Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:39]([N:41]([CH2:49][CH3:50])[CH:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)[CH3:40]>S([O-])(O)(=O)=O.[K+].FC(F)(F)C(O)=O>[CH2:49]([N:41]([CH2:39][CH3:40])[CH:42]1[CH2:47][CH2:46][CH:45]([NH:48][C:2]2[C:12]([F:13])=[CH:11][C:10]([C:14]3[CH:15]=[C:16]4[C:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[N:21][NH:20][C:17]4=[N:18][CH:19]=3)=[CH:9][C:3]=2[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH2:44][CH2:43]1)[CH3:50]
Reactant: CCN(CC)C1CCC(N)CC1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(F)c(F)c(C(=O)N(C)C)c3)cc12
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C1CCC(Nc2c(F)cc(-c3cnc4[nH]nc(-c5ccccc5OC)c4c3)cc2C(=O)N(C)C)CC1
Reaction time: 48 h

Procedure:
Into a 5 mL screw-cap vial were added 2,3-difluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (266 mg, 0.46 mmol) and 4-diethylamino-cyclohexylamine (468 mg, 2.74 mmol, mixture of cis/trans isomers). The vial was sealed and placed in heated block at 120° C. for 48 h. The reaction solution was suspended in 1 N aqueous potassium hydrogensulfate solution and loaded onto a 5 g C18 functionalized silica gel cartridge. The plug was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was dissolved in 5 mL trifluoroacetic acid. The resulting mixture was stirred for 1 h and then the reaction mixture was concentrated. The residue was dissolved in 2 mL of methanol and 200 μL ethylenediamine were added. The mixture was diluted with 2 mL of DMSO and purified by reverse-phase HPLC to afford 43.4 mg (0.63 mmol, 14%) of both diastereomers of 2-(4-diethylamino-cyclohexylamino)-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide separately as colorless powders. More polar diastereomer (21.3 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.81 (d, J=1.5 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 7.62 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.58 (dd, J1=14 Hz, J2=2 Hz, 1H), 7.45 (m, 1H), 7.30 (d, J=2 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.08 (td, J1=7.5 Hz, J2=1 Hz, 1H), 4.53 (dd, J1=8 Hz, J2=1.5 Hz, 1H), 3.82 (s, 3H), 3.12 (m, 1H), 2.75-3.05 (m, 7H), 2.44 (q, J=7 Hz, 4H), 1.89 (m, 2H), 1.69 (m, 2H), 1.19 (m, 4H), 0.93 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Less polar diastereomer (22.1 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.76 (s, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.64 (dd, J1=4.5 Hz, J2=1.5 Hz, 1H), 7.61 (t, J=2 Hz, 1H), 7.45 (m, 1H), 7.42 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 4.99 (dd, J1=10 Hz, J2=1 Hz, 1H), 3.82 (s, 3H), 3.68 (m, 1H), 3.32 (m, 1H), 2.97 (bs, 6H), 2.46 (q, J=7 Hz, 4H), 1.70 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H), 0.94 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].ClCCC(C)C(Cl)=O.[Cl:16][C:17]1[CH:26]=[C:21]([C:22]([NH:24]O)=[O:23])[C:20](O)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[O:4][CH:3]3[CH:2]([CH3:1])[CH2:7][CH2:6][O:5][N:24]3[C:22](=[O:23])[C:21]=2[CH:26]=1
Reactant: CC1CCOC1=O
Reactant: O=C(NO)c1cc(Cl)ccc1O
Agent: CC(CCCl)C(=O)Cl
Product: CC1CCON2C(=O)c3cc(Cl)ccc3OC12

Procedure:
40 g. of 2-methylbutyrolactone was converted to 45 g. of 4-chloro-2-methylbutryl chloride (b.p. 70°-72° C at 15 mm.) by the method detailed in Example 4. The acid chloride (15.5 g.) was reduced to the corresponding aldehyde, condensed with 5-chlorosalicylhydroxamic acid and the resulting intermediate was ring-closed according to the method described in Example 3. The product melted at 144°-146° C. after recrystallization from a mixture of trichloroethylene and hexane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH:19]1([C:22]#[CH:23])[CH2:21][CH2:20]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C1(C)C=CC=CC=1.C(NC(C)C)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:19]1([C:22]#[C:23][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(Br)c1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)NCCCc1cccc(C#CC2CC2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a degassed solution