Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[C:7]([C:12]1[C:13](=[O:25])[CH2:14][CH:15]([CH:19]2[CH2:24][CH2:23][CH2:22][S:21][CH2:20]2)CC=1O)(=[O:11])[CH2:8][CH2:9][CH3:10]>C(OC)(C)(C)C>[C:7]([C:12]1[C:13](=[O:25])[CH2:14][CH:15]([CH:19]2[CH2:24][CH2:23][CH2:22][S:21][CH2:20]2)[CH2:2][C:1]=1[Cl:6])(=[O:11])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(=O)C1=C(O)CC(C2CCCSC2)CC1=O
Solvent: COC(C)(C)C
Product: CCCC(=O)C1=C(Cl)CC(C2CCCSC2)CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
420 ml of oxalyl chloride were added at 0° to 5° C. to 141.2 g (0.5 mol) of 2-butyryl-3-hydroxy-5-(tetrahydrothiopyran-3-yl)cyclohex-2-en-1-one, and the mixture was stirred at room temperature for 16 hours and concentrated. The oil obtained was treated with methyl tert.-butyl ether, and the resulting solid was filtered off with suction and dried. This gave 125.9 g (84% yield) of 2-butyryl-3-chloro-5-(tetrahydrothiopyran-3-yl)cyclohex-2-en-1-one having a melting point of 97° C. (decomposition) (compound no. 312).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35](O)[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:41]2)=[CH:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35]([O:11][C:10](=[O:12])[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:16][CH:15]=2)([CH3:13])[CH3:14])[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH2:41]2)=[CH:28]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: CC(C)(OCc1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](OC(=O)C(C)(C)OCc3ccc(C(F)(F)F)cc3)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Yield: 80.6 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 786 mg of 2-(4-trifluoromethylbenzyloxy)-2-methylpropionic acid and 1.10 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.28 g of the title compound as a colorless foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23]Cl)[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1.[CH3:30][NH2:31].O.[OH-].[Na+]>CCO>[Cl:1][C:2]1[C:3]([N:27]([CH3:29])[CH3:28])=[CH:4][C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]4[S:19][CH:20]=[C:21]([CH2:23][NH:31][CH3:30])[N:22]=4)[CH:13]=3)[CH2:9][C:8](=[O:25])[NH:7][C:6]=2[CH:26]=1
Reactant: CN
Reactant: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CCl)cs3)c1)=N2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CNCc1csc(-c2cccc(C3=Nc4cc(N(C)C)c(Cl)cc4NC(=O)C3)c2)n1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A mixture of 8-chloro-4-[3-(4-chloromethyl-thiazol-2-yl)-phenyl]-7-dimethylamino-1,3-dihydro-benzo[b][1,4]diazepin-2-one (89 mg) and KI (3 mg) in a 8M solution of methylamine in EtOH (1 mL) was stirred at 20° C. for 20 h. H2O (25 mL) was added and the pH of the mixture was set to 11 by addition of 2N NaOH. The precipitate was collected by filtration and purified by chromatography on silica gel using MeOH as eluent. The product was stirred with 20% aqueous MeOH (10 mL) and the solid was isolated by filtration to give the title compound (49 mg) as a yellow powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[N:5]1([CH2:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: ClCCCn1ccc2ccccc21
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCn3ccc4ccccc43)CC2)c1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(3-chloropropyl)-1H-indole and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 404.2 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1.O.[OH-].[Na+].[H][H]>[Pt]=O.CN(C)C=O>[NH:1]1[C:5]([NH:6][C:7]([C:9]2[C:17](=[O:18])[N:16]3[C:12]([S:13][C:14]4[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:15]=43)=[N:11][CH:10]=2)=[O:8])=[N:4][N:3]=[N:2]1
Reactant: O=C(Nc1nnn[nH]1)c1cnc2sc3ccc([N+](=O)[O-])cc3n2c1=O
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc2sc3ncc(C(=O)Nc4nnn[nH]4)c(=O)n3c2c1

Procedure:
