Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[O:11])[O:9][C:8]([CH3:13])([CH3:12])[O:7][C:6]=2[CH:14]=1.CCN(C(C)C)C(C)C.[CH:24]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)Cl>[CH:24]1([CH2:29][CH2:30][C:31]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[O:11])[O:9][C:8]([CH3:12])([CH3:13])[O:7][C:6]=3[CH:14]=2)=[O:32])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Reactant: O=C(Cl)CCC1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC(=O)c2ccc(NC(=O)CCC3CCCC3)cc2O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
To a cold (0° C.) solution of 7-amino-2,2-dimethyl-4H-1,3-benzodioxine-4-one (1.93 g, 10.0 mmol) and DIEA (1.55 g, 12.00 mmol) in DCM (50 mL) was added drop-wise a solution of 3-cyclopentylpropionyl chloride (Aldrich, 1.93 g, 12.0 mmol) in DCM. The reaction was stirred at 0° C. for 1 hr, then at rt for 3 hrs. The reaction mixture was washed with an aqueous solution of HCl (1N). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (30/70)) gave 3.05 g (96%) of the title compound as a pale yellow oil. HPLC, Rt: 4.26 min (purity: 99.6%). LC/MS, M+(ESI): 318.2, M−(ESI): 316.2. 1H NMR (CDCl3) δ: 8.13 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.05 (dd, J=1.9 Hz, J=8.4 Hz, 1H), 2.41 (t, J=7.6 Hz, 2H), 1.80-1.45 (m, 15H), 1.17-1.00 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[C:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[C:10]=2[NH2:16])=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[CH:3]1.C(Cl)Cl.CO>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[C:6]([C:7]2[NH:16][C:10]3[C:11]([NH2:15])=[N:12][CH:13]=[N:14][C:9]=3[CH:8]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2ccccc2)c1C#Cc1ncnc(N)c1N
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: Cn1cnc(-c2ccccc2)c1-c1cc2ncnc(N)c2[nH]1
Yield: 6 %

Procedure:
6-[(1-Methyl-4-phenyl-1H-imidazol-5-yl)ethynyl]pyrimidine-4,5-diamine (intermediate 90) (50 mg) and CuI (3 mg) in DMF (2 mL) were heated at 110° C. under an inert atmosphere for 4 hours. The reaction mixture was loaded on to a 1 g SCX column prewashed with DCM:MeOH (3:1). The column was eluted with DCM:MeOH (3:1) and then the product eluted with 7N NH3/MeOH:DCM:MeOH (1:3:1). The product fraction was concentrated and then purified by flash chromatography on silica eluting with DCM:MeOH (9:1) to afford the title compound as a yellow solid (3 mg, 6%);
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])=[C:4]([F:15])[CH:3]=1.[Li]CCCC.[CH3:21][C:22]([CH3:24])=[O:23]>>[CH2:10]([O:9][CH:8]([O:12][CH2:13][CH3:14])[C:5]1[CH:6]=[CH:7][C:2]([C:22]([OH:23])([CH3:24])[CH3:21])=[CH:3][C:4]=1[F:15])[CH3:11]
Reactant: CC(C)=O
Reactant: CCOC(OCC)c1ccc(Br)cc1F
Agent: [Li]CCCC
Product: CCOC(OCC)c1ccc(C(C)(C)O)cc1F

Procedure:
The title compound was prepared as described in Example 15, Step 3 using 4-bromo-1-(diethoxymethyl)-2-fluorobenzene (2.8 g, 0.01 mol), n-BuLi (4.8 mL of 2.5M, 0.012 mol), and acetone (0.96 mL, 0.013 mol) as starting materials. 1H NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 7.47 (d, 1H), 7.26 (s, 1H), 7.28 (d, 1H), 5.74 (s, 1H), 3.62 (s, 2H), 3.47-3.52 (m, 2H), 1.48 (s, 6H), 1.16 (t, 6H).
Reaction SMILES: [C:1]([CH:3]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([NH:6][NH2:7])=[O:5])#[N:2].[F:14][C:15]([F:26])([F:25])[C:16](=O)[CH2:17][C:18](=O)[C:19]([F:22])([F:21])[F:20]>>[C:8]1([C:3]2[C:4]([OH:5])=[N:6][N:7]3[C:18]([C:19]([F:20])([F:22])[F:21])=[CH:17][C:16]([C:15]([F:14])([F:25])[F:26])=[N:2][C:1]=23)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C(=O)NN)c1ccccc1
Product: Oc1nn2c(C(F)(F)F)cc(C(F)(F)F)nc2c1-c1ccccc1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 28.1 %

