boronic acid (53 mg, 0.24 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (12 mg, 0.01 mmol) and 159 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by reverse phase using SP1® Purification System to give 72 mg (82% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [H-].[Na+].[N:3]1[C:4](=[S:12])[N:5]=[C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=12.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30])=[O:21].O>CN(C)C=O>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[NH:22][C:20](=[O:21])[N:19]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][S:12][C:4]1[NH:5][C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:3]=1
Reactant: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Reactant: S=C1N=C2CCCCC2=N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCN(CCCCCSc1nc2c([nH]1)CCCC2)C(=O)Nc1ccc(F)cc1F
Reaction time: 2 h
Yield: 18.2 %

Procedure:
Part B. To a suspension of sodium hydride (0.099 g, 0.004 mol; washed free of the mineral oil with hexane) in N,N-dimethylformamide (15 ml) under a nitrogen atmosphere, cooled to 0°, 4,5,6,7-tetrahydrobenzimidazol-2-thione (0.50 g, 0.0033 mol) was added slowly. The reaction mixture was stirred for two hours and then a solution of N-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptyl urea (1.38 g, 0.0033 mol) in N,N-dimethylformamide (5 ml) was added. The reaction mixture was stirred at 0° for one hour, at ambient temperature for one hour, then was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water and brine, then dried over magnesium sulfate and concentrated to give the crude product. The product was purified by flash chromatography on silica gel (250 ml) eluting with hexane: ethyl acetate (50:50::v:v) to give the title compound as a solid (0.30 g, 0.0006 mol), mp 98°-100°. 1H NMR (CDCl3) δ10.0-9.4 (bs,1H), 8.05-7.87 (m,1H), 6.91-6.75 (m,2H), 6.5-6.41 (d,1H,J=3.75 Hz), 3.42-3.2 (m,4H), 2.96-2.85 (t,2H,J=6.0 Hz), 2.61-2.45 (m,4H), 1.81-1.22 (m,20H), 0.88 (t,3H,J=6.5 Hz).
Reaction SMILES: [S:1]([OH:27])([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)=[CH:8][C@H:9]2[C:14](=[O:16])[NH2:15])(=[O:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[S:1]([OH:27])([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([CH2:17][CH2:18][NH2:19])=[CH:8][C@H:9]2[C:14](=[O:16])[NH2:15])(=[O:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(OS(=O)(=O)O)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC1=C[C@@H](C(N)=O)N2C[C@@H]1N(OS(=O)(=O)O)C2=O

Procedure:
To a suspension of (2S,5R)-4-(2-(tert-butoxycarbonylamino)ethyl)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]oct-3-en-6-yl hydrogen sulfate (Intermediate 229, 0.060 g, 0.15 mmol) in dichloromethane (2 mL) at 0° C. was added trifluoroacetic acid (0.100 mL). After 15 minutes the solvent was removed in vacuo and the residue was dried under high vacuum. Purified by reverse phase chromatography using acetonitrile/water to afford the title compound as a white solid after lyophilization (0.006 g, 13%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[N:23]([CH2:24][C:25]([OH:27])=O)[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]1.C(Cl)CCl.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([CH:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25]([N:30]3[CH2:35][CH2:34][CH:33]([CH2:36][OH:37])[CH2:32][CH2:31]3)=[O:27])=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: OCC1CCNCC1
Reactant: CC1(C)CN(CC(=O)O)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: O
Product: CC1(C)CN(CC(=O)N2CCC(CO)CC2)C(C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
[5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid (200 mg, 0.48 mmol) and piperidin-4-yl-methanol (111 mg, 0.96 mmol) were dissolved in pyridine (4 mL). The resulting yellow solution was stirred at room temperature for 10 min and then EDC (184 mg, 0.96 mmol) was added in a single portion. The reaction mixture was allowed to stir over night (16 h). Water (4 mL) was added and the mixture was concentrated under reduced pressure. The resulting residue was partitioned between ethyl acetate (50 mL) and 1 M aqueous potassium carbonate. The aqueous layer was back-extracted with ethyl acetate (3×50 mL) and the combined extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude residue was purified by silica gel chromatography (methylene chloride and methanol gradient) to afford pure 4-[2-(4-hydroxymethyl-piperidin-1-yl)-2-oxo-ethyl]-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide as a yellow foam (152 mg, 62%). The bis-HCl salt was prepared by adding 2 equivalents of conc. HCl to an ethanolic solution of the freebase. Concentration, followed by ether trituration afforded the salt as a free-flowing, yellow powder.
