Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:14]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1)(=[O:16])[CH3:15]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(=O)c1ccc2c(c1)Cc1ccccc1-2

Procedure:
Fluorene is acylated by acetic anhydride in an organic solvent, e.g., chlorobenzene in the presence of aluminum chloride at 18°-20° C at the initial stage of the process followed by heating to 40°-50° C to obtain 2-acetylfluorene at a yield of up to 74 weight percent. The latter is oxidized by chromic acid or by the salts thereof in an acetic acid medium at 50°-90° C for 4-12 hours to obtain 2-acetylfluorenone in a yield of 27-68 weight percent as calculated for 2-acetylfluorene, or 20-50 weight percent when calculated for fluorene. The resultant product is brominated in an organic solvent, e.g., chloroform at 50°-60° C or in acetic acid at 100°-110° C. The yield of the thus-formed 2-ω-dibromoacetylfluorenon equals 71-88 weight percent as calculated for 2-acetylfluorenone, or 35.4-44 weight percent when calculated for fluorene. Then 2-ω-dibromoacetylfluorenone is made to react with morpholine when heated to 50°-98° C for 1-2 hours to obtain 2-ω-bismorpholinoacetylfluorenone in a yield of 40-85 weight percent as calculated for 2-ω-dibromoacetylfluorenone, or 17.6-37.4 weight percent when calculated for fluorene.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:9]2[CH:17]=[CH:18][C:19]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[OH:30])=O)=[CH:20][C:8]=2[N:7]=1)(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].O1C2C=CC(C3C=CC4N(C5CCOCC5)C(COC(=O)C)=NC=4C=3)=CC=2N=C1>C1(C)C=CC=CC=1>[O:30]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:21]1[C:19]1[CH:18]=[CH:17][C:9]2[N:10]([CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)[C:6]([CH2:5][OH:4])=[N:7][C:8]=2[CH:20]=1
Reactant: CC(=O)OCc1nc2cc(C(=O)Nc3ccccc3O)ccc2n1C1CCOCC1
Agent: CC(=O)OCc1nc2cc(-c3ccc4ocnc4c3)ccc2n1C1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: O
Product: OCc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCOCC1

Procedure:
An eggplant flask (50 mL) was charged with 2-acetoxymethyl-5-(2-hydroxyanilinocarbonyl)-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 13-1) (0.50 g, 1.22 mmol) toluene (6.3 mL), and p-toluenesulfonic acid hydrate (1.60 g, 8.41 mmol), and this was refluxed for 1.5 hours. After being allowed to cool, the liquid was made neutral with saturated aqueous sodium hydrogen carbonate. The precipitated crystals were filtered off and washed successively with toluene and hexane, then dried under reduced pressure with heating to yield a mixture of the title compound and 5-(benzoxazol-5-yl)-2-acetoxymethyl-1-(tetrahydropyran-4-yl)benzimidazole (0.25 g: estimated to contain 0.57 mmol and 0.13 mmol, respectively, according to 1H-NMR) as a white powder. This mixture and methanol (7 mL) were charged to an eggplant flask (50 mL) to which was then added an aqueous solution of lithium hydroxide (1 M, 0.3 mL), and after stirring for 30 m the liquid was made pH 6 with dilute hydrochloric acid (1 M). The precipitated crystals were filtered off, washed with distilled water, and dried under reduced pressure with heating to yield the title compound (0.07 g, 16.4% yield) as a light pinkish-white powder.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:23])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[OH:25].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>CC(=O)CC>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[CH:12][C:11]=2[CH3:23])=[C:6]([F:24])[CH:5]=[CH:4][C:3]=1[O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2C)c1F
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methyl-phenyl]methyl amino]phenol (124 mg, 0.361 mmol, 1.0 eq) and Cs2CO3 (176.5 mg, 0.542 mmol, 1.5 eq) in 2-Butanone (10 mL) was added ethyl bromoacetate (72.4 mg, 0.433 mmol, 1.2 eq) and the reaction stirred 30 min. The reaction was filtered and the filtrate evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound as an oil/gum (100 mg, 65%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[Li+].[OH-]>>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[N:32][CH:33]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1

