Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][C:12]([CH3:14])=O)[C:7]=2[CH:15]=1.[N:16]1([C:22]2[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=2[N:30]=[CH:29][CH:28]=[CH:27]3)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][CH:12]([N:19]3[CH2:20][CH2:21][N:16]([C:22]4[CH:23]=[CH:24][CH:25]=[C:26]5[C:31]=4[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:17][CH2:18]3)[CH3:14])[C:7]=2[CH:15]=1
Reactant: c1cnc2c(N3CCNCC3)cccc2c1
Reactant: COc1ccc2occ(CC(C)=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc2occ(CC(C)N3CCN(c4cccc5cccnc45)CC3)c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred mixture of 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazino quinoline (213.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol) was added at room temperature. Reaction mixture was stirred at room temperature for 72 hrs. At the end, reaction mixture was neutralized with 10% NaHCO3 and extracted with chloroform. The organic layer was dried over anhydrous MgSO4, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown semi-solid. Yield: 60 mg (14%); (M+H): 402; 1HNMR (400 MHz, CDCl3): δ 8.90˜8.88 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.13˜8.10 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.60˜6.70 (m, 8H); 3.87 (s, 3H); 3.50˜2.50 (m, 11H); 1.15˜1.13 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:13])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
To a −78° C. solution of (3,4-dichloro-phenyl)-acetonitrile (5.0 g, 26.9 mmol) in THF (60 mL) was added LHMDS (1 M in THF, 28.2 mL, 28.2 mmol). The reddish orange solution was stirred at −78° C. for 1 h and MeI (1.76 mL, 28.2 mmol) was added. The mixture was allowed to warm to rt overnight. The mixture was diluted with 1 M HCl (20 mL) and extracted with Et2O (3×). The combined organic layers were dried (MgSO4) and concentrated to provide a dark brown oil. The crude product was purified by flash chromatography (hexanes/EtOAc) to provide a colorless oil (5.0 g, 93%). 1H NMR (400 MHz, CDCl3): 7.52-7.42 (m, 2H), 7.25-7.18 (m, 1H), 3.88 (q, J=7.3, 1H), 1.64 (d, J=7.3, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:12]([CH3:14])=[O:13])=[C:9]([NH2:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O:16][C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N:25]2[CH:29]=[C:28]([C:30]3[CH:31]=[N:32][N:33]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:34]=3[CH2:35][CH3:36])[N:27]=[CH:26]2)[CH:19]=1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:12]([CH3:14])=[O:13])=[C:9]([NH:11][C:17](=[O:16])[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([N:25]3[CH:29]=[C:28]([C:30]4[CH:31]=[N:32][N:33]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[C:34]=4[CH2:35][CH3:36])[N:27]=[CH:26]3)[CH:19]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Reactant: CS(=O)c1ccc(C(C)(C)C)cc1N
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)ccc4S(C)=O)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 156 was prepared from 5-tert-butyl-2-methanesulfinyl-phenylamine and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 566 [C33H35N5O2S+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>O1CCCC1>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CNCCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCc1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.3 %

Procedure:
A solution of chloroacetylchloride (10.0 g, 88.7 mmol) in tetrahydrofuran (50 mL) was added to a solution of N-methylphenethylamine (10.0 g, 73.9 mmol) and triethylamine (11.2 g, 110.8 mmol) in tetrahydrofuran (200 mL) cooled by a water/ice bath. The reaction mixture was allowed to warm to ambient temperature. After stirring for 6 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give SiO2, 1:1 ethyl acetate/hexane) to give 13.5 g (86.6%) of brown oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[N:9]1([C:14](N2C=CN=C2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1>CCl>[N:9]1([C:14]([O:8][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[O:15])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCC1CCCCO1
Agent: CCl
Product: O=C(OCC1CCCCO1)n1ccnc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
A mixture of (tetrahydro-2H-pyran-2-yl)methanol (369 mg, 3.18 mmol) and di(1H-imidazol-1-yl)methanone (1.0 g, 6.36 mmol) in 0.3 M CH3Cl (10 mL) was stirred at 50° C. for 3 h. After allowing the reaction to cool to room temperature, the solvent was evaporated under reduced pressure giving (tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (412 mg) which was used without further purification. LC/MS: m/z 211.1 (M+H)+ at 0.94 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Sc2ccccc2Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1ccc(Sc2ccccc2Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.4 %

Procedure:
To a solution of 4-[(2-bromophenyl)thio]benzaldehyde (Step 1, 5 g, 12.7 mmol) in ethanol under nitrogen (63 mL) was added sodium borohydride (5.7 g, 127.2 mmol). The reaction was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The residue was purified by flash column chromatography on silica, eluting with 40% ethyl acetate/isohexane, to yield {4-[(2-bromophenyl)thio]phenyl}methanol as a colourless oil (5.0 g, 99%). δH (400 MHz, d6 DMSO): 7.65–7.60 (1H, m), 7.41 (4H, s), 7.27–7.21 (1H, m), 7.14–7.08 (1H, m), 6.83 (1H, dd, J=1.4, 7.9 Hz), 5.32–5.28 (1H, m), 4.56–4.53 (2H, m).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11](O)[CH2:12][OH:13]>>[C:1]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: OCCO
Reactant: CCCCCCCC(=O)O
Product: CCCCCCCC(=O)OCCO