Procedure:
2-Cyano-2-phenylacetohydrazide [Int-1A] (1.00 g, 5.13 mmol, 1.0 eq) and 1,1,1,5,5,5-hexafluoropentane-2,4-dione (1.07 g, 5.13 mmol, 1.0 eq) were dissolved in 16.6 mL acidic acid and stirred for 3.5 h at 60° C. The reaction mixture was allowed to stir at rt overnight. The precipitate was isolated by filtration. The solid was washed with hexane and dried to give 500 mg (27% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=1)(=[O:33])=[O:32]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][S:31]([C:34]3[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[C:36]([OH:43])[CH:35]=3)(=[O:33])=[O:32])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1
Product: O=C(O)c1ccc(S(=O)(=O)Oc2ccc(-c3ccc(-c4c(Cc5ccccc5)sc5ccccc45)cc3)cc2)cc1O

Procedure:
The title compound was prepared from 4′-(2-Benzyl-benzo[b]thiophen-3-yl)-biphenyl-4-ol and 4-chlorosulfonyl-2-hydroxy-benzoic acid, in substantially the same manner, as described in Example 1 step g, and was obtained as a white solid, mp 236-238° C.; MS m/e 591 (M−H)+;
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1.F[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[C:28]#[N:29]>>[C:28]([C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[O:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][C@:10]3([CH2:16][CH2:15][NH:14][C:13]3=[O:17])[N:9]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:4][CH:3]=1)#[N:29]
Reactant: N#Cc1ccccc1F
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(O)cc2)CC[C@]12CCNC2=O
Product: CC(C)(C)OC(=O)N1[C@@H](c2ccc(Oc3ccccc3C#N)cc2)CC[C@]12CCNC2=O
Yield: 66 %

Procedure:
1,1-Dimethylethyl (2R,5R)-2-{4-[(2-cyanophenyl)oxy]phenyl}-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D28, 58 mg, 66%) was synthesized using a similar procedure as set out earlier in Description 13 using 1,1-dimethylethyl (2S,5R)-2-(aminocarbonyl)-5-(4-hydroxyphenyl)-2-methyl-1-pyrrolidinecarboxylate (D25, 66 mg, 0.198 mmol) and 2-fluoro-benzonitrile; Rt (HPLC): 5.34 min; MS: (ES/+) m/z: 456 [M+Na+]; C25H27N3O4 requires 433.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH3:17])([CH3:16])[C:4]=2[CH:3]=1.[CH:18]1[C:26]2[C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[S:23][C:22]=2[CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.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.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.[Pd]>[Br:15][C:8]1[CH:7]=[C:6]2[C:11]([C:12]3[CH:13]=[CH:14][C:2]([C:28]4[CH:29]=[CH:30][C:24]5[S:23][C:22]6[CH:21]=[CH:20][CH:19]=[CH:18][C:26]=6[C:25]=5[CH:27]=4)=[CH:3][C:4]=3[C:5]2([CH3:16])[CH3:17])=[CH:10][CH:9]=1
Reactant: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Reactant: OB(O)c1ccc2sc3ccccc3c2c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)c2cc(Br)ccc2-c2ccc(-c3ccc4sc5ccccc5c4c3)cc21
Reaction time: 12 h
Yield: 50 %

