Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([O:19][CH3:20])=[O:18])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>CN(C=O)C.O>[CH3:16][C:11]1[N:12]([CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[C:31]([O:30][CH3:29])[CH:32]=2)[C:13](=[O:15])[CH2:14][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:8][CH:7]=2)[C:10]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COc1cccc(CBr)c1
Reactant: COC(=O)C1=C(C)NC(=O)CC1c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(Cc2cccc(OC)c2)C(=O)CC1c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 0.1 %

Procedure:
The product from Example 5, Step 1 (0.627 g, 2.00 mmol, 1.00 equiv) and cesium carbonate (0.975 g, 3.00 mmol, 1.50 equiv) were combined in DMF (9 mL) for 15 minutes at rt. 3-Methoxybenzyl bromide (0.436 mL, 3.12 mmol, 1.56 equiv) was added and the reaction was heated to 100° C. for 6 hours. The reaction was diluted with H2O and extracted with Et2O. The organic phase was washed with H2O and satd. NaCl, dried over MgSO4 and concentrated en vacuo to provide 0.762 mg (88%) of the title compound as an oil. MS (ES+) m/e 434 [M+H]+
Reaction SMILES: [OH:1][C@@H:2]([CH3:26])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:9][CH:10]=1.[C:27](O)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C>ClCCl>[C:27]([O:1][C@@H:2]([CH3:26])[CH2:3][O:4][C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:7][CH:6]=1)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCc1ccc(-c2ccc(-c3ncc(OC[C@H](C)O)cn3)cc2)cc1
Reactant: CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCC(=O)O[C@@H](C)COc1cnc(-c2ccc(-c3ccc(CCC)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
A solution of (S)-2-tetrahydropyranyloxy-1-(p-toluenesulfonyloxy)-propane (192 g, 0.62 mol) prepared in the same manner as in a process described in Example 1 of the specification of Japanese patent application No. Sho 61-133269/1986 in tetrahydrofuran (hereinafter abbreviated to THF) (2,000 ml) was added to a mixture of 60% sodium hydride (31 g, 0.62 mol), 5-hydroxy-2-(4'-propyl-4"-biphenylyl)pyrimidine (150 g, 0.52 mol) and THF (1,200 ml), followed by agitating the resulting mixture at 60° C. for 4 hours, allowing it to cool down to room temperature, adding toluene, washing the resulting organic layer with an alkali and then with water, concentrating it, dissolving the concentrate in ethanol (2,000 ml), adding 6N-hydrochloric acid (40 ml), agitating the mixture at 60° C. for one hour, allowing it to cool down to room temperature, collecting deposited crystals and recrystallizing them from ethyl acetate (1,000 ml) to obtain (S)-5-(2'-hydroxypropyloxy)-2-(4'-propyl-biphenyl-4-yl)-pyrimidine (122 g), which was a liquid crystal and had phase transition points of C-Ch point 161.0° C. and Ch-I point 208.1° C. This (S)-5-(2'-hydroxypropoxy)-2-(4'-propyl-biphenyl-4-yl)pyrimidine (10 g, 0.029 mol), n-pentanoic acid (4.4 g, 0.044 mol), dicyclohexylcarbodiimide (hereinafter abbreviated to DCC) (24 g, 0.12 mol) and dimethylaminopyridine (hereinafter abbreviated to DMAP) (3.9 g) were dissolved in dichloromethane (150 ml), followed by agitating the solution at room temperature for 2 hours, filtering off deposited crystals, washing the filtrate with an alkali and then with water, concentrating it and twice recrystallizing the residue from ethanol (200 ml) to obtain (S)-5-(2'-valeryloxypropoxy)-2-(4'-propyl-biphenyl-4-yl)-pyrimidine (9.8 g).
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:29][CH3:30])=[C:12](/[C:15](/[CH3:28])=[C:16](/[F:27])\[CH:17]=[CH:18]\[C:19](\[CH3:26])=[CH:20]\[C:21]([O:23]CC)=[O:22])[CH:13]=2)[O:8][C:7]([CH3:32])([CH3:31])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C.C1COCC1>[C:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:29][CH3:30])=[C:12](/[C:15](/[CH3:28])=[C:16](/[F:27])\[CH:17]=[CH:18]\[C:19](\[CH3:26])=[CH:20]\[C:21]([OH:23])=[O:22])[CH:13]=2)[O:8][C:7]([CH3:32])([CH3:31])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1/C(C)=C(F)\C=C\C(C)=C\C(=O)O)C(C(C)(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure G, a solution of ethyl 7-(4-tert-butyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-6-fluoro-3-methyl-octa-2E,4E,6E-trienoate (Compound 109, 32 mg, 0.07 mmol) in ethanol and THF was hydrolyzed with 1M NaOH. Purification by flash chromatography (silica gel, 75:25 hexane/ethyl acetate) afforded the title compound as a light yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH2:17][CH3:18])[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=3)[C:6]([CH3:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[O:22]=[C:23]1[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:44]([O:46]C)=[O:45])[CH:39]=3)[CH:36]=2)[O:31][C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:24]1>>[CH:1]1([N:4]2[C:12]3[C:7](=[C:8]([O:16][CH2:17][CH3:18])[CH:9]=[C:10]([C:13]([N:28]4[CH2:29][CH2:30][C:25]5([CH2:24][C:23](=[O:22])[C:37]6[C:32](=[CH:33][CH:34]=[C:35]([C:38]7[CH:43]=[CH:42][N:41]=[C:40]([C:44]([OH:46])=[O:45])[CH:39]=7)[CH:36]=6)[O:31]5)[CH2:26][CH2:27]4)=[O:15])[CH:11]=3)[C:6]([CH3:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOc1cc(C(=O)O)cc2c1c(C)cn2C1CC1
Reactant: COC(=O)c1cc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)ccn1
Agent: Cl
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4ccnc(C(=O)O)c4)ccc2O3)cc2c1c(C)cn2C1CC1

