Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:14][CH:13]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-]>CO.[Pt]=O>[NH2:1][CH:4]([C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:17]=1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)CCCc1ccc(C(Cc2ccccc2)N=[N+]=[N-])cc1
Agent: O=[Pt]
Solvent: CO
Product: COC(=O)CCCc1ccc(C(N)Cc2ccccc2)cc1
Reaction time: 4.5 h
Yield: 75.8 %

Procedure:
To a solution of 3.10 g of methyl 4-[4-(1-azido-2-phenylethyl)phenyl]butyrate in 30 ml of methanol, 31 mg of platinum oxide was added, and hydrogenation was carried out at an ordinary temperature and under ordinary pressure for 4.5 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was added with dilute hydrochloric acid and washed with ether. The aqueous layer was made alkaline with potassium carbonate and then extracted with ether. The ether layer was washed with water and dried, and then the solvent was removed under reduced pressure to yield 2.16 g of brown oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.CC1(C)C(C)(C)OB(C2C=NNC=2)O1.ClC1C=CC(F)=C(C2C=C(C3C=NC=C(C4C=NN(CCN5CCCC5)C=4)C=3)C3C(=NC=CC=3)N=2)C=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C)C>COCCOC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([C:37]3[CH:36]=[N:35][N:34]([CH2:33][CH2:32][O:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)[CH:38]=3)[CH:3]=2)[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Fc1ccccc1-c1cc(-c2cncc(Br)c2)c2cccnc2n1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CN(C)C
Solvent: COCCOC
Solvent: O
Product: Fc1ccccc1-c1cc(-c2cncc(-c3cnn(CCOC4CCCCO4)c3)c2)c2cccnc2n1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
A slurry of 380 mg (1.00 mmol) 4-(5-bromo-pyridin-3-yl)-2-(2-fluoro-phenyl)-[1,8]naphthyridine, 354 mg (1.10 mmol) 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (prepared from 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole and 2-(2-bromo-ethoxy)-tetrahydro-pyran (in analogy to example 10) and 425 mg (2.00 mmol) tri-potassium-phosphate-trihydrate in 3 ml 1,2-dimethoxyethane was heated to 85° C. under nitrogen. Then 35.1 mg (0.05 mmol) bis-(triphenylphosphine)-palladium(II)-chloride and 14 μl trimethylamine were added. The reaction mixture was stirred for 16 hours at 85° C. The reaction mixture was cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and evaporated. The residue was chromatographed on a silica gel column with dichloromethane/methanol as eluent yielding yielding 2-(2-fluoro-phenyl)-4-(5-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-4-yl}-pyridin-3-yl)-[1,8]naphthyridine as yellow solid; HPLC-MS: 2.13 min, [M+H] 496.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(=O)([O-])[O-].[Ag+2].C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[C:6]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
A suspension of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (33.0 g), silver carbonate (35.0 g), benzyl bromide (44.4 g), and toluene (400 ml) was stirred at room temperature for 72 hrs. The mixture was filtered and the filtrate was concentrated. Trituration of the residue with petroleum ether gave 45.6 g (83%) of product.
Reaction SMILES: [O:1]=[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=[C:3]1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16]O)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)[Cl:25].S(Cl)(Cl)=O>O>[Cl:25][CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][N:9]([C:3]2[C:2](=[O:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:10][CH2:11]1
Reactant: O=c1cccccc1N1CCN(CCO)CC1
Reactant: ClC(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: O
Product: O=c1cccccc1N1CCN(CCCl)CC1

