Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21]Cl)=[N:19][N:18]=[C:17]1[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].[I-].[K+].[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])=[N:19][N:18]=[C:17]1[CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]
Reactant: O=C(NCc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl)OCc1ccccc1
Reactant: CCNCC
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(CC)Cc1nnc(CNC(=O)OCc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl

Procedure:
To a solution of 2',5-dichloro-2-(3-carbobenzoxyaminomethyl-5-chloromethyl-4H-1,2,4-triazol-4-yl)-benzophenone (1.32 g) in methanol (20 ml) and chloroform (20 ml), potassium iodide (0.4 g) and diethylamine (3 ml) are added, and the resultant mixture is refluxed for 5 hours. The reaction mixture is evaporated under reduced pressure to remove the solvent, and the residue is extracted with ethyl acetate. The ethyl acetate layer is washed with water, dried, and evaporated under reduced pressure to remove the ethyl acetate. The residue is treated with ether to give 2',5-dichloro-2-(3-carbobenzoxyaminomethyl-5-diethylaminomethyl-4H-1,2,4-triazol-4-yl)-benzophenone (1.1 g). The product is recrystallized from ether-ethyl acetate to give crystals melting at 89° to 94° C.
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[F:9][C:10]([F:22])([F:21])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH:19]=O)=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:7][O:8][CH:19]([CH2:18][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:9])([F:21])[F:22])=[CH:12][CH:13]=2)[O:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC(CO)CO
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CCCC1COC(CCc2ccc(C(F)(F)F)cc2)OC1
Yield: 36.1 %

Procedure:
2-Propyl-1,3-propanediol 17.4 g (147 mol) and the above 3-(4-trifluoromethylphenyl)propanal 20.0 g (98.9 mmol) were dissolved in toluene 200 ml, and PTS 1 g was added, and the mixture was refluxed with heating for 3 hours while removing water formed with Dien-Stark. The reactant was washed with a saturated sodium bicarbonate aqueous solution, and then with saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene), and recrystallized twice from ethanol to obtain 5-propyl-2-(2-(4-trifluoromethylphenyl)ethyl)-1,3-dioxane 10.8 g (35.7 mmol). The yield was 36.1% from 3-(4-trifluoromethylphenyl) propanal.
Reaction SMILES: [NH2:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9](OC(=O)C)(=[O:11])[CH3:10]>C(O)(=O)C>[C:9]([NH:1][CH:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:11])[CH3:10]
Reactant: CC(C)C(N)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)NC(C(=O)O)C(C)C
Reaction time: 0.17 h

Procedure:
11.7 g (0.10 mol) D,L-Valine were dissolved in 100 ml of acetic acid and treated with 11.2 g (0.11 mol) acetic anhydride at 90° C. Concentration was carried out after 10 minutes at 15 mbar and 100° C. After HPCL analysis the crystalline residue was shown to contain 95.6% Acetyl-D,L-valine and 2.8% N-Acetyl-D,L-valyl-D,L-valine.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22](OC)=[O:23].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>CO>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)[CH:10]=2)[C:5]([CH3:21])=[N:4][C:3]=1[C:22]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:23]
Reactant: COC(=O)c1nc(C)c2ccc(Oc3cc(F)cc(F)c3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3cc(F)cc(F)c3)ccc12
Temperature: 110 °C

Procedure:
A pressure glass reaction flask which included top threads for a screw cap lid can be fitted with a magnetic stirrer, charged with 8e, glycine (about 3 molar equivalents), methanol, and a sodium methoxide solution (with 1.2 molar eqivalents NaOCH3) and sealed. The reaction can then be heated to 110° C. for at least 6 h during which time the reaction forms a yellow suspension. The reaction can then be cooled to 20-25° C. and evaluated by HPLC. The reaction can be continued until less than 1% 8e remains as determined by HPLC, filtered, washed with methanol, dried under vacuum, dissolved in water and extracted with ethyl acetate to remove impurities to below 0.1%. The ethyl acetate can be removed and an acetic acid solution (with 3 molar eqivalents acetic acid) can be added over one hour. The suspension can be stirred at room temperature for at least 3 hours, filtered, and the solid washed with water (3×), cold acetone (5-10° C., 2×) and evaluated for impurities by HPLC. If acetone removable impurities are present, the flask can be charged with acetone and refluxed for at least 8 h, slowly cooled to 5-10° C., stirred for at least 2-3 h, filtered, washed with cold acetone (5-10° C., 3×) and dried under vacuum to obtain 2-[4-hydroxy-1-methyl-6-(3,5-difluoro-phenoxy)-isoquinoline-3-carboxamido]acetic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)(=[O:32])=[O:31])=[CH:26][C:25]=1[S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)(=[O:44])=[O:43].[CH3:54][C:55]1[CH:60]=[CH:59][C:58]([SH:61])=[CH:57][CH:56]=1.[OH-].[Na+]>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH3:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1.[CH3:54][C:55]1[CH:60]=[CH:59][C:58]([S:61][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)(=[O:32])=[O:31])=[CH:26][C:25]=2[S:42]([CH2:45][CH2:46][CH2:47][N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)(=[O:44])=[O:43])=[CH:57][CH:56]=1
Reactant: O=S(=O)(CCCN1CCOCC1)c1ccc(Cl)c(S(=O)(=O)CCCN2CCOCC2)c1
Reactant: Cc1ccc(S)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(Sc2ccc(S(=O)(=O)CCCN3CCOCC3)cc2S(=O)(=O)CCCN2CCOCC2)cc1