of tert-butyl 3-(3-bromophenyl)propylcarbamate (57) (1.0 g, 3.1 mmol) and cyclopropyl acetylene (2.9 mL, 3.4 mmol, 70% soln in toluene) in diisopropylamine (4 mL) was added PdCl2(PPh3)2 (0.120 g, 0.17 mmol), tri-o-tolylphosphine (0.048 g, 0.16 mmol) and CuI (0.026 g, 0.16 mmol). The resulting mixture was degassed and stirred under nitrogen at 90° C. for overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography (10-40% ethyl acetate-hexane gradient) gave tert-butyl 3-(3-(cyclopropylethynyl)phenyl)propylcarbamate. Yield (0.756 g, 79%). This alkyne was used for deprotection without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21](B(O)O)[CH:20]=1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[CH:20]=[N:19][C:28]4[C:23]([CH:22]=3)=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Reactant: OB(O)c1cnc2ccccc2c1
Product: CCCNC(=O)c1nnc2c(-c3cnc4ccccc4c3)cccc2c1N
Yield: 78.9 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3-quinoline boronic acid (168 mg, 0.97 mmol) were reacted to afford the title compound (93 mg, 80.5% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 9.24 (d, J=2.2 Hz, 1H), 8.50-8.60 (m, 2H), 8.18 (d, J=8.6 Hz, 1H), 7.88-7.98 (m, 3H), 7.82 (d, J=8.2 Hz, 1H), 7.76 (m, 1H), 7.59 (m, 1H), 3.47 (q, J=6.7 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=358 (M+H) HPLC 1.88 min.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.[C:11]([CH:15]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:13][CH3:14])=[O:12].[CH:43](Br)([CH2:45][CH3:46])[CH3:44]>>[C:11]([CH:15]([N:22]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29][N:30]2[C:34]3=[N:35][C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]3[N:32]=[C:31]2[CH2:41][CH3:42])=[CH:25][CH:24]=1)[CH:43]([CH2:45][CH3:46])[CH3:44])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([O:13][CH3:14])=[O:12]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(NC(C(=O)OC)c2ccccc2)cc1
Reactant: CCC(C)Br
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(N(C(C)CC)C(C(=O)OC)c2ccccc2)cc1

Procedure:
Using the general procedure for the alkylation of secondary amines with LiN(TMS)2 described in Step A of Example 29, 3-[4-(N-(1-carbomethoxy -1-phenylmethyl)amino)phenylmethyl]-5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]-pyridine (Step A, Example 28) was alkylated with sec-butyl bromide. Standard workup and purification by flash chromatography afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[I:9]I>CCO.[O-]S([O-])(=O)=O.[Ag+].[Ag+]>[Cl:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(Cl)nc1I
Temperature: 20 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
To a solution of 6-chloro-pyridin-3-ylamine (10.0 g, 77.8 mmol) in EtOH (150 mL) was added Ag2SO4 (12.1 g, 38.9 mmol) and I2 (23.7 g, 93.4 mmol) at room temperature. The mixture was stirred at 20° C. overnight. The solvent was removed by evaporation under vacuum. Water (100 mL) and EtOAc (200 mL) were added to the residue. The organic layer was separated and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate 7:1) to give 6-chloro-2-iodo-pyridin-3-ylamine (17.1 g, 86%). 1H NMR (DMSO, 300 MHz) δ 7.16 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 5.57 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH2:11][C@@H:12]([OH:29])[CH2:13][O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:16].N1C=CN=C1.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40].C(OCC)(=O)C>CN(C)C=O>[Si:43]([O:29][C@H:12]([CH2:11][N:7]1[CH2:8][CH2:9][CH2:10][C@H:6]1[CH2:5][C:4]1[CH:30]=[CH:31][C:32]([CH3:33])=[C:2]([F:1])[CH:3]=1)[CH2:13][O:14][C@@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH3:16])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44]