Procedure:
A mixture of 4-(2-oxo-3,5,7-cycloheptatrien-1-yl)-1-piperazine-ethanol (10.0 g, described in Example 7), potassium carbonate (26 g) and chloroform (150 ml) was stirred and cooled in an ice-bath. Thionyl chloride (11.7 g) was added dropwise over a period of 30 min and allowed to react with stirring at room temperature for 16 hr. Water (50 ml) was added and extracted with chloroform. After drying over magnesium sulfate, the extract was evaporated and the residue (11.0 g) was chromatographed on 500 g silica gel with ethyl acetate to yield 6.2 g of 2-[4-(2-chloroethyl)-1-piperazinyl]-2,4,6-cycloheptatrien-1-one mp 71°-73° C.; ir(CHCl3) 1560 cm-1 ; uv max(MeOH) 352 (ε=9730) and 255 nm(ε=14300); nmr(CDCl3) δ2.75 (m, 6H), 3.5 (m, 6H) and 7.0 (m, 5H) and Anal. Calcd for C13H17 --ClN2O: C, 61.77% H, 6.78% N, 11.08% and Found: C, 61.60% H, 6.79% N, 10.98%.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:8]=1[C:9]([OH:11])=[O:10].[CH3:17]O>>[OH:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:8]=1[C:9]([O:11][CH3:17])=[O:10]
Reactant: O=C(O)c1c(O)cccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(O)cccc1O

Procedure:
Concentrated sulfuric acid (40 ml) was carefully added to a solution of 2,6-dihydroxybenzoic acid (133 g, 0.86 mol) in absolute methanol (500 ml). The reaction mixture was heated at reflux temperature for 24 hours, cooled, and evaporated. The residue was added to aa saturated sodium hydrogencarbonate solution, and the resulting solid was collected by filtration, washed with water, and dried in vacuo over phosphorus peroxide; yield 49 g (34%). NMR (CDCl3, 60 MHz): δ4.02 (s, CO2CH3) p.p.m.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[H-].[Na+].Br[CH:14](O)[CH2:15][CH3:16].C(OCC)(=O)C>O1CCCC1>[CH2:14]([O:10][CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH2:15][CH3:16]
Reactant: OCCOCCOCCO
Reactant: CCC(O)Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCOCCOCCOCCO
Reaction time: 1 h
Yield: 17.9 %

Procedure:
Triethylene glycol (19.5 g, 0.13 mol) was dissolved in tetrahydrofuran (150 mL) and sodium hydride (2.60 g, 0.065 mol) was added portion wise over 0.5 h and the reaction was stirred for an additional 1 h. Then 1-bromopropanol (8.0 g, 0.065 mol) dissolved in tetrahydrofuran (30 mL) was added dropwise via addition funnel and the reaction was stirred overnight at room temperature. Crude reaction mixture was filtered through Celite, washed CH2Cl2, and evaporated to dryness. The resultant oil was dissolved in CH2Cl2 (250 mL), washed sat. NaCl (250 mL), H2O (250 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate) afforded 1 a yellowish oil (2.24 g, 18% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2)C=CC=1>[Cu]=O.N1C=CC=CC=1>[CH3:17][C:11]1[CH:10]=[C:15]([CH:14]=[CH:13][CH:12]=1)[O:16][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: Cc1cccc(O)c1
Reactant: O=Cc1cccc(Br)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: Cc1cccc(Oc2cccc(C=O)c2)c1
Temperature: 170 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
A mixture of 3-bromobenzaldehyde (7.01 g, 37.9 mmol), m-cresol (4.51 g, 41.7 mmol), copper oxide (II) (4.53 g, 56.9 mmol), potassium carbonate (7.86 g, 56.9 mmol), pyridine (50 mL) and quinoline (25 mL) was stirred under a nitrogen atmosphere at 170° C. for 24 hrs. The reaction mixture was cooled and pyridine was evaporated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was filtered off, and the filtrate was washed with 1 M hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound (5.80 g, 72%) as a pale-brown oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11][CH:12]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]=2[CH:25]=1)#[N:2].C(OC([C@H](CC)C(N)O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:70]([O:74][C:75]([NH:77][C@H:78]([CH2:81][CH3:82])[CH2:79]O)=[O:76])([CH3:73])([CH3:72])[CH3:71]>O1CCCC1>[C:70]([O:74][C:75]([NH:77][C@H:78]([CH2:81][CH3:82])[CH2:79][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH:12]([CH2:11][C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:25][C:7]=3[CH:8]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:23][CH:22]=1)=[O:76])([CH3:73])([CH3:72])[CH3:71]
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O)cc1
Reactant: CC[C@H](CO)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CC[C@@H](C(=O)OC(C)(C)C)C(N)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(OC[C@@H](CC)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.7 %