Procedure:
A stirred mixture of 10.0 g (0.0119 mole) of 4,4'-((4-chloro-1,3-phenylene)bis(sulfonyl-3,1-propanediyl))bismorpholine bis(4-methylbenzenesulfonate), 1.6 g (0.012 mole) of 90% p-thiocresol and 1.5 g (0.038 mole) of sodium hydroxide in 55 ml of water was warmed for 30 minutes at 65° to 70° C., during which time the crude product separated as a hard gum. The aqueous phase was decanted, and the gum was dissolved in a minimum of warm propanol-2. This solution was treated with a propanol-2 solution of an excess of p-toluenesulfonic acid monohydrate. On cooling, the solution yielded a crystalline product. Recrystallization from propanol-2 gave the pure product, 4,4'-((4-((4-methylphenyl)thio)-1,3-phenylene)bis(sulfonyl-3,1-propanediyl))bismorpholine bis(4-methylbenzenesulfonate), as buff crystals, m.p. 215.5°-216.5° C.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:31])[C:13]([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH2:14][CH2:15]O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]12([N:11]3[CH2:15][CH2:14][C:13]([CH2:17][C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)([CH2:24][C:25]4[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=4)[C:12]3=[O:31])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(CCO)(Cc1ccncc1)Cc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1N(C23CC4CC(CC(C4)C2)C3)CCC1(Cc1ccncc1)Cc1ccncc1
Reaction time: 18 h
Yield: 47.7 %