Reaction SMILES: [CH:1]1([NH:7][C:8]([O:10][CH:11]2[CH2:18][CH2:17][C:14]3([O:16][CH2:15]3)[CH:13]([C:19]3([CH3:25])[CH:21]([CH2:22][CH2:23][OH:24])[O:20]3)[CH:12]2[O:26][CH3:27])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)C>[C:28]([O:24][CH2:23][CH2:22][CH:21]1[O:20][C:19]1([CH:13]1[CH:12]([O:26][CH3:27])[CH:11]([O:10][C:8](=[O:9])[NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:18][CH2:17][C:14]21[O:16][CH2:15]2)[CH3:25])(=[O:30])[CH3:29]
Reactant: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CCO
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: COC1C(OC(=O)NC2CCCCC2)CCC2(CO2)C1C1(C)OC1CCOC(C)=O
Temperature: 25 °C
Reaction time: 1.1 h

Procedure:
A mixture of 6-cyclohexylcarbamoyloxy-4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-1-oxaspiro[2,5]-octane (5 mg), acetic anhydride (12 μl), pyridine (11 μl), and 4-dimethylaminopyridine (1 mg) in dichloromethane (1 ml) was stirred for 1.1 hours at ambient temperature. The mixture was diluted with diethyl ether and washed with brine (4×). The organic layer was dried and concentrated in vacuo. The residue was purified by column chromatography on silica gel to yield 4-[3-(2-acetoxyethyl)-2-methyloxiranyl]-6-cyclohexylcarbamoyloxy-5-methoxy-1-oxaspiro[2,5]octane as an oil (3.7 mg).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH2:4].C(=O)([O-])O.[Na+].O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:4][C:3]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: COc1cccc(F)c1N
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(F)c1NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a mixture of 2-fluoro-6-methoxyaniline (0.56 g), sodium hydrogen carbonate (0.67 g) and water (2 mL) in tetrahydrofuran (20 mL) was added a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (1.0 g) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=2/3) to give 4-chloro-N-(2-fluoro-6-methoxyphenyl)-3-nitrobenzenesulfonamide (0.56 g). This material was dissolved in N,N-dimethylformamide (15 mL). To the solution were added methyl iodide (0.15 mL) and sodium hydride (55%, 75 mg) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give 4-chloro-N-(2-fluoro-6-methoxyphenyl)-N-methyl-3-nitrobenzenesulfonamide (0.4 g). This material was dissolved in tetrahydrofuran (3 mL). To the solution were added methanol (3 mL) and nickel(II) bromide (12 mg). To the mixture was added sodium borohydride (0.12 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/4) to give the title compound (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[C:38]([CH2:37][C:31]3[C:32](=[O:36])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[C:29](=[O:52])[C:30]=3[CH3:51])[CH:39]=[CH:40][C:41]=2[O:47][C:48](=[O:50])[CH3:49])[CH:7]=[CH:6][N:5]=1
Reactant: COc1cc(N)ccn1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccnc(OC)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 62.3 %

Procedure:
4-Amino-2-methoxypyridine (0.167 g, 1.340 mmol), triethylamine (0.176 g, 1.740 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.147 g, 0.869 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.200 g, 0.416 mmol, 62%).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[O:11]=[C:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH:17]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:18]([O:20][C@@H:21]1[CH:26]2[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]2)[CH2:22]1)=[O:19]>CCOC(C)=O.C(#N)C>[Cl-:1].[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][N+:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:18](=[O:19])[CH:17]([N:13]1[CH2:14][CH2:15][CH2:16][C:12]1=[O:11])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:22]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCC1=O
Reactant: O=C(CCl)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCCC1=O)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
2-Chloro-1-phenylethanone (62.1 mg, 0.40 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(2-oxopyrrolidin-1-yl)-2-phenylacetate (120 mg, 0.36 mmol) in EtOAc (2.4 ml) and acetonitrile (1.2 ml). The pale yellow solution was stirred at room temperature for three days. The solvent was evaporated and the crude was purified by flash chromatography (DCM/MeOH=9/1) to collect the title compound (118 mg, 66.9% yield) as an off-white spongy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[CH:12]([Mg]Cl)([CH3:14])[CH3:13].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8]([C:7]([CH:12]([CH3:14])[CH3:13])=[CH:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: O=C1CCc2cc(Cl)ccc21