Procedure:
In 300 ml of tetrahydrofuran were dissolved 1.1 g of ethyl 3-(5-cyano-2-benzofuranyl)-2-(4-hydroxyphenyl)-propionate, 1.24 g of (2R)-2-tert-butoxycarbonyl-amino-1-butanol and 1.72 g of triphenylphosphine. The thus prepared solution was mixed with 1.14 g of diethyl azodicarboxylate and stirred at room temperature for 18 hours. The resulting solution was further mixed with 0.83 g of (2R)-2-tert-butoxycarbonylamino-1-butanol, 1.2 g of triphenylphosphine and 0.76 g of diethyl azodicarboxylate, and the mixture was stirred at room temperature for 18 hours. After concentrating the thus prepared reaction solution to dryness, the resulting residue was purified by subjecting it to silica gel column chromatography using a toluene/ethyl acetate mixture as a developing solvent, thereby obtaining 660 mg of ethyl 2-[4-[((2R)-2-tert-butoxycarbonylamino-1-butyl)oxy]phenyl]-3-(5-cyano-2-benzofuranyl)propionate in a colorless and oily form.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43])[CH3:37].Cl.O1CCOCC1.N>CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:43][C:42]3[CH:44]=[C:38]([CH2:36][CH3:37])[C:39]([N:47]4[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]4)=[CH:40][C:41]=3[O:45][CH3:46])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCc1cc(N)c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cc(Nc2nccc(-c3c(-c4ccc(OC)c(C(=O)Nc5c(F)cccc5F)c4)nc4ccccn34)n2)c(OC)cc1N1CCN(CCS(C)(=O)=O)CC1
Temperature: 180 °C
Yield: 38 %

Procedure:
In a microwave vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.246 g, 0.5 mmol) and 5-ethyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (0.171 g, 0.5 mmol) were taken up in 1,1,1-trifluoroethanol (3 mL) and 4M HCl in dioxane (0.25 mL, 1.0 mmol) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N NH3 in MeOH, and concentrated in vacuo onto silica gel and flash chromatographed. The desired fractions were combined and concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.150 g, 0.19 mmol, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.34 (dd, J=3.1, 2.2 Hz, 1H), 8.49 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.11 (d, J=1.3 Hz, 1H), 7.78 (dd, J=8.9, 1.4 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.54 (s, 1H), 7.33-7.50 (m, 2H), 7.28 (d, J=8.8 Hz, 1H), 7.18 (t, J=8.1 Hz, 2H), 6.94 (t, J=6.6 Hz, 1H), 6.83 (s, 1H), 6.57 (d, J=4.9 Hz, 1H), 3.98 (s, 3H), 3.80 (s, 3H), 3.28-3.40 (m, 2H), 3.06 (s, 3 H), 2.82-2.92 (m, 4H), 2.77 (t, J=6.5 Hz, 2H), 2.50-2.69 (m, 6H), 1.08 (q, J=7.0 Hz, 3H). MS (M+H, ES+) 797.
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:23]=[CH:22][C:10]([O:11][CH:12]([CH3:21])[C:13]([O:19][CH3:20])=[CH:14][C:15](OC)=[O:16])=[CH:9][CH:8]=2)=[C:4]([F:26])[CH:3]=1.CC(C[AlH]CC(C)C)C.CCOCC.C(O)(=O)C>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[CH:23]=[CH:22][C:10]([O:11][CH:12]([CH3:21])[C:13]([O:19][CH3:20])=[CH:14][CH2:15][OH:16])=[CH:9][CH:8]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=CCO)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a solution of 4.5 g (10.6 mmol) 4-(4-(4-bromo-2-fluorophenoxy)phenoxy)-3-methoxy-2-pentenoic acid, methyl ester in 25 ml toluene at -78° C. was added dropwise over a period of 30 min, 16.5 ml of 1.5M DIBAL-H in toluene, keeping the temperature below -60° C. The mixture was stirred for 21/2 hours at -78° C. To the mixture was added 17 ml of a 75:25:6 ether:acetic acid:water mixture, keeping the temperature below -60° C. The mixture was then allowed to warm to room temperature and the solid material was filtered off. The filtrate was washed twice with saturated NaHCO3 and once with water, dried over MgSO4 and the solvent was removed by rotary evaporation. The residue was purified by HPLC, eluting with 80:20 hexane:acetone, to give 3.1 g (74%) of the product as a pale yellow oil which was used immediately in the next reaction.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=1)(=O)=O.O[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:18][S:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][O:5][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)=[CH:9][CH:10]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Yield: 66.1 %

