Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].Cl[CH2:20][C:21]1[CH:40]=[CH:39][C:24]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:23][CH:22]=1.CC(C)([O-])C.[Na+].Cl>CN1CCCC1=O>[CH3:32][C:31]1[O:30][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:28][C:27]=1[CH2:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][O:1]/[N:2]=[C:3](/[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:40][CH:39]=1
Reactant: O=C(O)CCCCCC/C(=N\O)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(\CCCCCCC(=O)O)c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
(E)-8-(Hydroxyimino)-8-phenyloctanoic acid (1.0 g) and 4-{[4-(chloromethyl)phenoxy]methyl}-5-methyl-2-phenyl-1,3-oxazole (1.26 g) were dissolved in 1-methyl-2-pyrrolidone (10 ml), and the solution was ice-cooled. Sodium tert-butoxide (0.85 g) was added to the reaction mixture at not higher than −5° C. and the mixture was stirred at the same temperature for 30 min, and then at room temperature for 4 hr. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate (20 ml). The organic layer was washed with 10% brine (20 ml) and dried over anhydrous sodium sulfate. The organic layer was concentrated and acetone/water (1/1) (20 ml) was added to the obtained residue (brown oil). The mixture was dissolved under reflux and allowed to cool for crystallization. The crystals were collected by filtration, washed with H2O (5 ml) and dried in vacuo at 50° C. for 4 hr. Acetone/water (2/1) (30 ml) was added to the obtained crystals, the mixture was dissolved under reflux, and allowed to cool for crystallization. The crystals were collected by filtration and washed with water (5 ml). The crystals were dried in vacuo at 0° C. for 4 hr, and the objective product was obtained as white crystals (1.55 g, yield 86%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].Cl.[CH2:21](O)[CH3:22]>>[CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:21][CH3:22])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CCO
Reactant: COC1=C(OC)C(=O)C(CCCC(=O)O)=C(C)C1=O
Agent: Cl
Product: CCOC(=O)CCCC1=C(C)C(=O)C(OC)=C(OC)C1=O

Procedure:
A solution of 2,3-dimethoxy-5-methyl-6-(3'-carboxypropyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=2 in the free form) (0.8 part) in ethanol (3 volume parts) saturated with dry hydrogen chloride was stirred at room temperature for 1 hour. The residue upon removal of the solvent was subjected to chromatography on silica gel and eluted with chloroform to give 2,3-dimethoxy-5-methyl-6-(3'-ethoxycarbonylpropyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=2, in the form of ethyl ester) (0.88 part) as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#N)[C:3]=1[C:10]1[NH:19][C:18](=[O:20])[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]>[Zn].C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:10]1=[C:11]([C:12]([O:14][CH3:15])=[O:13])[CH:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:18](=[O:20])[N:19]1[CH2:8]2
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)[nH]c1-c1c(F)cccc1C#N
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1c(F)cccc1C2
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 1.04 g of methyl 2-(2-fluoro-6-cyanophenyl)1, 6-dihydro-6-oxo-5-phenylnicotinate, 0.98 g of zinc powder and 30 ml of acetic acid was heated to boiling under reflux for 30 minutes. The mixture was filtered while hot and the filtrate was evaporated in a vacuum. The residue was stirred overnight in 30 ml of water, whereupon the resulting crystals were filtered off under suction and washed with methylene chloride. By chromatography on silica gel with methylene chloride/diethyl ether (9:1) there was obtained yellow crystals which were recrystallized from ethyl acetate. There was obtained 0.23 g of methyl 10-fluoro-4,6-dihydro-4-oxo-3-phenylpyrido[2,1-a]isoindole-1-carboxylate with a m.p. of 134°-136°.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][C@@H:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([C:27]([C:46]1[CH:51]=[CH:50][C:49](O)=[C:48]([CH3:53])[CH:47]=1)([C:30]1[CH:35]=[CH:34][C:33]([B:36]2[O:40][C:39]([CH3:42])([CH3:41])[C:38]([CH3:44])([CH3:43])[O:37]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:28][CH3:29])[CH3:26].C(OCC)(=O)C>CN(C)C=O>[CH2:25]([C:27]([C:46]1[CH:51]=[CH:50][C:49]([O:10][CH2:11][C@@H:12]2[O:16][C:15](=[O:17])[CH2:14][CH2:13]2)=[C:48]([CH3:53])[CH:47]=1)([C:30]1[CH:35]=[CH:34][C:33]([B:36]2[O:40][C:39]([CH3:41])([CH3:42])[C:38]([CH3:43])([CH3:44])[O:37]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCC(=O)O2)cc1
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OC[C@H]2CCC(=O)O2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
(R)-(−)-Dihydro-5-(p-tolyl-sulfonyloxymethyl)-2(3H)-furanone (293 mg, 1.084 mmol) and potassium carbonate (180 mg, 1.301 mmol) were added to a solution of 4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenol (Example 15-(2); 171 mg, 0.434 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature, and the mixture was stirred at 110° C. for one hour. Ethyl acetate was added to the reaction solution. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=80/20 to ethyl acetate only) to give the title compound (164 mg, 76.8%).
Reaction SMILES: [OH:1][C:2]1([CH2:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][N:11]([C@H:20]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:21]([O:23]CC3C=CC=CC=3)=[O:22])[CH2:10]2)[CH2:4][CH2:3]1.[H][H]>[Pd].CO>[OH:1][C:2]1([CH2:37][CH2:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][N:11]([C@H:20]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:21]([OH:23])=[O:22])[CH2:10]2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@@H](C1CCCCC1)N1C[C@H](CN2CCC(O)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Yield: 99.4 %

