Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([NH:26]C(C)=O)[CH2:21][C:20]2[C:19]([OH:22])=[C:18]3[C:9]([C:10](=[O:24])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:23])=[C:8]([OH:25])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl>C(O)(=O)C>[C:1]([C:4]1([NH2:26])[CH2:21][C:20]2[C:19]([OH:22])=[C:18]3[C:9]([C:10](=[O:24])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[C:17]3=[O:23])=[C:8]([OH:25])[C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1(C(C)=O)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)C1(N)CCc2c(O)c3c(c(O)c2C1)C(=O)c1ccccc1C3=O
Reaction time: 1 h
Yield: 97 %

Procedure:
A mixture of 9-acetyl-9-acetamino-6,11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione (3.0 g), acetic acid (90 ml) and conc. hydrochloric acid (60 ml) was heated under reflux for 9 hours. The reaction mixture was concentrated under reduced pressure. The residue was admixed with a saturated sodium bicarbonate solution (1000 ml), followed by stirring for 1 hour. The precipitated crystals were collected by filtration to give 9-acetyl-9-amino-6,11-dihydroxy-7,8,9,10-tetrahydro-5,12-naphthacenedione (2.6 g). M.P., 190°-195° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH:11]=[N:12]O)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: ON=Cc1c[nH]c2ncnc(Cl)c12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: N#Cc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (E-4) (865 mg, 4.40 mmol, 1.0 eq) in DCM (20 mL), thionyl chloride (3.1 mL, 43.7 mmol, 10.0 eq) is added and the resulting mixture is stirred at RT overnight. The reaction mixture is concentrated in vacuo. The residue is suspended in water (60 mL) and saturated aqueous NaHCO3 is added to adjust the pH to 4. The solid is collected by filtration, rinsed with water followed by ethyl acetate to afford a first portion of product. The filtrate is then extracted with ethyl acetate (50 mL×3). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is combined with the first portion of product. The product is then re-crystallized in ethyl acetate/hexanes (1:1) and dried in vacuo to afford the final product, 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (E-5) as a pale solid.
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](C)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([OH:43])[CH:40]=[CH:41][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>>[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:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15](=[O:23])[C:14]3=[CH:24][CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([OH:43])[CH:38]=1
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc(N)c1-c1cccc(O)c1)c1nn2cccc2c(=O)n1-c1ccccc1
Yield: 13.8 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (134 mg, 0.28 mol) was treated with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (94 mg, 0.43 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (25 mg, 0.03 mol) and sodium carbonate (2M, 425 μl, 0.85 mol) according to the method described in Example 3 to give 26 mg (21% yield) of the title compound as a white solid. Purity 98%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[NH:34][C:33]([CH:35]=O)=[C:32]([CH3:37])[CH:31]=2)=[O:29])[CH2:24][CH2:23]1)[CH3:21]>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:33]4[NH:34][C:30]([C:28]([N:25]5[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:27][CH2:26]5)=[O:29])=[CH:31][C:32]=4[CH3:37])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: CCN1CCN(C(=O)c2cc(C)c(C=O)[nH]2)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN1CCN(C(=O)c2cc(C)c(C=C3C(=O)Nc4ncnc(Nc5ccc(F)c(Cl)c5)c43)[nH]2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 5-(4-ethyl-piperazine-1-carbonyl)-3-methyl-1H-pyrrole-2-carbaldehyde (74.8 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 93 mg (73%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.40 (br s, 1H, NH), 11.81 (br s, 1H, NH), 9.28 (br s, 1H), 8.33 (s, 1H), 7.72 (m, 1H), 7.33-7.45 (m, 3H), 6.58 (m, 1H), 3.68 (m, 4H, 2×CH2), 2.31-2.42 (m, 6H), 2.22 (s, 3H, CH3), 1.01 (t, J=7.2 Hz, 3H, CH2CH3). MS 510 [M++1].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[Si:11]([O:28][CH2:29][CH2:30][CH:31]=O)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Si:11]([O:28][CH2:29][CH2:30]/[CH:31]=[N:10]/[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=1)([C:24]([CH3:25])([CH3:26])[CH3:27])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NNc1cccc(Cl)c1
Reactant: CC(C)(C)[Si](OCCC=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCC/C=N/Nc1cccc(Cl)c1)(c1ccccc1)c1ccccc1