Procedure:
30 g (0.102 mole) 4-(methylsulfonyloxy)phenethyl methanesulfonate was dissolved in acetonitrile and slowly added to a mixture of 31.1 g (0.255 mole) p-hydroxybenzaldehyde and 41.46 g (0.3 mole) potassium carbonate in acetonitrile and refluxed until the starting material was consumed. The salt was filtered off, the solvent evaporated in vacuo, dichloromethane was added and the organic phase was washed with water. After evaporation of the solvent, purification by chromatography on silica gel using dichloromethane as eluent gave 21.6 g (yield 66%) of 4-[2-(4-formylphenoxy)ethyl]phenyl methanesulfonate.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH:9]([N:23]([C:25](=[O:40])[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH3:24])[CH:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C>O1CCCC1.CO>[F:33][C:32]([F:34])([F:35])[C:30]1[CH:31]=[C:26]([CH:27]=[C:28]([C:36]([F:38])([F:37])[F:39])[CH:29]=1)[C:25]([N:23]([CH:9]([CH:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:8][CH2:7][C:6]([OH:41])=[O:5])[CH3:24])=[O:40]
Reactant: CCOC(=O)CCC(C(c1ccccc1)c1ccccc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)C(c1ccccc1)c1ccccc1

Procedure:
45 ml of 1N sodium hydroxide are added to a solution of 15.2 g (27.6 mmol) of 4-[N-(3,5-bistrifluoromethyl-benzoyl)-N-methyl-amino]-5,5-diphenyl-pentanoic acid ethyl ester in 160 ml of tetrahydrofuran/methanol (2:1). After 2 hours the reaction mixture is concentrated by evaporation, diluted with water and rendered acidic with cold 2N hydrochloric acid. The white precipitate is filtered off, then washed with water and dried under a high vacuum at 50° C. The title compound is obtained in the form of a white solid. TLC: methylene chloride/methanol (95:5) Rf =0.21; Rt (HPLC)=18.5 min; 1H-NMR (400 MHz, d6 -DMSO, 120° C.) d 7.96 (br, 1H), 7.48-7.18 (m, 12H), 5.43 (br, 1H), 4.31 (d, 1H), 2.55 (br s, 3H). 2.36-2.19 (m, 2H), 1.91 (m, 1H), 1.73 (m, 1H); FAB-MS (M+H)+ =524.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:25])[C@H:14]([CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])[NH2:15].[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:48]=[CH:47][CH:46]=[C:45]3[C:41]=2[CH:42]=[N:43][N:44]3[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[Cl:26][C:27]1[CH:35]=[C:34]([C:36]([NH:38][CH2:39][C:40]2[CH:48]=[CH:47][CH:46]=[C:45]3[C:41]=2[CH:42]=[N:43][N:44]3[CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)=[O:37])[CH:33]=[CH:32][C:28]=1[C:29]([NH:15][C@H:14]([C:13]([O:12][CH3:11])=[O:25])[CH2:16][NH:17][C:18]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)=[O:19])=[O:30]
Reactant: O=C(NCc1cccc2c1cnn2C1CCCCO1)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1cccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1cccs1)NC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
Diisopropylethylamine (0.147 mL, 0.84 mmol) was added to a solution of 3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester hydrochloride (Example 301; 58 mg, 0.22 mmol), 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid (Example 39; 70 mg, 0.169 mmol), HBTU (78 mg, 0.21 mmol), and HOBT (27 mg, 0.20 mmol) in DMF (2 mL). The solution was allowed to stir at room temperature overnight, and it was then concentrated to remove most of the DMF. Ethyl acetate was added, and the solution was washed with saturated aqueous sodium hydrogen carbonate (twice), dilute acid, and brine, dried (MgSO4), filtered, evaporated and chromatographed (2% methanol/dichloromethane) to give N-[2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoyl]-3-(thiophene-2-carbonyl)amino-L-alanine, methyl ester (108 mg, 102%) as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41](O)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[C:39]([O:47][C:48](=[O:50])[CH3:49])=[C:40]([CH:44]=[CH:45][CH:46]=2)[C:41]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:42])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2OC(C)=O)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)Nc3ccc(OC)cc3)c2OC(C)=O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.7 %