To a suspension of 4.5 g. of N-(5-tetrazolyl)-7-nitro-4-oxo-4H-pyrimido[2,1-b]benzothiazole-3-carboxamide in 50 ml. of water and 25 ml. of dimethylformamide is added sufficient 1N aqueous sodium hydroxide to effect a solution. Platinum oxide (300 mg.) is added and the suspension shaken in a hydrogen atmosphere at an initial pressure of 30 p.s.i. When the theoretical amount of hydrogen is absorbed the spent catalyst is filtered and the filtrate treated with sufficient 6N hydrochloric acid to register acid to Congo red paper. The acidified filtrate is further diluted with 25 ml. of water and cooled in an ice bath. The desired product is filtered and recrystallized from dimethylformamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2].Br.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[Cl:23])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Nc2ccc(OC)c(OC)c2)n1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(OC)c(OC)c2)n1

Procedure:
A mixture of 2.18 g (7.1 mmol) 2-(3,4-Dimethoxy-phenylamino)-thiazole-4-carboxylic acid ethyl ester; hydrobromide, 1.87 g (10.7 mmol) 2-Chlorobenzoyl chloride and 2.96 ml (21.4 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 24 h. After evaporation of the volatiles the residue was taken up in MeOH and purified with flash column chromatography on silica eluting with a gradient of heptane/ethyl acetate to yield after evaporation of the product fractions 1.58 g (50%) of the title compound. MS (m/e): 446.9 (MH+, 100%)
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=[C:12]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[O:26][CH3:27])(=O)=O.[I-:28].[Na+]>CC(C)=O.CN(C)P(=O)(N(C)C)N(C)C>[I:28][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[C:15]([O:16][CH2:17][O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=[C:12]([O:22][CH2:23][O:24][CH3:25])[C:11]=1[O:26][CH3:27]
Reactant: [I-]
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCOS(C)(=O)=O)c1OC
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)=O
Product: COCOc1cc(OC)c(OCOC)c(CCCCI)c1OC
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1.5 Grams of 4-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]butyl methanesulfonate was dissolved in a mixed solvent of 40 ml of acetone with 4 ml of hexamethylphosphoric triamide, then 2 g of sodium iodide was added to thereto and the whole mixture was heated at 70° C. in an oil bath and stirred for 1.5 hours. After the completion of the reaction, the reaction mixture was concentrated under a reduced pressure, then 200 ml of diethyl ether was added thereto, and washed twice with 100 ml of water, further washed twice with 100 ml of a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure to yield 1.3 g of 1-(4-iodobutyl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene. Colorless oily substance.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1.[C:29]12[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:34]C(=O)O[C:30]2=[O:31]>C(O)C>[NH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:29]=1[C:30]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][N:9]=1)=[O:31]
Reactant: NCCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CCO
Product: Nc1ccccc1C(=O)NCCCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
The subtitled compound was prepared substantially in accordance with the method detailed in Example 39A using 16.5 g (0.0449 mol) of 2-(3-aminopropyl)-1-tritylimidazole and 7.5 g (O.046 mol) of isatoic anhydride, with the exception that after reducing the organic layer to dryness under reduced pressure to provide a solid the solid was filtered through silica gel using 3000 ml of methylene chloride followed by 4000 ml of a 2% methanol in methylene chloride solution. The resulting filtrate was reduced to dryness under reduced pressure to provide a foamy oil. This oil was dissolved in 1000 ml of boiling ethanol. The resulting solution was then reduced under reduced pressure to approximately 200 ml in volume and then cooled to 0° C. while solids precipitated. These solids were recovered by filtration and washed with ethanol to provide 18.6 g of the desired subtitled intermediate (m.p. 198.5°-207° C.).