Procedure:
Under N2 atmosphere were combined N-adamantan-1-yl-4-hydroxy-2,2-bis-pyridin4-ylmethyl-butyramide (50 mg, 0.24 mmol), triphenylphosphine (63 mg, 0.24 mmol), and diisopropylazodicarboxylate (0.047 ml, 0.24 mmol) in 5 ml THF and the resulting solution was allowed to stir for 18 hours. The reaction mixture was then placed directly on a silica gel column and eluted with 85:15 mix of EtOAc/MeOH to yield 46 mg of product as a gum which in turn could be crystallized from isopropylether/hexane to yield the desired product as a white solid, m.p. 163.5°-165° C.
Reaction SMILES: C/C=C(/C([O:7][C@@H:8]1[C:69]([CH3:71])([CH3:70])[CH2:68][CH:67]2[C@@:10]([CH2:74][OH:75])([C@H:11]([OH:73])[CH2:12][C@@:13]3([CH3:72])[C@:18]4([CH3:66])[CH2:19][CH2:20][CH:21]5[C@:26]([CH2:28][OH:29])([CH3:27])[CH:25]([O:30][C@@H]6O[C@H](C(O)=O)[C@@H](O[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[CH2:24][CH2:23][C@:22]5([CH3:65])[CH:17]4[CH2:16][CH:15]=[C:14]32)[C@H:9]1[O:76]C(C)=O)=O)\C.C/C=C(\C(O[C@@H:87]1[C:148](C)([CH3:149])[CH2:147][CH:146]2[C@@:89](CO)([C@H:90]([OH:152])[CH2:91][C@@:92]3([CH3:151])[C@:97]4([CH3:145])[CH2:98][CH2:99][CH:100]5[C@:105]([CH2:107][OH:108])([CH3:106])[CH:104]([O:109][C@@H]6O[C@H](C(O)=O)[C@@H](O[C@@H]7O[C@H](CO)[C@@H](O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[CH2:103][CH2:102][C@:101]5([CH3:144])[CH:96]4[CH2:95][CH:94]=[C:93]32)[C@H:88]1[O:155]C(C)=O)=O)/C.Cl.[CH2:160]([OH:162])[CH3:161]>>[CH3:70][C:69]1([CH3:71])[CH:8]([OH:7])[CH:9]([OH:76])[C:10]2([CH2:74][OH:75])[CH:67]([C:14]3[C:13]([CH3:72])([CH2:12][CH:11]2[OH:73])[C:18]2([CH3:66])[CH:17]([C:22]4([CH3:65])[CH:21]([CH2:20][CH2:19]2)[C:26]([CH2:28][OH:29])([CH3:27])[CH:25]([OH:30])[CH2:24][CH2:23]4)[CH2:16][CH:15]=3)[CH2:68]1.[CH3:144][C@@:101]12[C@H:96]3[CH2:95][CH:94]=[C:93]4[C@@H:146]5[CH2:147][C:148]([CH3:149])([CH3:87])[C@@H:161]6[O:152][C@@H:90]([C@@:89]5([CH2:88][OH:155])[C@H:160]6[OH:162])[CH2:91][C@@:92]4([CH3:151])[C@:97]3([CH3:145])[CH2:98][CH2:99][C@H:100]1[C@:105]([CH2:107][OH:108])([CH3:106])[C@@H:104]([OH:109])[CH2:103][CH2:102]2
Reactant: C/C=C(/C)C(=O)O[C@H]1[C@H](OC(C)=O)[C@@]2(CO)C(CC1(C)C)C1=CCC3[C@@]4(C)CCC(O[C@@H]5O[C@H](C(=O)O)[C@@H](O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)[C@](C)(CO)C4CC[C@@]3(C)[C@]1(C)C[C@H]2O
Reactant: C/C=C(\C)C(=O)O[C@H]1[C@H](OC(C)=O)[C@@]2(CO)C(CC1(C)C)C1=CCC3[C@@]4(C)CCC(O[C@@H]5O[C@H](C(=O)O)[C@@H](O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O)[C@](C)(CO)C4CC[C@@]3(C)[C@]1(C)C[C@H]2O
Reactant: CCO
Agent: Cl
Product: CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(CO)C5CCC4(C)C3(C)CC(O)C2(CO)C(O)C1O
Product: CC1(C)C[C@H]2C3=CC[C@@H]4[C@@]5(C)CC[C@H](O)[C@](C)(CO)[C@@H]5CC[C@@]4(C)[C@]3(C)C[C@H]3O[C@@H]1[C@H](O)[C@]32CO

Procedure:
In Justus Liebigs Annalen der Chemie 1963, 669, 183-188 Kuhn R. and Loew I. described the hydrolysis of escin in the solution of 4 N hydrochloric acid in ethanol, the separation of the intermediate, and its subsequent hydrolysis under basic conditions with potassium hydroxide in methanol. The hydrolysis products were separated by chromatography on silica gel, yielding protoescigenin and escigenin.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([N:9]1[CH:18]=[C:17]3[CH2:19][CH2:20][CH2:21][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]1=[O:22])[CH2:2]2.N12CCC(CC1)C(N1C(O)C3CCCC4C3=C(C=CC=4)C1=O)C2>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([N:9]1[CH:18]=[C:17]3[CH2:19][CH2:20][CH2:21][C:15]4[C:16]3=[C:11]([CH:12]=[CH:13][CH:14]=4)[C:10]1=[O:22])[CH2:2]2
Reactant: O=c1c2cccc3c2c(cn1C1CN2CCC1CC2)CCC3
Agent: O=C1c2cccc3c2C(CCC3)C(O)N1C1CN2CCC1CC2
Product: O=c1c2cccc3c2c(cn1[C@@H]1CN2CCC1CC2)CCC3

Procedure:
A preferred process for preparing 2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one is that in which the 2-(1-azabicyclo[2.2.2]oct-3-yl)-3-hydroxy-2,3,3 a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one is 2-(1-azabicyclo[2.2.2]oct-3S-yl)-3-hydroxy-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one and is dehydrated to give (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1H-benz[de]isoquinolin-1-one, preferably wherein the dehydration is catalyzed with hydrochloric acid or sulfuric acid, and the (S)-2-(1-azabicyclo[2.2.2]oct-3S-yl)-3-hydroxy-2,3,3a,4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one is prepared by the preferred process described above.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(CC)CC)C.[CH3:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH:24]=O.C([BH3-])#N.[Na+]>CO>[CH2:12]([O:11][C:9]([C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@@H:3]1[NH:2][CH2:24][CH2:23][C:22]([CH3:27])([CH3:26])[CH3:21])=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: CC(C)(C)CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1NCCC(C)(C)C
Reaction time: 18 h
Yield: 1.3 %