Procedure:
2,7-dibromo-9,9-dimethyl-9H-fluorene (5.0 g, 14.201 mmol), dibenzo[b,d]thiophen-2-ylboronic acid (1.62 g, 7.10 mmol), Pd(pph3)4 (820 mg, 0.71 mmol), K2CO3 (1.96 g, 14.201 mmol) were put in a 250 mL two-neck flask and dissolved in toluene/H2O. The solution was refluxed and stirred for 12 hours. After completion of the reaction, the solution was distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of hexane and methylenechloride (9:1). The solution was distilled under reduced pressure and was re-crystallized in a solution of methylene chloride and petroleum ether such that the white solid compound was obtained, (1.61 g, yield: 50%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:31]2[N:32]=[C:33]([O:41][C@@H:42]([C@H:44]3[CH2:48][NH:47][C:46](=[O:49])[CH2:45]3)[CH3:43])[C:34]3[N:35]([N:37]=[CH:38][C:39]=3[CH3:40])[CH:36]=2)[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[O:50]1[CH2:53][C:52](=O)[CH2:51]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:31]2[N:32]=[C:33]([O:41][C@@H:42]([C@H:44]3[CH2:48][NH:47][C:46](=[O:49])[CH2:45]3)[CH3:43])[C:34]3[N:35]([N:37]=[CH:38][C:39]=3[CH3:40])[CH:36]=2)[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:26][CH2:27][N:28]([CH:52]2[CH2:53][O:50][CH2:51]2)[CH2:29][CH2:30]1
Reactant: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCNCC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2cn3ncc(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C2COC2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
N,N-diisopropylethylamine (0.02 mL, 0.09 mmol) was added to a mixture of (R)-4-((R)-1-(6-(3-methoxy-4-(piperazin-1-yl)phenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yloxy)ethyl)pyrrolidin-2-one 2,2,2-trifluoroacetate 5.60 (21.45 mg, 0.04 mmol) in THF (1.5 mL) at room temperature. 3-Oxetanone (0.03 mL, 0.39 mmol) was added, followed by sodium triacetoxyborohydride (58 mg, 0.27 mmol) and mixture was heated at 50° C. After 3 hours, mixture was cooled to room temperature, diluted with 20 mL ethyl acetate, and washed with 8 mL water/10 mL sat Na2CO3(aq). Layers were separated and aqueous layer was extracted with ethyl acetate. Combined organics were dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (0-12% MeOH/CH2Cl2) to yield (R)-4-((R)-1-((6-(3-methoxy-4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-3-methylpyrazolo[1,5-a]pyrazin-4-yl)oxy)ethyl)pyrrolidin-2-one 5.63 (9 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[N:4]=1.[OH:14][CH2:15][C:16]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.CC(C)([O-])C.[K+]>O1CCCC1.O>[Cl:13][C:5]1[N:4]=[C:3]([CH2:2][O:14][CH2:15][C:16]2([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: FC(F)(F)c1cc(Cl)nc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc(Cl)n2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(bromomethyl)-6-chloro-4-(trifluoromethyl)pyridine (1.1 g, 4.1 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (1.0 g, 3.4 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. The reaction was treated with potassium tert-butoxide (763 mg, 6.8 mmol) portion wise. The reaction was stirred at 0° C. for 1 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over magnesium sulfate, and concentrated. Column chromatography on silica gel (10% ethyl acetate/hexanes) gave 837 mg (52%). 1H-NMR (CDCl3, 400 MHz) δ 7.31-7.38 (m, 6H), 7.18 (s, 1H), 4.48 (s, 2H), 3.74-3.79 (m, 2H), 3.50 (s, 2H), 2.99-3.06 (m, 2H), 2.21-2.25 (m, 2H), 1.83-1.86 (m, 2H), 1.42 (s, 9H). Mass spec.: 485.11 (MH)+.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:49]([O:50][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([O:43][CH2:44][CH:45]=[C:46]([CH3:48])[CH3:47])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:58]([CH3:60])[CH3:59])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>O1CCCC1>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:49]([OH:50])[CH:41]6[CH:42]([O:43][CH2:44][CH:45]=[C:46]([CH3:48])[CH3:47])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:58]([CH3:60])[CH3:59])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)=CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Yield: 118.4 %