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C1=CCc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 5-chloro-1-indanone (3.59 g) in anhydrous tetrahydrofuran (40 ml) was added to a solution of isopropyl magnesium chloride (103 ml, 2M ethereal solution) under nitrogen at a rate to produce gentle refluxing. After the addition, the reaction solution was further stirred at room temperature for 11/4 hr, then poured into water (200 ml) and extracted with diethyl ether (3×150 ml). The combined ether solutions was washed with water, and condensed to an oil. This oil dissolved in benzene (250 ml) with a catalytic amount of p-toluenesulfonic acid was refluxed for 1.5 hr and then poured into water (200 ml). A few drops of diethylamine were added. The aqueous solution was separated and extracted with diethyl ether (3×100 ml). The combined organic phases were washed sequentially with dilute hydrochloric acid, saturated sodium bicarbonate solution and water, then dried (MgSO4) and condensed under reduced pressure. The residue was purified on a flash column (eluted with 5% ether in hexane) to give 6-chloro-3-isopropyl-1H-indene (2.94 g).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:10](=[S:19])[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].Cl.[Cl:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[NH2:30]>CN(C)C=O.O>[ClH:23].[NH2:30][C@@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@H:24]1[S:19][C:10]1[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: N[C@@H]1CCCC[C@H]1Cl
Reactant: S=c1[nH]c2ccccc2cc1-c1ccccc1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N[C@@H]1CCCC[C@H]1Sc1nc2ccccc2cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Sodium hydride (0.68 g. of a 50% w/w dispersion in mineral oil) was added to a solution of 3-phenylquinolin-2-thione (1.6 g.) in dimethylformamide (10 ml.) at ambient temperature. When all the hydrogen had evolved, trans-2-chlorocyclohexylamine hydrochloride (1.2 g.) was added and the reaction mixture was stirred at 60° for 20 hr. The reaction mixture was cooled to ambient temperature, diluted with water (100 ml.), and extracted with ethyl acetate (2×30 ml.). The ethyl acetate extract was washed with water (2×10 ml.) and then dried (MgSO4). The solvent was evaporated and the residue was chromatographed on basic alumina (100 g., Brockmann Grade III), eluted with increasing concentrations of chloroform in petroleum ether, followed by chloroform. The chloroform eluate was evaporated. The residue was dissolved in diethyl ether (100 ml.), and ethereal hydrogen chloride was added until precipitation was complete. The solvent was evaporated and the residue was crystallised from ethyl acetate to give 2-(trans-2-aminocyclohexylthio)-3-phenylquinoline hydrochloride, m.p. 223°- 5°.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].N([O-])=O.[Na+].C(#N)C.O.[ClH:28]>O.Cl[Cu]>[Br:9][C:6]1[CH:5]=[C:4]([CH:10]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:2]([Cl:28])[C:7]=1[OH:8]
Reactant: CCOC(=O)C(CC(C)C)c1cc(N)c(O)c(Br)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Cl)c(O)c(Br)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(3-amino-5-bromo-4-hydroxyphenyl)-4-methylpentanoate 1 (4 g, 0.012 mol) was dissolved in a mixture of ACN/H2O/HCl 60 mL/30 mL/8 mL at 0° C. A solution of NaNO2 (0.919 g, 1.1 eq) in water (10 mL) was added dropwise at 0° C. and the reaction mixture was stirred for 1 h at 0° C. A solution of CuCl (5.99 g, 0.060 mol) in water (10 mL) was added dropwise to the reaction mixture at 0° C. The reaction mixture was then heated to 50° C. for 2.5 h. upon which the mixture was poured into ice water, extracted with ethyl acetate (3×100 mL) The combined organic layers were washed with water (200 mL) and brine (100 mL), dried over NaSO4 and concentrated in vacuo to give crude black oil which was purified by chromatography over silica gel (hexane/EtOAc) to give ethyl 2-(3-bromo-5-chloro-4-hydroxyphenyl)-4-methylpentanoate as yellow oil 2.2 g, (47.3%). 1HNMR (CDCl3, 200 MHz): 7.38 (s, 1H); 7.4 (s, 1H); 5.80 (bs, 1H); 4.13 (q, 2H); 3.51 (t, 1H); 1.93-1.56 (m, 2H); 1.51 (m, 1H); 1.21 (t, 3H), 0.97 (d, 6H);