Procedure:
In the same manner as described in Example 42 except using 1-cyclopropyl-4-ethoxy-3-methyl-1H-indole-6-carboxylic acid and methyl 4-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)pyridine-2-carboxylate dihydrochloride, the title compound was obtained as a colorless amorphous substance. 1H-NMR (400 MHz, DMSO-d6) δ: 8.72 (1H, d, J=4.9 Hz), 8.25 (1H, d, J=1.5 Hz), 8.15-8.11 (2H, m), 7.94 (1H, dd, J=6.0, 2.0 Hz), 7.28 (1H, dd, J=6.0, 2.9 Hz), 7.12 (1H, d, J=1.0 Hz), 6.99 (1H, d, J=1.0 Hz), 6.48 (1H, s), 4.45-4.10 (1H, br m), 4.08 (2H, q, J=6.8 Hz), 3.67-3.19 (4H, m), 2.97 (2H, s), 2.32 (3H, s), 2.12-1.74 (4H, br m), 1.37 (3H, t, J=6.8 Hz), 1.03-0.98 (2H, m), 0.88-0.85 (2H, m); MS [M+H]+=580.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)=[CH:15][CH:14]=1)[OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]1(C2C3C(=C4C(=CC=3)C(C3C=CC=CC=3)=CC=N4)N=CC=2)C=CC=C[CH:30]=1.C(N(CC)CC)C>C(OCCCC)=C.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[C:4]([Si:1]([O:8][CH2:9][CH2:10][CH:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)=[CH:15][CH:14]=1)[O:12][CH:29]=[CH2:30])([CH3:3])[CH3:2])([CH3:6])([CH3:7])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: c1ccc(-c2ccnc3c2ccc2c(-c4ccccc4)ccnc23)cc1
Agent: [Pd+2]
Agent: C=COCCCC
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: C=COC(CCO[Si](C)(C)C(C)(C)C)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
3-(tert-Butyldimethylsilyloxy)-1-[4-(3,4-dichlorobenzyloxy)phenyl]propan-1-ol (300 mg, 0.680 mmol) produced in Example 27 (27B), palladium(II) trifluoroacetate (12 mg, 0.036 mmol), and 4,7-diphenyl-1,10-phenanthroline (12 mg, 0.036 mmol) were dissolved in butyl vinyl ether (5 mL), and triethylamine (20 μL, 0.14 mmol) was added thereto, and the resulting mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hours. After cooling to room temperature, the reaction solution was filtered, and the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 96:4 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (275 mg, yield: 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]=[O:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].Br[C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]([C:37]1[CH:38]=[CH:39][C:40]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:41][CH:42]=1)[OH:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(OC(F)(F)F)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The above 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole-3-carboxaldehyde and 1-bromo-4-(trifluoro-methoxy)benzene were treated in a manner similar to Example 25-(2) to give crude 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indol-3-yl 4-(trifluoromethoxy)phenyl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:15]C)=[O:13])[NH:7]2.[Mg].ClCCl.[Cl-].[NH4+]>CO>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH:6]([C:12]([O:14][CH3:15])=[O:13])[NH:7]2
Reactant: CCOC(=O)c1cc2c(OC)cccc2[nH]1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1Cc2c(cccc2OC)N1
Temperature: 25 °C