Reactant: COC(=O)CCc1ccccc1[C@@H](C)OC[C@H](O)CN1CCC[C@H]1Cc1ccc(C)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of methyl 3-{2-[(1R)-1-({(2R)-3-[(2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidin-1-yl]-2-hydroxypropyl}oxy)ethyl]phenyl}propanoate (596 mg, 1.30 mmol) which had been obtained in Example 2 (2a), in N,N-dimethyl formamide was added with imidazole (221 mg, 3.25 mmol) and tert-butyl(chloro)dimethylsilane (294 mg, 1.95 mmol), and stirred at room temperature. After stirring for 24 hours, the reaction solution was added with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=85/15) to give the title compound as a pale yellow oily substance (676 mg, yield 91%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=O.C(OC(C1C2C=C(OC)C=CC=2OC=1C1C=CC(F)=CC=1)=O)C.CI.C(=O)([O-])[O-].[K+].[K+].[C:54](#[N:56])C>>[CH3:54][NH:56][C:3]([C:5]1[C:9]2[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=2[O:7][C:6]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:2]
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC)cc12
Reactant: CC#N
Agent: CCOC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
Preparation of compound 12(b)(i) and compound 12(b)(ii) (2-(4-fluoro-phenyl)-5-methoxy-benzofuran-3-carboxylic acid methyl ester and 2-(4-fluoro-phenyl)-5-methoxy-benzofuran-3-carboxylic acid ethyl ester). Methyl iodide (0.43 mL, 6.99 mmol) was added to a mixture of the compounds 12(a)(i) and 12(a)(ii) (1.00 g, 3.49 mmol), potassium carbonate (milled, 1.21 g, 8.73 mmol) and anhydrous acetonitrile (15 mL) under an argon atmosphere. The reaction mixture was heated to reflux under argon for 18 hours, and then cooled to room temperature and stirred for 24 hours. The mixture was diluted with acetonitrile (10 mL) and filtered, followed by evaporation of the solvent. The crude solid was diluted with 60:40 ethyl acetate/hexanes, re-filtered, and purified by HPLC (silica gel, ethyl acetate/hexanes) to provide 0.85 g (78%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[CH3:17]I.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2([C:13]([O:15][CH3:16])=[O:14])[CH3:17])=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCCc2ccc(OC)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)CCCc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
7-Methoxytetralin-1-yl-carboxylic acid, methyl ester (0.4 g; 1.8 mmol; from step (i) above) and MeI (0.13 mL, 2.0 mmol) were added to a slurry of NaH (55% in oil; 87 mg; 2.0 mmol) in DMF (5 mL) and the mixture was stirred at RT overnight. The resultant mixture was poured onto water, and the water mixture was extracted with EtOAc:toluene 3 times. The combined organic layer was washed with water, dried (Na2SO4), and concentrated. Flash chromatography (Si-gel; heptane:EtOAc; 4:1) yielded 0.18 g (42%) of the sub-title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11]([O:13]CC)=O)=[O:6])[CH:2]=[CH2:3].[Cl:19][C:20]1[N:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1>[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1>[Cl:19][C:20]1[N:25]=[C:24]([CH2:26][C:11]([C:10]2[CH:9]=[C:8]([NH:7][C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH2:3])[CH:18]=[CH:17][CH:16]=2)=[O:13])[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)OCC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
Ethyl 3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (20.0 g, 80.24 mmol) was dissolved in 1M LiHMDS in THF (260 mL) and cooled to 0° C. A solution containing 2-chloro-4-methylpyrimidine (10.32 g, 80.24 mmol) in 20 mL dry THF was added to the reaction mixture. The reaction was stirred at 0° C. for 2 h, quenched with MeOH (100 mL), dried directly onto silica, and purified via flash chromatography EtOAc/CH2Cl2 0-100% gradient run over 60 min. The desired fractions were combined and the solvent was removed to give the title compound (13.6 g, 51% yield); ES-LCMS m/z 332 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:11][C@H:10]2[C@H:5]([O:6][C:7]([CH3:13])([CH3:12])[O:8][CH2:9]2)[C@H:4]1[OH:14].[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:22][C:21]1[CH:23]=[CH:24][C:18]([S:15]([O:14][C@@H:4]2[C@H:5]3[O:6][C:7]([CH3:12])([CH3:13])[O:8][CH2:9][C@H:10]3[O:11][C@@H:3]2[O:2][CH3:1])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1O
Solvent: c1ccncc1
Product: CO[C@H]1O[C@@H]2COC(C)(C)O[C@@H]2[C@H]1OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