Procedure:
To a solution of ethyl cis-2-amino-1-cyclohexanecarboxylate hydrochloride (1.00 g, 4.6 mmol) in methanol (10 mL) was added triethylamine (0.72 mL, 5.1 mmol), 3,3-dimethylbutyraldehyde (0.67 mL, 5.1 mmol), and sodium cyanoborohydride (213.0 mg, 3.2 mmol) at 25° C. After stirring for 18 h, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-50% ethyl acetate in hexanes) to afford the desired product, cis-2-(3,3-dimethylbutylamino)-cyclohexanecarboxylic acid ethyl ester (31.2 mg, 0.061 mmol, 25%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 0.99 (9H, s), 1.22-1.29 (1H, m), 1.35 (3H, t, J=7.0 Hz), 1.40-1.51 (1H, m), 1.58-1.77 (5H, m), 1.90-1.94 (1H, m), 2.12-2.15 (1H, m), 2.37-2.40 (1H, m), 2.96 (1H, bs), 3.09 (1H, bs), 3.22-3.33 (2H, m), 4.21-4.35 (2H, m). LC-MS (ESI) calcd for C15H29NO2 255.22, found 256.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2C)[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=NO)[CH:5]=[CH:6][CH:7]=1.C1(B(O)[OH:33])C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1cccc(Br)c1
Product: O=C(CC(c1ccccc1)c1cccc(Br)c1)c1ccncc1

Procedure:
In analogy to example 1, step 1, from (E)-3-(3-bromo-phenyl)-1-pyridin-4-yl-propenone (example 11) and phenylboronic acid was prepared the title compound as a colorless oil, MS (ESI+): m/z=380.1 ([M+H]+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=3)[C:5]2=[CH:4][CH:3]=1.C[Si]([C:45]#[CH:46])(C)C.C(N(CC)CC)C.[OH-].[Na+]>CN(C)C=O.CO.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:45]#[CH:46])[CH:27]=[CH:26][C:25]=3[O:31][C:32]3[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(Oc2ccc(I)cc2C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)cc(C)n1
Agent: [Cu]I
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C#Cc1ccc(Oc2cc(C)nc(C)c2)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Yield: 53.4 %

Procedure:
In a manner similar to the method described in example 6a, racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,6-dimethyl-4-pyridinyloxy)-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.62 g, 0.9 mmol) was reacted with trimethylsilyl acetylene (0.89 g, 9 mmol), CuI (5 mg), triethylamine (2.74 g, 27 mmol), and dichlorobis(triphenylphosphine) palladium (0) (50.7 mg, 0.07 mmol) in anhydrous N,N-dimethylformamide, and then treated with aqueous NaOH in methanol to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2,6-dimethyl-4-pyridinyloxy)-5-ethynyl-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a pale yellow solid (Yield 0.28 g, 53%)
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=O)[CH:17]=[CH:18][C:19]=1[Cl:20].[C:25]1([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH:34]([CH2:38][OH:39])[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:33][CH:34]2[CH2:38][OH:39])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: OCC1CN(Cc2ccccc2)CCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCN(Cc2ccccc2)CC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
1,1'-Carbonyldiimidazole (236 mg) was added to a stirred solution of 3,4-dichlorophenylacetic acid (314 mg) in dry dichloromethane (6 ml) at room temperature under nitrogen. The resulting solution was stirred at room temperature for 1 h and added dropwise to a cooled solution of 4-(phenylmethyl)-2-piperazinemethanol (300 mg) in dry dichloromethane (3 ml) and stirred at room temperature for 19 h. The reaction mixture was diluted with dichloromethane (5 ml) and washed with 2N sodium carbonate solution (3×10 ml). The organic layer was dried and evaporated to give an oil which was purified by flash column chromatography eluting with dichloromethane:ethyl acetate (2:1) to dichloromethane:ethyl acetate (1:1) to dichloromethane:methanol (9:1) to give the title compound as a solid (200 mg). m.p. 148°-150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14].[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21].[Cl-].[Al+3].[Cl-].[Cl-]>Cl>[Cl:1][C:2]1[C:13]([C:20](=[O:21])[C:16]2[S:15][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:14]
Reactant: O=C(Cl)c1cccs1
Reactant: O=C(O)C1Cc2ccc(Cl)c(Cl)c2O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1cccs1)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Temperature: 0 °C