Procedure:
Compound 57d (0.58 g, 1.1 mmol) was hydrolyzed with LiOH using the procedure described in Example 54, Step E. The title compound 125 was obtained as a yellow solid. 1H-NMR (300 MHz, CD3OD) δ (ppm): 8.81 (d, J=1.5 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.16 (dd, J=8.1, 2.1 Hz, 1H), 8.09 (d, J=5.7 Hz, 1H), 8.00 (t, J=8.4 Hz, 1H), 7.92-7.87 (m, 3H), 7.80-7.73 (m, 2H), 7.63-7.54 (m, 2H), 6.40 (d, J=5.7 Hz, 1H), 4.13-4.10 (m, 4H), 4.00-3.97 (m, 4H), 3.23 (t, J=7.5 Hz, 2H), 2.71 (t, J=7.5 Hz, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H26N6O3: 507.2 (M+H). Found: 507.1.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[C:12]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:11]=[C:10]([CH3:24])[C:9]=1[CH3:25]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([CH3:25])=[C:10]([CH3:24])[N:11]=[C:12]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:13]=1[NH2:14]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCl)c1C
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCl)c1C
Reaction time: 8 h
Yield: 88 %

Procedure:
A solution of N-(5-chloropentyl)-2,3-dimethyl-5-nitro-6-phenoxypyridin-4-amine (30.86 g, 85 mmol) in toluene (200 mL) was added to a Parr vessel containing a mixture of 5% platinum on carbon (25.24 g) and toluene (100 mL). The vessel was placed under hydrogen pressure (30 psi, 2.0×105 Pa) and allowed to shake overnight. The reaction mixture was filtered through a layer of Celite® filter aid. The filtrate was concentrated under reduced pressure to provide 24.97 g of N4-(5-chloropentyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine as a thick off white oil.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[C:9]2[CH:10]=[N:11][NH:12][C:13]=2[CH:14]=1)([O-:5])=[O:4].Br[CH:20]([CH3:22])[CH3:21].IC>CS(C)=O.CN(C)C=O>[CH3:21][CH:20]([N:12]1[C:13]2[CH:14]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[C:9]=2[CH:10]=[N:11]1)[CH3:22]
Reactant: CC(C)Br
Reactant: COC(=O)c1cc([N+](=O)[O-])cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])cc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium hydride (1.142 g, 45.2 mmol) was added to N,N-Dimethylformamide (DMF) (100 mL) which was cooled in a ice water bath. A DMSO solution (20 mL) of methyl 6-nitro-1H-indazole-4-carboxylate (5 g, 22.61 mmol) was then added dropwise. After 15 minutes was added 2-bromopropane (4.25 mL, 45.2 mmol) dropwise and the contents were stirred at room temperature for 16 hours. Next added iodomethane (2.83 mL, 45.2 mmol) and let stir at room temperature for 3 hours followed by heating at 50° C. for 3 hours. The solvent was removed in vacuo. The residue was purified via silica gel chromatography (eluent: 0% to 25% EtOAc:Hex) to afford the product as 1.39 g (23%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.07 (s, 3H), 8.61-8.63 (m, 1H), 8.64 (s, 1H), 8.73 (d, J=2.02 Hz, 1H); LCMS (ES) [M+H]+ 264.0
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].O.[C:11]1(C)[CH:16]=CC(S(O)(=O)=O)=C[CH:12]=1>C(O)(C)C.CCOCC>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH:11]([CH3:16])[CH3:12])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: CCOCC
Solvent: CC(C)O
Solvent: O
Product: CC(C)OC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Yield: 955.6 %