Compound 35.3 (35.42 g, 174 mmol) was dissolved in anhydrous pyridine, cooled to 0° C. and then treated with tosyl chloride (52.96 g, 278 mmol). The mixture was stirred at r.t. for 16 h and the solvent was removed under reduced pressure. The residue was dissolved in CH2Cl2, and washed with 3×100 mL water. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was subjected to a reverse phase column chromatography eluting with 50% EtOAc in hexane to give compound 35.4 (57.88 g, 93% yield).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([CH3:25])[C:22]([OH:24])=O.Cl.[C:27]1([C:33]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:41]3[C@H:37]([CH2:38][NH:39][CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[C:43]1([C:33]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@H:41]3[C@H:37]([CH2:38][N:39]([C:22](=[O:24])[C@H:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[O:14][CH3:13])[CH3:25])[CH2:40]3)[C@@H:36]([OH:42])[CH2:35][CH2:34]2)[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COc1ccccc1[C@H](C)C(=O)O
Reactant: O[C@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@@H]21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@H]2[C@@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@H]2O
Reaction time: 1 h
Yield: 29 %

Procedure:
0.37 g of carbonyldiimidazole is added to a solution, cooled to +4° C., of 0.41 g of (S)-2-(2-methoxyphenyl)propionic acid in 15 cm3 of dry dichloromethane. The mixture is stirred for one hour at +4° C. and then a solution of 0.75 g of (3aR,4S,7aR)-7,7-diphenyl-4-perhydroisoindolol hydrochloride is added. The reaction mixture is stirred at room temperature for 20 hours and then then washed twice with 10 cm3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 3.6 cm, height 37 cm), eluting under a nitrogen pressure of 0.5 bar with an ethyl acetate and cyclohexane mixture (50/50 by volume) and collecting fractions of 50 cm3. Fractions 21 to 41 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is triturated in isopropyl oxide and then dried. 0.3 g of (3aR,4S,7aR)-7,7-diphenyl-2-[(S)-2-(2-methoxyphenyl)propionyl]-4-perhydroisoindolol is obtained in the form of a white meringue.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[O:13][B:14](OC)[O:15]C>O1CCCC1.CCOCC>[CH2:5]([C:6]1[CH:11]=[CH:10][C:9]([B:14]([OH:15])[OH:13])=[CH:8][CH:7]=1)[CH2:4][CH3:3]
Reactant: BrCCCc1ccccc1
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of magnesium shavings (217 mg, 8.9 mmol) in 3 mL of dry tetrahydrofuran under argon, a crystal along with a solution of 4-bromopropylbenzene (1.69 g, 8.5 mmol) dissolved in 6 mL of tetrahydrofuran was added at such a rate that a gentle reflux was maintained. The solution was refluxed for an additional 0.5 h, cooled to room temperature and added in portions over 10 minutes to a solution of trimethylborate (924 mg, 8.9 mmol) previously dissolved in 4 mL of dry ether at -78° C. After 30 minutes, the solution was warmed to room temperature where stirring continued for 90 minutes, then the reaction was quenched by the addition of 2 mL of a 10% hydrochloric acid solution. The tetrahydrofuran was removed under reduced pressure and the remaining residue was extracted into diethyl ether (3×25 mL). The combined ether extracts was extracted with 1M NaOH (3×25 mL) and the resulting aqueous layer was acidified to pH 2.0 using 6N HCl, then reextracted back into diethyl ether (3×25 mL). The combined organic layers was washed with water (1×25 mL), brine (1×25 mL) and dried over magnesium sulfate. Evaporation of solvent left a brown solid which was filtered through a small plug of silica gel using 11.0 MeOH/CACl3. Evaporation left 448 mg (32%) of a brown solid, m.p. 90°-93° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[N:23]=[N:24][CH:25]=[CH:26]C=3)[C@H:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S([O-])([O-])(=O)=O.[Mg+2].C([N:44](CC)CC)C.C(C=O)=O>C(O)C>[F:34][C:2]([F:35])([F:1])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[N:23]=[N:24][CH:25]=[CH:26][N:44]=3)[C@H:16]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CCN(CC)CC