Procedure:
Ethyl 4-methoxyindole-2-carboxylate (0.95 g, 4.33 mmol) was dissolved in methanol (10 ml) and magnesium shavings (0.471 g, 19.37 mmol) were then added, with stirring, at room temperature under a nitrogen atmosphere. After the reaction started, a water bath was used to maintain the reaction temperature between 15-20° C. This mixture was stirred overnight. At the end of the reaction, dichloromethane (200 ml) was added to the mixture, followed by ammonium chloride solution (200 ml). The organic phase was separated out and the aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic phases were dried over magnesium sulphate and the solvent was removed to give a brown oil.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.CN(CC1CCCCC1)C1C=CC(F)=C(F)C=1F.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:26]1([CH2:25][N:15]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[C:17]=2[F:24])[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc(F)c(F)c2F)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CN(CC1CCCCC1)c1ccc(F)c(F)c1F
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCCC2)c2ccc(F)c(F)c2F)s1

Procedure:
The title compound was prepared via {2-[3-(cyclohexylmethyl)-3-(2,3,4-trifluoro-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using (methyl-cyclohexylmethyl-(2,3,4-trifluorophenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:10]2[CH2:15][CH2:14][C:13](=[CH:16][C:17]#[CH:18])[CH2:12][CH2:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(Br)(Br)(Br)[Br:20].[OH-].[K+]>C1C=CC=CC=1>[Br:20][C:18]#[C:17][CH:16]=[C:13]1[CH2:14][CH2:15][N:10]([C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=2)[CH2:11][CH2:12]1
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: BrC(Br)(Br)Br
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#CBr)CC1
Temperature: 65 °C
Reaction time: 11 h

Procedure:
A mixture of Compound 1c (200 mg, 0.82 mmol), CBr4 (0.54 mg, 1.65 mmol), potassium hydroxide (0.138 mg, 2.46 mmol), 18-C-6 crown ether (21.8 mg, 0.823 mmol) and 10 mL of benzene was stirred at 65° C. for 11 h.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:5][CH2:6][C:7]([O:9]CC1C=CC=CC=1)=[O:8]>[C].[Pd].CO>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 164 %

Procedure:
To a mixture of (S)-2-tert-butoxycarbonylamino-pentanedioic acid 5-benzyl ester 1-methyl ester (370 mg, 0.70 mmol; 66% purity) described in Manufacturing Example 2-1 and methanol (4 mL) was added palladium-carbon (40 mg, 0.19 mmol; 50% water content) at room temperature, which was stirred for 5 hours at room temperature under a hydrogen atmosphere (1 atm). The reaction mixture was replaced with nitrogen and filtered through a Celite pad. The solvent was evaporated from the filtrate under a reduced pressure, so as to obtain (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-methyl ester (300 mg) in a crude form. The crude product thus obtained was used directly in the next reaction. To a mixture of 3-(3-(4-(pyridin-2-yloxymethyl)-benzyl)-isoxazol-5-yl)-pyridin-2-ylamine (150 mg, 0.42 mmol) described in Reference Example 1 and acetonitrile (3 mL) were added (S)-2-tert-butoxycarbonylamino-pentanedioic acid 1-methyl ester (crude, 220 mg), N-methylmorpholine (46 μL, 0.42 mmol), and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate (180 mg, 0.46 mmol) in this order at 0° C., which was stirrer overnight at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1), so as to obtain the titled compound (37 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16](Cl)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccnc(Cl)c2)CC1
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: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccnc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)CC1

Procedure:
202 mg (0.68 mmol) of 4-(2-chloropyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, 256 mg (0.81 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane and 187 mg (1.36 mmol) of potassium carbonate are dissolved in 6 ml of acetonitrile and 650 μl of water. The reaction mixture is degassed a number of times, 78 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium are added under nitrogen atmosphere, the mixture is irradiated in the microwave at 120° C. for 90 min, subsequently diluted with water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4 and evaporated. The crude product is purified by column chromatography on RP silica gel.
Reaction SMILES: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)[C:12](=O)[CH:11]=C1.C(OC(Cl)=O)C(C)C>C(N(CC)CC)C>[CH:11]1[C:12]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:21]=1[OH:23]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1C=CC(=O)[C@@H]1CCCCCCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Product: Oc1ccc2ccccc2c1