Procedure:
A mixture of 20 mg (0.032 mmol) 2-(R)-(3-(S)-((4-hydroxy-4-(3-phenylpropyl)piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step J) and 3 mg of 10% palladium on carbon in 0.5 mL of MeOH was stirred under one atmosphere of hydrogen for 18 h. The reaction was filtered through a 0.45 nylon filter and concentrated to give 16.5 mg (97%) of the title compound: ESI-MS 519 (M+H); HPLC B: 5.07 min.
Reaction SMILES: [C@H:1]1([OH:12])[CH:7]([OH:8])[C@@H:6](O)[C@H:5](O)[C:3](=[O:4])[C@@H:2]1[OH:11].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([OH:8])=[C:1]([OH:12])[C:2]=1[OH:11]
Reactant: O=C1[C@@H](O)[C@H](O)C(O)[C@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Oc1ccc(O)c(O)c1O
Temperature: 4 °C
Reaction time: 9 h
Yield: 54.3 %

Procedure:
A solution of myo-2-inosose (11.0 g, 61.2 mmol) in 310 mL of degassed 0.5 M H2SO4 was refluxed under Ar. After 9 h, the solution was cooled to 4° C. and then adjusted to pH 4 by addition of saturated aqueous NaHCO3. Concentration of the reaction solution to 100 mL was followed by continuous liquid-liquid extraction for 18 h using t-butyl methyl ether (500 mL). Upon concentration of the organic layer to 100 mL, a precipitate formed which was filtered, washed with cold hexanes, and dried to afford 1 (4.72 g, 54%) as a tan powder. Addition of hexanes (300 mL) to the filtrate followed by filtering, washing, and drying of the resulting precipitate afforded additional 1 (1.08 g, 12%). mp 162-164° C. 1H NMR (d6-acetone): δ7.24 (s, 4 H), 6.20 (s, 2 H). 13C NMR (d6-acetone): δ139.7, 134.7, 106.2. Anal. Calcd for C6H6O4: C, 50.71; H, 4.23. Found: C, 50.63; H, 4.32. HRMS (FAB) calcd for C6H6O4 (M+H+): 142.0266. Found: 142.0268.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([NH:9][C@H](C2C=CC=CC=2)C)[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:9][C@H:8]1[CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:4][C@H:3]1[CH2:2][OH:1]
Reactant: [H][H]
Reactant: C[C@H](N[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1CO)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](CO)C1
Reaction time: 8 h