Procedure:
A solution of L-pyroglutamic acid (Aldrich, 25.0 g, 195 mmol) and para-toluenesulfonic acid mono hydrate (3.71 g, 19.5 mmol) was refluxed in isopropanol (40 mL) under nitrogen for 6 hours using a Dean-Stark trap variation (condensate returned through a Soxhlet extractor filled with 4 Å molecular sieves). After cooling to room temperature, the reaction was diluted with ether, washed with saturated aqueous sodium bicarbonate and then saturated aqueous NaCl, dried (MgSO4) and evaporated to give a colorless syrup. It crystallized upon setting. Triturating the crystalline residue in hexane provided 31.9 g (96%) of isopropyl pyrrolidin-5-one-2(S)-carboxylate as white prisms: 1H NMR (300 MHz, Chloroform-D) δ 6.35 (br s, 1 H), 5.04 (sept. 1H, J=6.2Hz), 4.18 (dd, 1H, J=8.4, 5.3Hz), 2.51-2.28 (m, 3H), 2.27-2.12 (m, 1H), 1.24 (d, 6H, J=6.2Hz). LCMS m/z 172 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(F)(F)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4,4-difluoropiperidin-1-yl)quinolin-7-yl]ethanone (20 mg, 0.06 mmol) and ammonium acetate (47.5 mg, 0.616 mmol) in methanol (0.35 mL) and acetonitrile (0.35 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (7.7 mg, 0.12 mmol) was added to the resulting mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with sat. sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The crude amine was used directly in the next step. LCMS calculated for C16H19ClF2N3 (M+H)+: m/z=326.1; Found: 326.0.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[C:3]1=[O:20].[C:21]([O:24][CH2:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:47]=2)[C:42]1=[O:54])(=[O:23])[CH3:22].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.O>[C:21]([O:24][CH2:25][C:26]1[C:31]([C:6]2[CH:5]=[C:4]([N+:17]([O-:19])=[O:18])[C:3](=[O:20])[N:2]([CH3:1])[CH:7]=2)=[CH:30][CH:29]=[CH:28][C:27]=1[N:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[C:46]([C:50]([CH3:53])([CH3:52])[CH3:51])[CH:47]=2)[C:42]1=[O:54])(=[O:23])[CH3:22]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)OCc1c(-c2cc([N+](=O)[O-])c(=O)n(C)c2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Temperature: 100 °C
Yield: 81.7 %

Procedure:
A 100-mL three-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 122b (560 mg, 2.00 mmol), 103f (830 mg, 2.00 mmol), sodium carbonate (848 mg, 8.00 mmol), dioxane (30 mL) and water (6 mL). This mixture was degassed with nitrogen for 15 min. Tetrakis(triphenyl-phosphine)palladium (231 mg, 0.200 mmol) was added. After heating at 100° C. for 5 h, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (200 mL). The resulting mixture was washed with saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel to afford an 81% yield (800 mg) of 122c as a crude product, which was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14]/[CH:15]=[CH:16]/[CH:17]=O)[CH2:7][CH2:6]2.[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][NH:27][CH:28]=[CH:29][C:30](=[O:32])[CH3:31])[CH:23]=[CH:24][CH:25]=1>>[C:30]([C:29]1[CH:15]([CH2:14][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:13])[CH:16]=[CH:17][N:27]([CH2:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=2)[CH:28]=1)(=[O:32])[CH3:31]
Reactant: COc1ccc2c(c1)CCC(C/C=C/C=O)C2=O
Reactant: CC(=O)C=CNCc1cccc(Cl)c1
Product: COc1ccc2c(c1)CCC(CC1C=CN(Cc3cccc(Cl)c3)C=C1C(C)=O)C2=O