Procedure:
Following the procedure of Example 1 but using 0.506 g. of PGA1, 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.327 g. of β-naphthol, there is obtained a crude residue. This residue is subjected to silica gel chromatograhy, eluting with ethyl acetate-hexane (2:3) followed by ethyl acetate-hexane (7:3). The residue obtained by concentration of selected fractions, 0.45 g., is crystallized from ethyl acetate diluted with two volumes of hexane as the title compound, white free-flowing crystals, m.p. 49.0°-50.0° C., having Rf 0.5 (TLC on silica gel in ethyl acetate-hexane (1:1)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:35])[NH:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23](OS(C(F)(F)F)(=O)=O)=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N#N.C([O-])([O-])=O.[K+].[K+].[CH2:44]([N:47]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]1)[CH:45]=[CH2:46]>CC#N.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:35])[NH:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:45]([CH2:44][N:47]3[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48]3)=[CH2:46])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCN1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1C(=O)OC(C)(C)C
Temperature: 80 °C

Procedure:
A solution of 2-[(6-trifluoromethanesulfonyloxy-1,2,3,4-tetrahydro-naphthalen-1-ylcarbamoyl)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (624 mg, 1.19 mmol) in CH3CN (6 mL) was purged with N2, and then added palladium(II)acetate (Strem Chemicals, 20 mg, 0.09 mmol), 1,1′-bis(diphenylphosphino)ferrocene (Aldrich, 211 mg, 0.38 mmol), K2CO3 (Aldrich, 299 mg, 2.16 mmol) and 1-allylpiperidine (Lancaster, 904 mg, 7.22 mmol). The mixture was heated to 80° C. overnight, cooled to RT, diluted with water (10 mL), and extracted with ether. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (26% EtOAc-Hexane) to provide the title compound. MS (ESI): 496 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:13]=[C:12]([N:22]4[CH2:26][C@@H:25]([O:27][CH3:28])[CH2:24][C@H:23]4[C:29](O)=[O:30])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.Cl.C(N=C=NCCCN(C)C)C.[NH2:44][C@@H:45]1[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]1.O.N1(O)C2C=CC=CC=2N=N1.CCN(CC)CC>CN(C=O)C>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:13]=[C:12]([N:22]4[CH2:26][C@@H:25]([O:27][CH3:28])[CH2:24][C@H:23]4[C:29]([NH:44][C@@H:45]4[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]4)=[O:30])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(c2nc(Nc3cc(C4CC4)[nH]n3)nc(N3CCOCC3)n2)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@H]1C[C@@H](C(=O)N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)N(c2nc(Nc3cc(C4CC4)[nH]n3)nc(N3CCOCC3)n2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
To a solution of 112B (900 mg, 1.653 mmol) in DMF (10 ml) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (951 mg, 4.96 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (993 mg, 4.96 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (253 mg, 1.653 mmol), and Et3N (1.382 ml, 9.92 mmol). The reaction mixture was stirred at RT for 14 h. The crude reaction mixture was purified by prep. HPLC to give 112C (800 mg, 79%). LC/MS [M+H]+: 613; Ret time (Method F): 2.99 min.
Reaction SMILES: CSCS(C)=O.[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][C:16]=1[CH:17]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO.[C:28]([O:31][CH2:32]C)(=[O:30])C>[OH-].[Na+]>[CH2:7]([O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][C:16]=1[CH2:17][C:28]([O:31][CH3:32])=[O:30])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOc1ccc(OCc2ccccc2)c(C=O)c1
Reactant: CCOC(C)=O
Agent: CSCS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1ccc(OCc2ccccc2)c(CC(=O)OC)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A mixture of methyl methylthiomethyl sulfoxide (1.94 g) and finely triturated sodium hydroxide (0.01 g) was stirred at 70° C. for 30 min. 2-Benzyloxy-5-ethoxybenzaldehyde (2.0 g) and methanol (10 mL) were added to the reaction mixture, and the mixture was further heated under reflux for 24 hrs. To the reaction mixture was added ethyl acetate, and the organic layer was washed successively with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. A mixture of the obtained residue and 10% hydrogen chloride-methanol (100 mL) was heated under reflux for 24 hrs. The reaction mixture was concentrated, and then ethyl acetate was added to the residue. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-(2-benzyloxy-5-ethoxyphenyl)acetate as a yellow oil (1.60 g, 69%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).