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][NH:12][C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH:23]=[O:24].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:1]1[C:5]2[CH:6]=[C:7]([N:10]3[CH2:14][CH2:13][N:12]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[CH:23]=[O:24])[C:11]3=[O:15])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C1NCCN1c1ccc2ncsc2c1
Reactant: O=Cc1ccncc1Br
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Yield: 28.7 %

Procedure:
Using the same reaction conditions as in Example 14, 1-benzothiazol-6-yl-imidazolidin-2-one (I-84b: 588.7 mg, 2.688 mmol) was reacted with 3-bromo-pyridine-4-carbaldehyde (500 mg, 2.688 mmol), 1,4-dioxane (10 mL), copper iodide (51.2 mg, 0.2688 mmol), trans-1,2-diamino cyclohexane (92.33 mg, 0.8064 mmol) and potassium phosphate (1.711 g, 8.064 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 250 mg of 3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (28.9% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[N:10]1[C:19]2[C:18](=O)[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:10]1[C:19]2[CH:18]([NH:5][CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[NH2:1])[CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CCCc2cccnc21
Reactant: NCc1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccccc1CNC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 64 h
Yield: 53.1 %

Procedure:
Using General Procedure B: To a solution of 2-aminobenzylamine (0.36 g, 2.9 mmol) and 6,7-dihydro-5H-quinolin-8-one (0.43 g, 2.9 mmol) in CH2Cl2 (15 mL) was added NaBH(OAc)3 (0.92 g, 4.4 mmol) and the mixture stirred at room temperature for 64 h. Purification of the crude material by column chromatography on silica gel (2% MeOH/CH2Cl2) gave (5,6,7,8-tetrahydroquinolin-8-yl)-(2-aminobenzyl)-amine (0.39 g, 52%) as a yellow oil. 1H NMR (CDCl3) δ 1.80 (m, 1H), 1.94 (m, 2H), 2.17 (m, 1H), 2.79 (m, 2H), 3.84 (m, 1H), 3.87 (d, 1H, J=11.7 Hz), 4.02 (d, 1H, J=12.0 Hz), 6.64 (d, 1H, J=7.8 Hz), 6.67 (t, 1H, J=7.8 Hz), 7.09 (m, 3H), 7.38 (d, 1H, J=3.0 Hz), 8.38 (d, 1H, J=3.9 Hz).
Reaction SMILES: N1C2NCCCC=2C=CC=1CC(N)[OH:13].CCOC(/N=N/C(OCC)=O)=O.CC1(C)[C@H](C2C=CC(O)=CC=2)[C@@H]1CC(OCC)=O.[C:45]1([P:51]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>CN(C=O)C>[C:58]1([P:51](=[O:13])([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: NC(O)Cc1ccc2c(n1)NCCC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: CCOC(=O)C[C@H]1[C@@H](c2ccc(O)cc2)C1(C)C
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridyl)-aminoethanol (0.832 g, 4.8 mmol) and DEAD (0.835 g, 4.8 mmol) in DMF (10 mL) was added to a solution of ethyl (cis)2,2-dimethyl-3-(p-hydroxyphenyl)cyclopropaneacetate (0.560 g, 0.2.39 mmol) and triphenylphosphine (0.1.26 g, 4.8 mmol) in dimethylformamide (10 mL) and was stirred for 4 h at rt. The solvent was removed and the residue was purified by hplc to afford the desired ester along with some triphenylphosphine oxide. The residue in ethanol (20 mL) water (20 mL) was added lithium hydroxide (1 g) and was stirred for 18 h. The reaction mixture was concentrated and the residue in water was added trifluoroacetic acid (2 mL) and was purified on hplc to afford the desired product as a solid. 1H NMR (CD3OD) δ 7.58 (d, 1H, J=7.4 Hz), 7.06 (m, 2H), 6.80(m, 2H), 6.70 (d, 1H, J=7.3 Hz), 4.24 (t, 2H, J=5.9 Hz), 3.48 (m, 2H), 3.13 (t, 2H, J=5.9 Hz), 2.8 (m, 2H), 1.99-2.02 and 2.27-2.33 (m, 2H), 1.93 (m, 2H), 1.83 (d, 1H, J=9 Hz), 1.23 (s, 3H), 1.18 (m, 1H), 0.89 (s, 3H). Anal. Calcd for C23H28N2O3: Mol. Wt, 380.2100. Found: 379.2036 (M−H, HRMS).