Procedure:
A mixture of (3R,4S)-tert-butyl 3-(hydroxymethyl)-4-((S)-1-phenylethylamino)piperidine-1-carboxylate (38 g, 113.6 mMol) and Pd(OH)2 (5 g) were stirred in methanol (250 mL) at rt under 50 psi hydrogen. After overnight stirring, the reaction mixture was filtered through Celite. The solution was concentrated to get the desired product, (3R,4S)-tert-butyl 4-amino-3-(hydroxymethyl)piperidine-1-carboxylate as a pale oil (quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[CH:7][C:8]3[CH:14]([CH3:15])[CH2:13][N:12](C(=O)C(F)(F)F)[CH2:11][CH2:10][C:9]=3[N:22]=[C:5]2[O:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:1][C:2]1[C:6]2=[CH:7][C:8]3[CH:14]([CH3:15])[CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[N:22]=[C:5]2[O:4][CH:3]=1
Reactant: Cc1coc2nc3c(cc12)C(C)CN(C(=O)C(F)(F)F)CC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1coc2nc3c(cc12)C(C)CNCC3
Temperature: 60 °C
Yield: 45.5 %

Procedure:
A mixture of 2-(allyloxy)-3-iodo-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (300 mg, 682 μmol), Pd(PPh3)2Cl2 (120 mg, 170 μmol), NaOAc (168 mg, 2.04 mmol) and DMA (20 ml) was heated for 30 min at 125 ° C. The reaction mixture was concentrated in vacuo and purified by column chromatography to give 68.0 mg (32%) of 3,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H -furo[3′,2′:5,6]pyrido[2,3-d]azepine. H-NMR (CDCl3) δ 7.68 (2× s, 1H), 7.46 (2× s, 1H), 4.25-3.25 (m, 7H), 2.24 (2× d, 3H), 1.44 (2×d, 3H) ppm. A mixture of 3,5-dimethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-furo[3′,2′:5,6]pyrido[2,3-d]azepine (62.0 mg, 199 μmol), K2CO3 (80 mg) and MeOH (6 ml) was heated for 1 h at 60° C. The reaction mixture was concentrated in vacuo and purified by column chromatography to give 19.6 mg (46%) of 3,5-dimethyl-6,7,8,9-tetrahydro-5H-furo[3′,2′:5,6]pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.69 (s, 1H), 7.47 (d, 1H), 3.63-3.33 (m, 5H), 3.06 (t, 1H), 2.87 (t, 1H), 2.25 (d, 3H), 1.54 (d, 3H) ppm.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@@H:14]2[C:18]([OH:20])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[S:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>C(Cl)Cl>[CH:1]1([CH2:10][C:11]([CH:13]2[S:17][CH2:16][NH:15][C@@H:14]2[C:18]([N:35]2[CH2:36][CH2:37][S:33][CH2:34]2)=[O:20])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Reactant: C1CSCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)N1CCSC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 54.7 %

Procedure:
0.60 g .COPYRGT.f 3-(2-indanylacetyl)-L-thioproline was suspended in 5 ml of methylene chloride. To the suspension was added 0.46 g of WSC HCl with stirring at room temperature. After 5 minutes, 0.18 g of thiazolidine dissolved in 5 ml of methylene chloride was added to the mixture, and the mixture was stirred for 17 hours at room temperature. The reaction mixture was washed with water, diluted hydrochloric acid, and saturated sodium hydrogen carbonate in this order. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to produce 0.40 g of 3-[3-(2-indanylacetyl)-L-thioprolyl]thiazolidine as a colorless oil (yield: 55%).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[N:18]=[CH:17][C:16]([NH2:19])=[CH:15][N:14]=2)[O:5][CH2:4][CH2:3]1.[CH3:20][C:21]([O:24][C:25]([NH:27][C@:28]([CH3:40])([CH2:38][CH3:39])[C:29](=[O:37])SC1C=CC=CN=1)=[O:26])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1>[CH3:40][C@:28]([NH:27][C:25](=[O:26])[O:24][C:21]([CH3:23])([CH3:22])[CH3:20])([C:29]([NH:19][C:16]1[CH:17]=[N:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH:2]([CH3:1])[CH2:3][CH2:4][O:5]3)=[N:14][CH:15]=1)=[O:37])[CH2:38][CH3:39]
Reactant: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Sc1ccccn1
Reactant: CC1CCOc2cccc(Oc3ncc(N)cn3)c21
Solvent: Cc1ccccc1
Product: CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)Nc1cnc(Oc2cccc3c2C(C)CCO3)nc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 78.2 %