Procedure:
A solution of (3-chlorophenyl)hydrazine hydrochloride and TEA (3 mL, 21.5 mmol) and 3-(tert-butyldiphenylsilyloxy)propanal (21.5 mmol) in toluene was stirred at rt overnight. The reaction mixture was then quenched with H2O (100 mL) and extracted with EtOAc (2×). The organic layers were dried (MgSO4) and evaporated to a reddish oil. The crude product was then purified using silica gel chromatography. The desired product was isolated as a red oil. MS(ESI) m/z: 437.1 (M-Boc)+. 1H NMR (400 MHz, CDCl3) δ 7.84-7.59 (m, 4H), 7.50-7.29 (m, 6H), 7.18-6.90 (m, 1H), 6.77 (dt, J=8.1, 2.0 Hz, 1H), 3.98-3.68 (m, 2H), 2.63-2.38 (m, 2H), 1.12-0.90 (m, 9H) ppm.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[C:20]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH2:11][CH2:10][CH:9]2[CH2:21][OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N.[Li].C(O)C>CCOCC>[N:1]1([CH2:7][CH:8]2[CH:20]3[CH:12]([C:13]4[CH2:14][CH:15]=[CH:16][CH2:17][C:18]=4[CH2:19]3)[CH2:11][CH2:10][CH:9]2[CH2:21][OH:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCC2=C(Cc3ccccc32)C1CN1CCCCC1
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: CCOCC
Product: OCC1CCC2C3=C(CC=CC3)CC2C1CN1CCCCC1
Yield: 79.2 %

Procedure:
A solution of 16.3 g of crude 1,2,3,4-tetrahydro-1-(piperidinomethyl)fluorene-2-methanol, in the form of the free base, dissolved in 300 ml of ether is added to 1.5 liter of liquid ammonia. An amount of 8.4 g (1.2 moles) of lithium ribbon is added over 1.5 hr. and then 150 ml of abs. ethanol added over 60 minutes; the ammonia is evaporated and the residue cooled and partitioned between 400 ml of water and 300 ml of ether. The aqueous layer is washed with 2 × 250 ml of ether, and then the extracts are combined, washed with sat. sodium chloride solution, dried, and evaporated in vacuo to give 13.1 g (0.0434 moles) of the above titled compound.
Reaction SMILES: Cl[C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C@H:11]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C@@H:12]2[OH:21])[CH2:4][C@@H:3]1[OH:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:28])[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: C[C@]12C[C@H](Cl)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Product: CN1CCN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]43)C[C@@H]2O)CC1
Yield: 67 %

Procedure:
The compound was prepared according to Example 11 from 2β-chloro-3α,17β-dihydroxy-16β-piperidino-5α-androstane and from N-methyl-piperazine. Yield: 67.0% of 2β-N-methyl-piperazino-16β-piperidino-3α,17β-dihydroxy-5α-androstane; m.p. 230°-234° C; [α]D25 = +81.7 (c = 1 in chloroform).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([OH:8])[C:5]([OH:7])=[O:6].[N+:9]([C:12]1[CH:22]=[CH:21][C:15]([CH2:16][O:17][C:18](Cl)=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>[OH-].[Na+].CCOCC>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][C:18]([NH:1][CH2:2][CH2:3][C@H:4]([OH:8])[C:5]([OH:7])=[O:6])=[O:19])=[CH:21][CH:22]=1)([O-:11])=[O:10]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Reactant: NCC[C@H](O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(NCC[C@H](O)C(=O)O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A 2.82 g portion of (2S)-4-amino-2-hydroxybutyric acid was dissolved in 15 ml of 2N sodium hydroxide, and to the solution cooled on an ice bath were simultaneously added dropwise 6.13 g of p-nitrobenzyloxycarbonyl chloride dissolved in ether and 7.5 ml of 4N sodium hydroxide. After 2 hours of stirring at the same temperature, the solution was washed with ether, an aqueous layer was adjusted to acidic with concentrated hydrochloric acid, and a precipitated solid material was collected by filtration, washed with water and then dried to yield 4.48 g of (2S)-4-(p-nitrobenzyloxycarbonyl) amino-2-hydroxybutyric acid.
Reaction SMILES: [CH2:1]([N:9]=[C:10]=[S:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:12]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:12]1([CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]2[CH2:20][CH2:21][N:22]([C:10](=[S:11])[NH:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:23][CH2:24]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: CCCCCCCCN=C=S
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=S)N1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 6.0 g (0.035 mole) of n-octylisothiocyanate was dissolved in 25 ml of toluene, treated with 8.80 g (0.035 mole) of 4-diphenylmethylpiperidine and stirred at 25° for twelve hours. The mixture was cooled, filtered and evaporated. Chromatography of the residue through silica gel using chloroform as an eluent afforded a brown oil, 4-(diphenylmethyl)-N-octyl-1- piperidinecarbothioamide. A mixture of 1.0 g (0.0024 mole) of this material, 3 g of Raney Nickel and 15 ml of isopropanol was refluxed three hours, cooled, and filtered. Evaporation of the filtrate afforded an oil which was converted to a fumarate identified as 4-(diphenylmethyl)- 1-[(octylimino)methyl]piperidine (E)-2-butenedioate (1:1) hydrate by thin layer chromatography.
Reaction SMILES: [C:1]([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>C1COCC1>[C:1]([NH:20][C:21]1[CH:22]=[C:23]([CH2:27][CH2:28][OH:29])[CH:24]=[CH:25][CH:26]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1cccc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1cccc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a stirred suspension of [3-(tritylamino)phenyl]acetic acid (30.00 g, 76.24 mmol) in THF (126 mL) under nitrogen at 0° C. was added dropwise a solution of borane dimethyl sulfide complex in THF (2 M, 76.2 mL, 152 mmol) over a period of 45 min while maintaining the temperature at ≦1.8° C. The resulting slightly yellow homogeneous solution was stirred at room temperature for 18 h. Saturated aqueous sodium bicarbonate solution (˜300 mL) was added slowly (strongly effervescent upon initial addition) and the resulting mixture was stirred at room temperature overnight. The mixture was extracted with EtOAc (2×˜330 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (25.6 g, 86% yield) as a white solid.
Reaction SMILES: [C:1]1([C:7]2([N:13]3[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+].Cl.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:26][CH:16]1[CH2:17][CH2:18][N:13]([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:14][CH2:15]1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(C2(c3ccccc3)CCCCC2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: NC1CCN(C2(c3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(1-Phenylcyclohexyl)-4-piperidone (0.245 g) and ammonium acetate (1 g) were dissolved in 3.5 ml dry methanol. After stirring at room temperature for 10 minutes, sodium cyanoborohydride (0.1 g) was added and the reaction stoppered. After 20 hours, 0.1 ml concentrated hydrochloric acid was added followed by 10 ml water and the mixture was stirred for 1.5 hours. The solution was basified with potassium carbonate to pH 9 and extracted with methylene chloride. The methylene chloride was dried over Na2SO4 and removed in vacuo. The product distilled as a colorless, clear oil at 90°-130° C. in vacuo (about 5 mmHg).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:18]([OH:22])[C:19](O)=[O:20])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][NH2:37].O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@@H:9]1[C:14]([NH:16][CH:17]([CH:18]([OH:22])[C:19](=[O:20])[NH:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Reactant: NCc1ccccn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCc1ccccn1)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 33.9 %