Procedure:
p-Methoxyaniline (0.104 g, 0.845 mmol), triethylamine (0.085 g, 0.845 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.143 g, 0.845 mmol) were added to a methylene chloride solution (20 ml) of 3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.158 g, 0.422 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=30:1) and then recrystallized from isopropyl ether to obtain the titled compound (0.066 g, 0.138 mmol, 33%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][CH:18]2[C:16]([C:20]#[N:21])([CH2:17]2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C(OCC)C.O1CCCC1>[NH2:21][CH2:20][C:16]12[CH2:17][CH:18]1[CH2:19][N:14]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:15]2
Reactant: N#CC12CC1CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: NCC12CC1CN(Cc1ccccc1)C2
Reaction time: 18 h

Procedure:
Lithium aluminum hydride (70 ml of a 1M solution in diethyl ether, 70 mmol) was added to a solution of 3-benzyl-1-cyano-3-azabicyclo[3.1.0]hexane (3.35 g, 16.9 mmol) in tetrahydrofuran (200 ml). After 18 hours at room temperature, the reaction mixture was treated sequentially with water (2.6 ml), sodium hydroxide (2.6 ml of a 15% aqueous solution), and water (7.8 ml). The mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the title product as a viscous, slightly yellow oil (3.47 g, 100% yield), which was used without purification. 1H NMR (CDCl ): 7.20 (m, 5H), 3.54 (AB quartet, J=12 Hz, 2H), 2.92 (d, J=8 Hz, 1H), 2.87 (d, J=9 Hz, 1H), 2.81 (d, J=13 Hz, 1H), 2.59 (d, J=13 Hz, 1 H), 2.33 (dd, J=8, 4 Hz, 1H), 2.25 (d, J=7 Hz, 1H), 1.10 (m, 1H), 0.97 (m, 1H), 0.30 (dd, J=8, 5 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][CH:12]=[O:13].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>>[CH:2]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][CH:12]=[O:13])=[O:1]
Reactant: COc1ccc(NC=O)c(CO)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Product: COc1ccc(NC=O)c(C=O)c1

Procedure:
5.00 g of the product from stage 2 were oxidised with pyridinium dichromate as described in Example 1, stage 2, 3.62 g (72% of theory) of the title compound being obtained.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]([OH:11])[CH2:9][CH3:10])[CH2:4][CH2:3]1>C(OC)(C)(C)C.O.OS(O)(=O)=O>[CH2:9]([C:8]([CH:5]1[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]1)=[O:11])[CH3:10]
Reactant: CCC(O)C1CCC(C)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: COC(C)(C)C
Product: CCC(=O)C1CCC(C)CC1
Temperature: 22.5 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
A solution of 44 g (0.3 mol) of the alcohol of Example 1 in 200 ml of methyl tert-butyl ether (MTBE) was treated at not more than 20° C. with a solution of 42.9 g of Na2Cr2O7*2H2O in 210 ml of water and 35 ml of concentrated H2SO4. After the mixture had been stirred for approximately 16 hours at 20-25° C., the phases were separated and the aqueous phase was extracted with MTBE. After washing with water and drying, the combined organic phases [lacuna] distilled. The distillation gave 34.3 g of 4-methylcyclohexyl ethyl ketone as a colorless oil of b.p.50 of 114-116° C. According to 13C NMR analysis, the ratio between the cis and trans isomers in the mixture amounted to approximately 30:70.