Procedure:
31 mg of compound (42) was stirred together with 1.23 ml of dry tetrahydrofuran and 55.3 μl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution at room temperature for 3 hours. The reaction solution was concentrated in vacuo to give the crude reaction product. It was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×20 cm) and eluted with n-hexane-ethyl acetate (4:1) to give 31.7 mg of compound (43) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[C:13](B1OC(C)(C)C(C)(C)O1)([CH3:15])=[CH2:14].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1)([CH3:15])=[CH2:14]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Brc1cccc(C2OCCO2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cccc(C2OCCO2)c1
Temperature: 90 °C
Yield: 66.3 %

Procedure:
A degassed solution of 2-(3-bromo-phenyl)-[1,3]dioxolane (3.46 ml, 22.6 mmol) in dimethoxyethane (60 ml) was added into a tube which has been charged with a mixture of 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (3.8 g, 22.6 mmol) and an aqueous solution of sodium carbonate (1M, 20 ml); tetrakis(triphenylphosphine)palladium(0) (0.266 g) is then added, the tube is sealed and heated to 90° C. overnight. After cooling of the reaction mixture, water (20 ml) was added, the aqueous layer separated and extracted with dichloromethane (3×20 ml). The combined organic layers were dried over sodium sulphate and evaporated. The crude product was purified by chromatography on silica gel using cyclohexane as the eluent. There were obtained 2.85 g (68% of theory) of the 2-(3-isopropenyl-phenyl)-[1,3]dioxolane.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].C[O:12][CH:13](Cl)Cl.[Cl-].[NH4+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:10][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[CH:6]=[C:5]([CH3:9])[C:4]=1[CH:13]=[O:12]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(C)c(C)c(O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1cc(C)c(C=O)c(O)c1C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
A solution of 2,3,5-trimethylphenol (13.6 g, 100 mmol,) in dichloromethane (20 mL) was ice-cooled, titanium tetrachloride (41.7 g, 220 mmol) was added dropwise over 0.5 hr under nitrogen atmosphere, and the reaction mixture was stirred for 1 hr. Dichloromethyl methyl ether (11.5 g, 100 mmol) was added dropwise, and the mixture was further stirred for 6 hr. The reaction mixture was treated with saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The extract was washed successively with diluted hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-50:50) to give the title compound (6.58 g, yield 40%) as pale-brown crystals.
Reaction SMILES: [CH2:1]([C:3]([OH:33])([CH2:31][CH3:32])[CH2:4][CH2:5]/[CH:6]=[C:7](\[C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][CH:30]=1)[O:12][CH2:13][C:14]1[CH:15]=[C:16]([C:24](OC)=[O:25])[C:17](=[CH:22][CH:23]=1)[C:18](OC)=[O:19])/[CH3:8])[CH3:2].[BH4-].[Li+]>>[OH:25][CH2:24][C:16]1[CH:15]=[C:14]([CH:23]=[CH:22][C:17]=1[CH2:18][OH:19])[CH2:13][O:12][C:11]1[CH:10]=[C:9](/[C:7](/[CH3:8])=[CH:6]\[CH2:5][CH2:4][C:3]([CH2:31][CH3:32])([OH:33])[CH2:1][CH3:2])[CH:30]=[CH:29][CH:28]=1
Reactant: CCC(O)(CC)CC/C=C(/C)c1cccc(OCc2ccc(C(=O)OC)c(C(=O)OC)c2)c1
Agent: [BH4-]
Agent: [Li+]
Product: CCC(O)(CC)CC/C=C(/C)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 53(e), by reacting 431 mg (0.95 mmol) of dimethyl 4-[3-((Z)-5-ethyl-5-hydroxy-1-methylhept-1-enyl)phenoxymethyl]-phthalate with 83 mg (3.8 mmol) of lithium borohydride, a colourless oil is obtained (m=286 mg; Y=76%).
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH2:34]([N:36]([CH2:42][CH3:43])[CH:37]1[CH2:41][CH2:40][NH:39][CH2:38]1)[CH3:35]>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:39]4[CH2:40][CH2:41][CH:37]([N:36]([CH2:42][CH3:43])[CH2:34][CH3:35])[CH2:38]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CCN(CC)C1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C1CCN(c2ccc3c(C(=O)NC[C@@]4(O)CCC[C@@H](C)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-diethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 3H), 0.83 (d, 3H). m/z: 474 [M+H]
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N:15][NH2:16])[C:4]=2[CH:3]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[N+:15]=[N-:16])[C:4]=2[CH:3]=1
Reactant: NN=C1c2ccccc2-c2ccc(F)cc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: [N-]=[N+]=C1c2ccccc2-c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 101 %