Procedure:
3-((R)-1-benzyl-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid (300 mg, 0.757 mmol) and pyridin-2-ylmethanamine (94 μl, 98 mg, 0.908 mmol) were dissolved in 13 ml dichloromethane and cooled to 5° C. At this temperature 1-hydroxybenzotriazole hydrate (127 mg, 0.832 mmol), EDC (160 mg, 0.832 mmol) and triethylamine (1.58 ml, 127 mg, 1135 mmol) were successively added. After stirring overnight at room temperature the reaction mixture was concentrated under reduced pressure, water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were successively washed with aq. saturated NaHCO3 solution and brine, dried over Na2SO4 and the solvent was removed under reduced pressure. Column chromatography on silica gel using dichloromethane/MeOH (97/3), followed by dichloromethane/MeOH (95/5), resulted in the title compound (125 mg, yield: 34%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].Br[CH2:42][C:43]([O:45][CH3:46])=[O:44]>>[C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH2:42][C:43]([O:45][CH3:46])=[O:44])[CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Li+]
Product: COC(=O)CN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)C1c1ccccc1C
Yield: 31.9 %

Procedure:
In a manner similar to the method described in example 24c, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (1.02 g, 1.86 mmol) prepared in example 24b was reacted with LiH (86 mg, 10.9 mmol) (Aldrich) and methyl bromoacetate (0.57 g, 3.72 mmol) (Aldrich) to give racemic 2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-[(methoxycarbonyl)-methyl]-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester as a white solid (Yield: 0.37 g, 32%).
Reaction SMILES: [C-]#N.[Na+].Br[C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2.[CH3:24][NH:25]CCNC.[OH-].[NH4+]>[Cu]I.O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([S:14]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([C:24]#[N:25])=[CH:13][CH:12]=3)[CH:8]=[CH:9]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CNCCNC
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(Br)ccc32)cc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C#N)ccc32)cc1
Temperature: 110 °C
Reaction time: 24 h
Yield: 85.9 %