Reaction SMILES: [C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Li+:14].[Li+].[Li+].[OH-].[Li+].[Cu:19].C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Cu+2:19].[Li+:14].[Li+:14]
Reactant: [Cu]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: [Cu+2]

Procedure:
10 millimoles of lithium citrate were dissolved in 10 milliliters of water. To this solution, 10 millimoles of cupric chloride (CuCl2.2H2O) were added gradually with stirring. A deep blue solution was formed. This was neutralized to a pH of about 7 with 10 millimoles of lithium hydroxide (LiOH.H2O). This solution, when evaporated to dryness, gave a deep blue, semicrystalline solid. This solid was ground to a fine powder and the lithium chloride was extracted with 50 milliliters of dry methanol, five times, at 35° C. The blue solid which remained behind was evacuated to remove methanol and desiccated. An attempt was made to crystallize the salt from water-organic solvent systems, but apparently due to the extremely hygroscopic nature of the salt and the high negative charge on the ionized molecule, the solid obtained was microcrystalline to amorphous. The following formula is proposed for the 1:1 complex of copper and citrate based on elucidation of the structure and analyses described hereinafter.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=O)[CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1.CN.[C:19]([BH3-])#[N:20].[Na+]>O1CCCC1>[CH3:19][NH:20][CH:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [BH3-]C#N
Reactant: O=C(CN1CCCC1)c1cccnc1
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CNC(CN1CCCC1)c1cccnc1
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
9 g (34.22 mmoles) of 1-(3-pyridinyl)-2-(1-pyrrolidinyl) ethanone dihydrochloride were suspended in 110 ml of tetrahydrofuran containing 20% of monomethylamine. After 15 mins. of stirring, 3.6 g (57.32 mmoles) of sodium cyanoborohydride were added at room temperature. After 24 h the reaction mixture was evaporated in vacuo to dryness. The residue was taken up with conc. NaOH solution and exhaustively extracted with diethyl ether. The organic solution was dried and evaporated in vacuo to dryness. 4.2 g of the crude product were obtained and used, without further purification, in the following step.
Reaction SMILES: COC(=O)C[C@H]1[CH2:10][CH2:9][C@H:8]([O:11][CH3:12])[CH2:7][CH2:6]1.[CH3:14][O:15][C:16](=[O:25])[CH2:17][N:18]1CCC(O)CC1>>[CH3:14][O:15][C:16](=[O:25])[CH2:17][N:18]1[CH2:6][CH2:7][CH:8]([O:11][CH3:12])[CH2:9][CH2:10]1
Reactant: COC(=O)C[C@H]1CC[C@H](OC)CC1
Reactant: COC(=O)CN1CCC(O)CC1
Product: COC(=O)CN1CCC(OC)CC1

Procedure:
The title compound can be prepared in accordance with the general method of intermediate B, step 3 from (4-hydroxy-piperidin-1-yl)-acetic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCCCCCC.C(OO)(C)(C)C.NC1C=CC=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.CCCCCC.C(OCC)(=O)C.O>[C:2]([CH:3]1[CH2:4][C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:11]1[C:12]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21])(=[O:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Nc1ccccc1CCC(=O)c1ccccc1)OCc1ccccc1
Agent: CC(C)(C)OO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(c1ccccc1)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Reaction time: 5 h
Yield: 10 %

Procedure:
A reactor was charged with 359 mg (1.0 mmol) of benzyl 2-(3-oxo-3-phenylpropyl)phenylcarbamate (an2) obtained in Synthesis Example 6, 36.9 mg (0.10 mmol) of tetrabutylammonium iodide (Bu4N+I−), and 50 mL of ethyl acetate as a solvent to prepare a solution. Subsequently, 364 μL of 5.5 M decane solution (manufactured by Aldrich) containing 2.0 mmol of tert-butyl hydroperoxide (TBHP) as an oxidizing agent was added to the solution in an amount corresponding to 2 equivalents based on the aniline derivative (an2). After adjusting the temperature of the reaction system to room temperature (about 20° C.), the mixture was stirred for 5 hours, and then stirred (reacted) at 50° C. for 42 hours. After cooling the reaction mixture including the reaction product to room temperature, the reaction mixture was added to 20 mL of water, and extracted twice with ethyl acetate. The resulting organic layer was sequentially washed with a saturated sodium sulfite (Na2SO3) aqueous solution, an NaCl aqueous solution, and water, followed by the addition of anhydrous sodium sulfate (Na2SO4). The solvent was then evaporated under reduced pressure to obtain a concentrate including a crude product. The concentrate was subjected to silica gel flash column chromatography (eluant: hexane/ethyl acetate=6/1) to obtain benzyl 2-benzoylindoline-1-carboxylate (white solid) represented by the formula (as2). The yield was 10% (see Table 1-2). The analysis data for the resulting compound (as2) is shown below.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([NH:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:18])[CH3:17])[CH:13]=2)[C:8](=[O:19])[CH2:7]1)=[O:4].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[F:1][C:2]([F:20])([F:21])[C:3]([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH:16]([CH3:17])[CH3:18])[CH:13]=2)[C@@H:8]([OH:19])[CH2:7]1)=[O:4]
Reactant: CC(C)Oc1ccc2c(c1)C(NC(=O)C(F)(F)F)CC2=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc2c(c1)[C@H](NC(=O)C(F)(F)F)C[C@@H]2O
Temperature: 25 °C
Reaction time: 6 h
Yield: 25 %

Procedure:
Step AU (4). To a solution of 2,2,2-trifluoro-N-(6-isopropoxy-3-oxo-2,3-dihydro-1H-inden-1-yl)acetamide (20 g, 66 mmol) in THF (200 mL) at −78° C. was added L-Selectride (70 mL, 70 mmol). The reaction mixture was allowed to warm to rt and stir for 6 h. The reaction was quenched with HCl (1.0 N, 70 mL) and the resulting mixture was extracted with EtOAc (200 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (10-40% EtOAc/Hexane) to afford 5 g (25% yield) of cis-2,2,2-trifluoro-N-(3-hydroxy-6-isopropoxy-2,3-dihydro-1H-inden-1-yl)acetamide. LC-MS (M−H2O+H)+=286.14, (M+Na)+=326.10. 1H NMR (300 MHz, CDCl3) δ 1.31-1.32 (d, 6H) 1.5 (s, 1H) 1.9-2.0 (m, 1H) 2.0-2.2 (m, 1H) 2.8-2.9 (m, 1H) 4.5-4.6 (m, 1H) 5.1-5.2 (m, 1H) 5.3-5.4 (m, 1H) 6.8-6.9 (m, 2H) 7.3-7.4 (d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][N:16]([C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:17]([CH:19]1[C:24](=O)[C@@:23]2([CH3:29])[C:26]([CH3:28])([CH3:27])[C@@H:20]1[CH2:21][CH2:22]2)=[O:18])=O)(C)(C)C>ClCCl>[CH3:37][O:36][C:33]1[CH:32]=[CH:31][C:30]([N:16]2[C:17](=[O:18])[C:19]3[C@@H:20]4[C:26]([CH3:28])([CH3:27])[C@@:23]([CH3:29])([CH2:22][CH2:21]4)[C:24]=3[NH:15]2)=[CH:35][CH:34]=1
Reactant: COc1ccc(N(NC(=O)OC(C)(C)C)C(=O)C2C(=O)[C@]3(C)CC[C@H]2C3(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-n2[nH]c3c(c2=O)[C@H]2CC[C@]3(C)C2(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
Trifluoroacetic acid (15 mL) was added to a cooled (0° C.) solution of crude N′-(4-methoxy-phenyl)-N′-((1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (˜18.5 mmol) in dichloromethane (15 mL), and the solution was stirred at ˜0° C. for 15 min and then at room temperature for 2.5 h. The solvent was evaporated and the residue was dissolved in dichloromethane (150 mL) and washed with water (4×250 mL) until the pH of the aqueous washing was ˜5. The organic layer was washed with brine (150 mL), dried (magnesium sulfate), and then the flask was wrapped in aluminum and stored in a freezer overnight. The magnesium sulfate was filtered off, and the solvent was evaporated to give an orange/red semi-solid which was triturated with 10% dichloromethane/hexanes, filtered, and washed with hexanes. The solid was crushed, washed again with hexanes, and then dried under vacuum to give (4S,7R)-2-(4-methoxy-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (3.95 g, 72%) as a tan solid.