Procedure:
2-[(4-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-5-pyrimidinamine (Intermediate 217, 144 mg, 0.56 mmol) was dissolved in toluene (8.0 mL) and S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 86 mg, 0.28 mmol) was added. The reaction mixture was stirred at 140° C. for 20 minutes. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 134 mg, 0.43 mmol) was added and the mixture was stirred at 140° C. for 15 minutes. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 100 mg, 0.32 mmol) was added and the reaction mixture was stirred at 50° C. overnight and at 80° C. and for 4 hours. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 100 mg, 0.32 mmol) was added and the reaction mixture was stirred at 80° C. for 20 hours. Additional S-2-pyridinyl (2R)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-2-methylbutanethioate (Intermediate 139, 50 mg, 0.16 mmol) was added and the reaction mixture was stirred for additional 30 hours at 80° C. After cooling volatiles were removed and the residue was purified by flash chromatography (Biotage SP1) on silica gel using a 10 g SNAP silica cartridge as column and cyclohexane/ethyl acetate from 10:0 to 1:1 as eluents affording the title compound (100 mg).
Reaction SMILES: FC(F)(F)C([O-])=O.C(OC([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N+:18]([CH2:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]([O:46][CH3:47])=[O:45])=[CH:40][CH:39]=2)([CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)[CH2:17]1)=O)(C)(C)C.[ClH:48]>O1CCOCC1>[ClH:48].[Cl-:48].[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N+:18]([CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[CH:40][C:41]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:43]=2)([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=2)[CH2:17]1
Reactant: COC(=O)c1ccc(CCC[N+]2(CCCc3ccc(C(=O)OC)cc3)CCCC(NC(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CCC[N+]2(CCCc3ccc(C(=O)OC)cc3)CCCC(N)C2)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-tert-butoxycarbonylamino-1,1-bis-[3-(4-methoxycarbonyl-phenyl)-propyl]-piperidinium trifluoroacetate (200 mg, 0.3 mmol) is dissolved in dioxane (10 ml), a 4 M solution of HCl in dioxane (10 ml, 40 mmol) is added, stirred at room temperature overnight and concentrated in vacuo. LC (method F): tR=1.49 min; Mass spectrum (ESI+): m/z=453 [M]+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[C:38]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]2)=[O:22])[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(S(C)(=O)=O)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(S(C)(=O)=O)CC2)n3-c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 108 h
Yield: 42.7 %

Procedure:
A suspension of 0.20 g (0.43 mmol) [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methanesulfonyl-piperazin-1-yl)-methanone (example 1), 0.20 g (1.30 mmol) 3-chlorophenylboronic acid, 0.16 g (0.86 mmol) copper(II) acetate and 0.14 mL (0.14 g, 1.73 mmol) pyridine in 5 mL chloroform was stirred 4.5 days at room temperature. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 75:25 v/v) as eluant to afford 105 mg (42%) of the desired compound as a light-brown foam. MS (ISP): 572.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH:13]=[CH:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CO.C(O)(=O)C>[Pd].O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(-c2ccc(F)cc2)s1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(-c2ccc(F)cc2)s1
Reaction time: 24 h

Procedure:
40 mg of 5% palladium on carbon were added to a solution of 500 mg (2.0 mmol) of 3-[5-(4-fluoro-phenyl)-thiophen-2-yl]-acrylic acid in 20 ml of tetrahydrofuran, and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for 24 h. 10 ml of methanol and 40 mg of 5% palladium on carbon were added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for further 24 hours. 10 ml of acetic acid were added and the reaction mixture was hydrogenated at atmospheric pressure and room temperature for another 24 h. The mixture was filtered and evaporated, and the product was purified by preparative RP HPLC eluting with a gradient of 0 to 100% acetonitrile in water (+0.01% TFA). After lyophilization, the product was obtained as a solid. Yield: 400 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[NH:5][C:6]1[N:11]=[C:10]([C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)[CH:9]=[CH:8][N:7]=1>CO.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[NH:5][C:6]1[N:11]=[C:10]([C:12]2[NH:13][CH:14]=[N:15][CH:16]=2)[CH:9]=[CH:8][N:7]=1
Reactant: Clc1cccc(Nc2nccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)n2)c1
Agent: Cl
Solvent: CO
Product: Clc1cccc(Nc2nccc(-c3cnc[nH]3)n2)c1
Reaction time: 0.25 h
Yield: 75.1 %