Procedure:
An oven dried screw cap test tube was charged with NaCN (106 mg, 2.163 mmol), dried KI (60 mg, 0.361 mmol, 20 mol %), CuI (34 mg, 0.178 mmol, 10 mol %), 5-bromo-1-(toluene-4-sulfonyl)-1H-indole (630 mg, 1.803 mmol), evacuated and backfilled with argon three times. N,N′-dimethylethylenediamine (195 μL, 1.832 mmol) and anhydrous toluene (1.1 mL) were added under argon. The tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 24 h. The resulting yellow suspension was cooled to room temperature, 2 mL of ethyl acetate, 1 mL of ammonium hydroxide (30%) and 1 mL of water were added. The mixture was stirred at 25° C. for 10 min, then the organic layer was separated and the aqueous layer was extracted three times with ethyl acetate (3×2 mL). The organic layers combined were washed with 5 mL of water and dried over MgSO4. The solvent was removed at reduced pressure. Purification of the residue by flash chromatography on silica gel (2×15 cm; hexane/ethyl acetate 10:1) provided 459 mg (86% yield) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:24]=[C:23]([CH3:25])[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[OH:16])=[C:9]([CH3:26])[CH:8]=2)=[N:3]1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[S:29]>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH3:26])[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[O:16][C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[S:29])=[C:23]([CH3:25])[CH:24]=2)=[N:3]1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1nccn1C
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(OC(=S)Oc1ccccc1)c1nccn1C
Yield: 78.5 %

Procedure:
To a solution of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-hydroxy-butyl]-1-methylimidazole (690 mg, 1.94 mmol) in 30 ml of acetonitrile was added at 20° C. 473 mg (3.88 mmol) of DMAP and 403 mg (2.33 mmol) of phenyl chlorothioformate, and the mixture was stirred at 20° C. for 3 h. The solvent was concentrated in vacuo and the residue was partitioned between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/1-4/1) to afford 750 mg (78%) of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-phenoxythiocarbonyloxy-butyl]-1-methylimidazole, as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([N+]([O-])=O)[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].P([O-])([O-])([O-])=[O:21].[K+].[K+].[K+].CCOCC>CO.[Cl-].[Cl-].[Ti+2]>[CH3:1][CH:2]([C:8](=[O:21])[CH2:9][CH:10]=[C:11]([CH3:13])[CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: O=P([O-])([O-])[O-]
Reactant: COC(=O)CC(C)C(CC=C(C)C)[N+](=O)[O-]
Agent: [Ti+2]
Agent: C[O-]
Agent: [Cl-]
Solvent: CCOCC
Solvent: CO
Product: COC(=O)CC(C)C(=O)CC=C(C)C
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of methyl 3,7-dimethyl-4-nitro-6-octenoate (24.55 g, 0.107 m) in methanol (10 ml) is added dropwise to a solution of sodium methoxide (6.37 g, 0.118 m) in methanol (250 ml) at room temperature under nitrogen. The mixture is stirred for 1 hour, added to a mixture of 20% titanous chloride (170 ml, 0.267 m) and pH 7 buffer (potassium phosphate monobasicsodium hydroxide buffer) solution (340 ml). The resulting mixture is stirred for 30 minutes after which it is treated with ether (1 l). The organic phase is separated, dried (Na2SO4) and evaporated in vacuo to give the crude product (15.4 g). This material is purified by column chromatography on silica gel (300 g, 2% ethyl acetate in hexane) to give methyl 3,7-dimethyl-4-oxo-6-octenoate as a colorless liquid (6.8 g, 35%). ir (neat) 1705 and 1735 cm-1 ; nmr (CDCl3) δ: ##STR9##
Reaction SMILES: [NH2:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5]([CH2:6][N:7]([CH3:13])[C:8]2=[O:12])=[CH:4][CH:3]=1.[CH2:14]([O:16][C:17]1[C:18](=O)[C:19](=[O:24])[C:20]=1[O:21]CC)[CH3:15]>C(O)C>[CH2:14]([O:16][C:17]1[C:20](=[O:21])[C:19](=[O:24])[C:18]=1[NH:1][C:2]1[C:10]([OH:11])=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][N:7]([CH3:13])[C:8]2=[O:12])[CH3:15]
Reactant: CN1Cc2ccc(N)c(O)c2C1=O
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc3c(c2O)C(=O)N(C)C3)c(=O)c1=O
Temperature: 60 °C
Yield: 72.7 %

Procedure:
A mixture of 0.19 g (1.07 mmol) of 6-amino-7-hydroxy-2-methyl-2,3-dihydroisoindol-1-one and 0.80 g (4.70 mmol) of 3,4-diethoxycyclobut-3-ene-1,2-dione in 10 ml of ethanol was heated at 60° C. for 24 hours. The reaction medium was concentrated and was taken up with diethyl ether with stirring (formation of a precipitate). The solid obtained was filtered off, washed twice with diethyl ether and dried. 235 mg of product were obtained. Yield=73%.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=1)[CH2:13][CH2:14][N:41]1[CH2:42][CH2:43][CH:38]([C:36]([C:28]2[S:27][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=2)=[O:37])[CH2:39][CH2:40]1)[C:3](=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(c1nc2ccccc2s1)C1CCNCC1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3s2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 2.7 using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)benzamide and 4-(benzthiazole-2-carbonyl)piperidine to give the title compound.