Procedure:
To a well stirred mixture of 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid (2.6 g.) and thiophene-2-carbonyl chloride (4 ml.) protected from the atmosphere with a calcium chloride tube is added anhydrous aluminum chloride (6.0 g.) over a one-hour period. The reaction mixture is heated at 80°-90° C. for 31/2 hours then poured into ice water (100 ml.) and hydrochloric acid (10 ml.). The product is extracted into ether, washed with water, then extracted into aqueous sodium bicarbonate (100 ml.) from which the sodium salt of the product precipitates. The sodium salt of the product is placed in a separatory funnel with dilute hydrochloric acid (100 ml.) and ether (100 ml.) and shaken until the solid dissolves. The ether solution is washed with water, brine, dried over magnesium sulfate and the ether distilled at reduced pressure. The (±)6,7-dichloro-2,3-dihydro-5-(2-thenoyl)benzofuran-2-carboxylic acid melts at 187° C. after crystallization from butyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.ClC[C:12]([OH:14])=[O:13].[CH2:15]([OH:17])C.[H-].[Na+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]([CH:15]=[O:17])[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(CO)c1
Reactant: O=C(O)CCl
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cccc(C(C=O)C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of 3-methylbenzyl alcohol (4.93 g, 40 mmol), chloroacetic acid (7.68 g, 81 mmol), and ethanol (0.04 mL) in 100 mL of anhydrous tetrahydrofuran was added to a mixture of sodium hydride (16.12 g, 403 mmol) in 50 mL anhydrous tetrahydrofuran dropwise over 55 minutes at 0° C. The cooling bath was removed and the solution was heated to reflux for 14.25 hours. The solution was cooled to room temperature, quenched with water and extracted with ether. The aqueous layer was acidified, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give (3-methylphenyl)-3-oxo-propanoic acid as an orange oil (6.58 g) which also contained chloroacetic acid. The oil was used in the next step without purification.
Reaction SMILES: CCO[C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[O:5].[NH2:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=2[N:20]=1>CC(C)=O>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2[N:20]=[C:16]([NH:15][C:4](=[O:5])[CH2:6][C:7](=[O:8])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[S:17][C:18]=2[CH:24]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: COc1ccc2nc(N)sc2c1
Solvent: CC(C)=O
Product: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1

Procedure:
Ethyl benzoyl acetate (9.5 ml) and 2-amino-6-methoxy benzothiazole (9.01 g) are heated to 140° under house vacuum for 2 hours. After cooling, the residue is taken up in acetone and filtered. The precipitate is dissolved in hot DMF to give an amide, N-(6-methoxybenzothiazol-2-yl)-3-oxo-3-phenylpropanamide (II).
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([S-:12])#[N:11].[K+].CN(C=O)C>C1(C)C=CC=CC=1.O>[S:12]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:10]#[N:11]
Reactant: O=Cc1ccc(I)cc1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#CSc1ccc(C=O)cc1
Temperature: 140 °C
Yield: 20.2 %

Procedure:
Under an argon atmosphere, a mixture of 4-iodobenzaldehyde (232 mg, 1.00 mmol), KSCN (95.0 mg, 1.00 mmol), CuSCN (120 mg, 1.00 mmol) and DMF (7.5 mL) was heated with stirring in an oil bath maintained at 140° C. for 12 h. After cooling, the mixture was diluted with toluene and water, and then filtered through a Celite bed. The aqueous phase was extracted with toluene, the organic fractions were combined and washed with water, dried and concentrated. The resulting dark oil was chromatographed on silica gel using centrifugal preparative chromatography to obtain off-white crystals (33 mg, 20%). mp 82-83° C.; 1H NMR (CDCl3) δ7.63, 7.92 (AA′BB′, 2H, ArH), 10.01 (s, 1H, CHO); 13C NMR (CDCl3) δ109.4, 129.3, 131.6, 132.9, 191.3; EI-MS obsd 163.0092, calcd exact mass 163.0092 (C8H5NOS); Anal. Calcd. for C8H5NOS: C, 58.88; H, 3.09; N, 8.58; S, 19.65; Found: C, 58.85; H, 2.99; N, 8.61; S, 19.68.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([NH2:23])[CH2:21][NH2:22]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][CH:10]([NH:22][CH2:21][CH2:20][NH2:23])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCN
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: NCCNC1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 4,4-diphenylcyclohexanone (2.5 g) and ethylenediamine (10 g) and p-toluenesulfonic acid (100 mg) in benzene (200 mL) was refluxed for 4 h in Dean-Stark trap to remove the water that formed. Solvent was evaporated and the residue was redissolved in methanol (60 mL) and cooled to 0° C. To this, sodium borohydride (2 g) was added in portions and the mixture was stirred at room temperature for 3 h. Solvent was evaporated, the residue was dissolved in dichloromethane (300 mL), washed with brine (3×500 mL), dried (potassium carbonate), and the solvent evaporated to leave the product as a colorless viscous oil (2.94 g, 100%). The 1H-NMR showed this product to be pure and was used in the next step without any further purification.