Procedure:
A mixture of 2-(3-chloroanilino)-4-(1-triphenylmethylimidazol-4-yl)pyrimidine (Method 2; 256 mg, 0.5 mmol) in MeOH (3 ml) and 2M hydrochloric acid (1 ml) was stirred for 15 minutes. The volatiles were removed by evaporation and the residue partitioned between EtOAc and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried and the solvent removed by evaporation. The residue was purified by column chromatography eluting with DCM and 7M methanolic ammonia solution (99.5:0.5 increasing in polarity to 93:7) to give the title compound 102 mg, (75%) as a solid. NMR: 6.95 (dd, 1H), 7.25-7.33 (m, 2H), 7.73 (dd, 1H), 7.81 (d, 2H), 8.06 (s, 1H), 8.46 (d, 1H), 9.68 (s, 1H), 12.48 (br s, 1H); m/z: 270.
Reaction SMILES: C([SiH](CC)CC)C.[CH:8]1([CH2:14][CH:15]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)CCC[CH2:10][CH2:9]1>FC(F)(F)C(O)=O>[CH2:14]([CH:15]1[CH2:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[O:16]1)[CH2:8][CH2:9][CH3:10]
Reactant: c1ccc2c(c1)CC(CC1CCCCC1)O2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCC1Cc2ccccc2O1

Procedure:
Reduction of 15 g (86.0 mmole) of the above product with triethylsilane in trifluoroacetic acid by the method of Preparation D, Part (iv), and purification of the crude product on a silica gel column, eluting with hexane and hexane containing 5% ethyl acetate and distillation of the combined product fractions gave 15.5 g of the title compound as a clear oil, b.p. 114°-120° C. 15 Torr. M.S. (m/e): 176 (M+), TLC Rf 0.55, hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=4)[OH:25])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11](COCC[Si](C)(C)C)[N:10]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH:24]([C:26]4[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=4)[OH:25])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[NH:11][N:10]=1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(O)c4ncccc4C)c3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cccc(C(O)c4ncccc4C)c3)cc12
Reaction time: 6 h
Yield: 14 %

Procedure:
The material from step 1 was dissolved in dichloromethane and 1 mL of trifluoroacetic acid was added. The resulting mixture was left at room temperature for 6 h. The solvent was then completely evaporated and the residue dissolved in dichloromethane. 0.5 mL (450 mg, 7.5 mmol) of ethylene diamine was added. After 2 h at room temperature the mixture was evaporated and the crude purified by mass-triggered reverse-phase HPLC to afford 52 mg (0.12 mmol, 14%) of {3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-(3-methyl-pyridin-2-yl)-methanol as an off-white solid. 1H-NMR (500 MHz, DMSO-d6) a 8.80 (d, 1H), 8.42 (d(d), 1H), 8.27 (d, 1H), 7.71 ((t), br. 1H), 7.68 (dd, 1H), 7.62 (d(m), 1H), 7.57 (d(m), 1H), 7.47 (dd(d), 1H), 7.43 (t, 1H), 7.34 (d(m), 1H), 7.26-7.23 (m, 2H), 7.10 (ddd, 1H), 5.99 (s, 1H), 3.84 (s, 3H), 2.27 (s, 3H) (exchangeable protons not visible in 1H-NMR); MS: m/z 423.2 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:16][C:17]1([CH3:27])[C@H:19]([CH:20]=[C:21]([Cl:23])[Cl:22])[C@H:18]1[C:24](Cl)=[O:25]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[CH3:16][C:17]1([CH3:27])[C@H:19]([CH:20]=[C:21]([Cl:22])[Cl:23])[C@H:18]1[C:24]([O:9][CH:6]1[CH2:7][CH:8]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH2:5]1)=[O:25]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@H]1C(=O)Cl
Reactant: C=CCC1=CCC(O)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=CCC1=CCC(OC(=O)[C@@H]2[C@@H](C=C(Cl)Cl)C2(C)C)C1
Yield: 57.8 %

Procedure:
To a mixture of (RS)-3-(2-propenyl)-3-cyclopenten-1-ol (100 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (82 mg) and toluene (5 ml), (1R)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (181 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 145 mg of (RS)-3-(2-propenyl)-3-cyclopenten-1-yl (1R)-trans-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarboxylate (Compound No. 29). Yield 57% nD25 1.5100