Procedure:
The title compound 63 is prepared according to the procedure reported in step D of Example 8 with aldehyde 54 (100 mg, 0.41 mmol) and enamine 64 (90 mg, 0.42 mmol) as reactants. Purification by column chromatography on SiO2 (Petroleum Ether/EtOAc=2:1) afford the title compound 63 as a yellow solid. (Yield 70 mg, 39%).
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[CH3:12][O:13][C@@H:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15]([OH:17])=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[C:40]1([C:46]2([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@H:54]3[C@H:50]([CH2:51][NH:52][CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[C:56]1([C:46]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:54]3[C@H:50]([CH2:51][N:52]([C:15](=[O:17])[C@@H:14]([O:13][CH3:12])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:53]3)[C:49](=[O:55])[CH2:48][CH2:47]2)[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Reactant: CO[C@H](C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H](C(=O)N1C[C@@H]2C(=O)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Reaction time: 0.25 h
Yield: 40 %

Procedure:
Hydroxybenzotriazole monohydrate (1 g) is added to a solution of (S)-α-methoxyphenylacetic acid (1.23 g) in dry dimethylformamide (20 cc), cooled to +5° C.; stirring is continued for 15 minutes and N,N'-dicyclohexylcarbodiimide (1.53 g) is then added. The mixture is stirred for 1 hour at +5° C. and a solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.43 g) and diisopropylethylamine (1.28 cc) in dry dimethylformamide (10 cc) is then added. The reaction mixture is stirred at +5° C. for 2 hours and then at ambient temperature for 2 hours. The reaction mixture, taken up in ethyl acetate (100 cc), is filtered; the filtrate is washed with distilled water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (diameter 2.2 cm, height 27 cm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 20 cc fractions. Fractions 68 to 177 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from isopropyl ether (15 cc); the crystals obtained are drained and then dried. (3aR,7aR)-7,7-diphenyl-2-[(S)-2-methoxy-2-phenylacetyl]-4-perhydroisoindolone (1.3 g) is obtained in the form of white crystals melting at 130° C.; [α]D20 =-230° (c=1, methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][CH3:14])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.CCCCCC.[CH3:27][S:28]SC>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([S:28][CH3:27])=[C:11]([CH2:13][CH3:14])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1csc(NC(=O)OC(C)(C)C)n1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1nc(NC(=O)OC(C)(C)C)sc1SC
Temperature: 25 °C