Procedure:
A mixture of (12) (6.5 g, 30.6 mmoL) and activated manganese dioxide (13 g, 150 mmoL, 5 eq) in tetrahydrofuran (300 mL) was stirred at room temperature for 18 h. The reaction was then filtered through celite and concentrated to provide 6.5 g (100%) of product (13) as a red solid which was used without further purification. A sample recrystallized from ether/hexane provided the following data: mp 89°-90 ° C.; IR (KBr) 2075, 1180 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.88-7.79 (m, 2H), 7.49-7.26 (m, 3H), 7.15 (bdd, 1H, J=2.3, 8.9Hz), 7.01 (ddd, 1H, J=2.3, 8.5, 9.3 Hz); MS m/z 210 (M+), 182 (base peak).
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[CH2:20][CH2:21][C:22]([OH:24])=O)[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH:38][C:22](=[O:24])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]1[CH:5]=[C:6]([C:14]([F:15])([F:17])[F:16])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1
Reactant: COc1ccccc1CN
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1CNC(=O)CCC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This is the compound of Example 3. It can be prepared also by the following synthesis method: a mixture of 0.495 g of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pentanoic acid, 0.137 g of 2-methoxy-benzylamine, 0.21 g of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride, 0.134 g of 4-dimethylaminopyridine and 10 ml of methylene chloride is stirred at room temperature for 16 hours and then concentrated by evaporation. The residue is chromatographed (silica gel, hexane/ethyl acetate 1:1). In this way the title compound is obtained in the form of a colourless amorphous solid. 1H-NMR, 400 MHz, DMSO, 150°, delta (ppm): 7.95(s, 1H), 7.50(s, 2H), 7.43(s, 1H), 7.3-7.1(m, 6H), 6.95(d, 1H), 4.23(d,2H), 3.80(s, 3H), 2.9-2.7(m, 5H), 2.25(m, 2H), 1.92(m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:24][O:25][C@@H:26]1[CH2:30][NH:29][C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C>[CH3:24][O:25][C@@H:26]1[CH2:30][N:29]([C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)[C@H:28]([CH2:31][O:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)[CH2:27]1
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@H](OC)CN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 97.3 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (375 mg, 1.19 mmol), methyl 4-[(2S,4S)-4-methoxy-2-pyrrolidinyl]methoxybenzoate (317 mg, 1.19 mmol), EDC.HCl (342 mg, 1.79 mmol), HOBT (242 mg, 1.79 mmol) and Et3N (0.83 ml, 5.95 mmol) in DMF (5 ml) was stirred at room temperature for 13 h. The mixture was poured into ice water and extracted with EtOAc. The combined extracts were washed with ice water and brine. After dried over Na2SO4, the extracts were concentrated in vacuo. The residue was chromatographed on silica gel [50 g, CHCl3/Aectone (10/1)CHCl3/MeOH (20/1)], to give methyl 4-[(2S,4S)-4-methoxy-1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxybenzoate (650 mg, 98%) as a pale brown amorphous solid 1H-NMR (CDCl3) δ2.03 (m, 1H), 2.31 (s, 3H), 2.32 (m, 1H), 3.29 (d, J=1.0 Hz, 3H), 3.57-3.68 (m, 5H), 3.88 (d, J=1.0 Hz, 3H), 3.99-4.06 (m, 2H), 4.46 (m, 1H), 6.19 (m, 1H), 6.80 (s, 1H), 6.81 (d, J=9.0 Hz, 1H), 6.96-7.19 (m, 4H), 7.29 (m, 2H), 7.50 (d, J=6.7 Hz, 1H), 7.95-8.10 (m, 3H); MS (ESI) m/z 562 (M++1).