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3cccnn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: O=CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3nccnn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
The amidrazone hydrochloride of (b) above (200 mg) was dissolved in ethanol (2 ml). Magnesium sulphate was added (100 mg) and the mixture stirred for 30 min. Triethylamine (0.06 ml) was added followed by glyoxal (90 mg, trimeric dihydrate). This mixture was allowed to stir for 12 h. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated to afford a brown oil. This was purified by column chromatography on silica using hexane in ethyl acetate (95%) to afford the title compound. 1H NMR (360 MHz, CDCl3) δ 1.53-1.72 (2H, m, CH2), 1.98-2.22 (2H, m, CH2), 2.42-2.53 (1H, m, NCHH), 3.14-3.22 (1H, m, NCHH), 3.61 (1H, bs, CHO), 3.74-3.81 (2H, m, NCHPh+OCHH), 4.04 (1H, d, J=12 Hz, NCHHtriazine), 4.19 (1H, d, J=12 Hz, OCHH), 4.47 (1H, d, J=12 Hz, NCHHtriazine), 7.24-7.37 (4H, m, ArH), 7.48-7.6 (4H, m, ArH), 7.70 (1H, s, ArH), 8.6 (1H, s, ArH). MS (CI+) m/z 497 (M+ 1, 100%). The following examples illustrate pharmaceutical compositions according to the invention.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5](S([O-])(=O)=O)[CH:4]=[C:3]([CH3:11])[CH:2]=1.[Na+].[NH2-:14].[Na+].N>>[CH3:12][C:1]1[CH:6]=[CH:5][C:4]([NH2:14])=[C:3]([CH3:11])[CH:2]=1
Reactant: Cc1cc(C)cc(S(=O)(=O)[O-])c1
Reactant: [NH2-]
Agent: N
Agent: [Na+]
Product: Cc1ccc(N)c(C)c1
Yield: 84.4 %

Procedure:
In a 200-ml autoclave were placed 22.9 grams (0.11 mole) of anhydrous sodium 5-m-xylene sulfonate, 9.7 grams (0.24 mole) of sodium amide and 80 ml of liquid ammonia in the same manner as in Example 1. The resultant mixture was heated at 150° C for 5 hours. The reaction pressure in the autoclave was 135 atm. during the reaction. After the ammonia was removed, 20 ml of water was added to the reaction mixture for hydrolysis. Thereafter the product was treated in the same manner as in Example 1, whereby 11.3 grams of sym. -m-xylidine boiling at 221° to 222° C was obtained. Yield was 84.4%
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>CCCCCCC>[CH:1]1([Li:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: [Li]CCCC
Reactant: C1=Cc2ccccc2C1
Solvent: CCCCCCC
Product: [Li]C1C=Cc2ccccc21
Reaction time: 8 h
Yield: 99.2 %

Procedure:
To distilled indene (15.0 g, 129 mmol) in heptane (200 mL) was added BuLi (82 mL, 131 mmol, 1.6 M in hexanes) at room temperature. The resulting reaction mixture was stirred overnight. The mixture was filtered and the filter cake washed with heptane (3×30 mL) to give indenyllithium (15.62 g, 99% yield). Indenyllithium (6.387 g, 52.4 mmol) was added as a solid over 5 minutes to a stirred solution of C6F5CH2—Br (13.65 g, 52.3 mmol) in toluene (100 mL) at room temperature. The reaction mixture was heated to 50° C. and stirred for 4 h. The product mixture was filtered and washed with toluene (3×20 mL). The combined filtrates were evaporated to dryness to afford 1-C6F5CH2-indene (13.58 g, 88%). To a stirred slurry of TiCl4.2THF (1.72 g, 5.15 mmol) in toluene (15 mL) was added solid (t-Bu)3P═N—Li (1.12 g, 5 mmol) at room temperature. The resulting reaction mixture was heated at 100° C. for 30 min and then allowed to cool to room temperature. This mixture containing ((t-Bu)3P═N)TiCl3 (1.85 g, 5 mmol) was used in the next reaction. To a THF solution (10 mL) of 1-C6F5CH2-indene (1.48 g, 5 mmol) cooled at −78° C. was added n-butyllithium (3.28 mL, 5 mmol, 1.6 M in hexanes) over 10 minutes. The resulting dark orange solution was stirred for 20 minutes and then transferred via a double-ended needle to a toluene slurry of ((t-Bu)3P═N)TiCl3 (1.85 g, 5 mmol). The cooling was removed from the reaction mixture which was stirred for a further 30 minutes. The solvents were evaporated to afford a yellow pasty residue. The solid was re-dissolved in toluene (70 mL) at 80° C. and filtered hot. The toluene was evaporated to afford pure (1-C6F5CH2-Indenyl)((t-Bu)3P═N)TiCl2 (2.35 g, 74%).