Procedure:
The above prepared (4-ethyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.12 g, 4.90 mmol) was dissolved in 12 mL of abs. THF and treated at −78° C. with a solution of nBuLi in hexane (6.53 mL, 1.5M, 2 eq.). The reaction mixture was kept for 15 Min. at −78° C. and then allowed to reach RT. After recooling to −78° C., methyldisulfanylmethane (0.870 mL, 2 eq.) was added and the mixture kept for 30 Min. at this temperature and then slowly warmed to RT. Pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/ethyl acetate=85/15), afforded 1.067 g of the title product as off-white solid.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[CH:11][C:12]=3[OH:17])[C:7](=[O:21])[C:6]=2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][CH:3]=1.[C:25]1([O:31][CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>B(O)(O)O.S(=O)(=O)(O)O>[OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[CH:10]=[C:11]([C:28]4[CH:29]=[CH:30][C:25]([O:31][CH3:32])=[CH:26][CH:27]=4)[C:12]=3[OH:17])[C:7](=[O:21])[C:6]=2[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][C:3]=1[C:28]1[CH:29]=[CH:30][C:25]([O:31][CH3:32])=[CH:26][CH:27]=1
Reactant: O=C1c2c(O)ccc([N+](=O)[O-])c2C(=O)c2c([N+](=O)[O-])ccc(O)c21
Reactant: COc1ccccc1
Agent: O=S(=O)(O)O
Agent: OB(O)O
Product: COc1ccc(-c2cc([N+](=O)[O-])c3c(c2O)C(=O)c2c(O)c(-c4ccc(OC)cc4)cc([N+](=O)[O-])c2C3=O)cc1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
9.9 g of 1,8-dihydroxy-4,5-dinitroanthraquinone are dissolved in a mixture of 15.6 g of boric acid and 228 g of 100 percent sulphuric acid. The solution obtained is cooled down to -10° to 0° C. and 7.4 g of anisole are added dropwise. The temperature is maintained for a further 1 hour at 0° C. and then the mixture is poured onto 240 g of ice and heated to reflux for 4 hours. The solid is filtered off with suction, washed with water to neutrality and dried at 60° C. 12.6 g of 1,8-dihydroxy-2,7-di(4-methoxyphenyl)-4,5-dinitroanthraquinone, corresponding to a yield of 77% of theory, are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:13](=[O:14])[N:12]2[C:7]([CH2:8][O:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=32)=[N:6]1.[I-].[K+].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][N:5]3[C:13](=[O:14])[N:12]4[C:7]([CH2:8][O:9][C:10]5[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=54)=[N:6]3)[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1n(CCCCl)nc2n1-c1ccccc1OC2
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCN2CCN(c3ccccc3)CC2)nc2n1-c1ccccc1OC2
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A stirred solution of 1.32 g. (0.005 mole) of 2-(3-chloropropyl)2,4-dihydro-1H-[1,2,4]triazolo[3,4-c][1,4]benzoxazin-1-one in 25 ml. of dry DMF was treated with 0.83 g. (0.005 mole) of potassium iodide and 1.78 g. (0.011 mole) of N-phenylpiperazine. The resulting mixture was kept at 50° C. for 18 hours, at 85° C. for 2 hours and at 105° C. for 2.5 hours. The mixture was then cooled, poured into ice water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with dilute brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on 125 g. of silica gel and eluted therefrom with a 1.5% v/v methanol in chloroform mixture. The eluted product was crystallized in the manner described in example 1, hereinabove, from an ethyl acetate/Skellysolve®B hexane mixture to give in two crops 0.74 g., m.p. 95°-96.5° C., and 0.37 g., m.p. 94°-96° C. of the titled compound. The analytical sample has a melting point of 96°-96.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28](Cl)(=[O:37])[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28](=[O:37])[CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and hydrocinnamoyl chloride.
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[N:11]=[C:12]([Br:33])[S:13][C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[CH2:22][N:23]2[C:27]3=[N:28][CH:29]=[CH:30][CH:31]=[C:26]3[CH:25]=[CH:24]2)[CH2:17][CH2:16]1.[H-].[Na+].[CH3:36][Si:37]([CH2:40][CH2:41][O:42][CH2:43]Cl)([CH3:39])[CH3:38]>C1COCC1>[Br:33][C:12]1[S:13][C:14]([N:15]2[CH2:20][CH2:19][N:18]([C:21](=[O:32])[CH2:22][N:23]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:26]4[CH:25]=[CH:24]3)[CH2:17][CH2:16]2)=[C:10]([C:2]2[N:1]([CH2:43][O:42][CH2:41][CH2:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[N:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(Cn1ccc2cccnc21)N1CCN(c2sc(Br)nc2-c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2nc(Br)sc2N2CCN(C(=O)Cn3ccc4cccnc43)CC2)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a yellow solution of Example 38 (542 mg) in THF (6 mL) was added NaH (62 mg, 60% in mineral oil) at 0° C. The resulting pale yellow foaming suspension was stirred at 0° C. for 15 min under argon, then SEMCl (182 mg) was added and stirring was continued for 1.25 h. The reaction mixture was quenched by addition of water. Phases were separated and the org. layer was washed with water and brine. The aq. layers were extracted twice with EA. The combined org. layers were dried over MgSO4, filtrated off, evaporated and dried in high vacuo. The crude was purified by CC (Biotage, SNAP 25 g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in % B: 5 for 4CV, 5 to 15 over 6CV, 15 for 3CV) to afford 530 mg of light yellow solid. LC-MS (B): tR=0.91 min; [M+H]+: 652.48.