Procedure:
Anhydride of caprylic acid (0.477 mol; 129 g) was dropwise added into boiling dry ethylene glycol (3.16 mol; 196 g) and the mixture was refluxed for further 4 hours. The mixture was cooled, extracted twice with benzene (100+20 ml), benzene was evaporated in a rotation evaporator, and the residue was distilled. 2-Hydroxyethyl caprylate was obtained in the yield of 142.75 g (159% of theory), which is the evidence that almost 2/3 of caprylic acid formed was esterified with glycol under the experimental conditions. The raw fractions had purity 88.9 to 97.5% of 2-hydroxyethyl caprylate. Further procedure was carried out according to example 1.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[O:4]CC1.Cl>CO>[N:15]1[CH:16]=[CH:17][C:12]([O:11][CH:8]2[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]2)=[CH:13][CH:14]=1
Reactant: c1cc(OC2CCC3(CC2)OCCO3)ccn1
Agent: Cl
Solvent: CO
Product: O=C1CCC(Oc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
4-(1,4-Dioxaspiro[4.5]decan-8-yloxy)pyridine (1.6 g, 6.808 mmol, 1.0 eq.) was dissolved in MeOH (16 ml). 6 M HCl solution (16 ml) was added at 0° C. to the solution and the mixture was then stirred for 16 hours at RT. After monitoring by TLC, the solvent was removed under reduced pressure and the residue was taken up in water (50 ml), adjusted to pH 9 with NaHCO3 solution and extracted with DCM (2×75 ml). The combined org. phases were washed with water and sat. NaCl solution (in each case 100 ml), dried over sodium sulfate and concentrated under reduced pressure and dried. The crude product was used in the next stage without being purified further. Yield: 89% (1.15 g, 6.052 mmol)
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:25]([N:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])(=[O:27])[CH3:26]>>[C:25]([N:28]1[CH2:32][CH2:31][N:30]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:29]1=[O:33])(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C(C)=O)C4=O)nc3)CC2)c(C)c1
Yield: 63.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (1.17 g) described in Preparation Example 145 and 1-acetylimidazolidin-2-one (461 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (834 mg) was obtained.
Reaction SMILES: B.O1CCCC1.[Br:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([NH2:16])=O)=[CH:10][CH:9]=1>CO>[Br:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[CH2:14][NH2:16])=[CH:10][CH:9]=1
Reactant: CC(Oc1ccc(Br)cc1)C(N)=O
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(CN)Oc1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A 1M solution of borane in tetrahydrofuran (8.2 ml, 8.2 mmol) was added dropwise to 2-(4-bromo-phenoxy)-propionamide (0.2 g, 0.82 mmol) and the solution was stirred overnight at reflux then subsequently hydrolysed by slow addition of excess of methanol and refluxing for a further 2 hours. The solvent was removed under reduced pressure and aqueous ammonium chloride was added. The aqueous phase was extracted twice with ethyl acetate and the organics were combined, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the desired product. Yield 0.13 g, 68%. LCMS method: 2, RT: 2.74 min; MI: 271-273 [M+1].
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.[C:33]1([CH2:39][CH2:40][C:41](Cl)=[O:42])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:41](=[O:42])[CH2:40][CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)N1CCN(C(=O)Nc2noc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added 3-phenylpropionyl chloride (0.124 ml, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 142 mg (67.6%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][CH3:21])=[N:8][C:7]=1[OH:22].[NH2:26][C:27]1[CH:28]=[C:29](B(OC(C)(C)C)OC(C)(C)C)[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].O>CCO.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(COC)OC>[NH2:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:25]=[CH:24][CH:23]=[C:4]([CH2:5][C:6]3[C:15]4[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=4)[C:9]([CH2:20][CH3:21])=[N:8][C:7]=3[OH:22])[CH:3]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OB(OC(C)(C)C)c1cccc(N)c1
Reactant: CCc1nc(O)c(Cc2cccc(Br)c2)c2cc(OC)c(OC)cc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CCc1nc(O)c(Cc2cccc(-c3cccc(N)c3)c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a stirred solution of 4-(3-bromobenzyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28138 (79 mg, 0.196 mmol) in EtOH (0.9 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added di-tert-butyl 3-aminophenylboronate (49 mg, 0.393 mmol), Pd(PPh3)2Cl2 (10.0 mg), a 2 N aq. Na2CO3 solution (0.3 mL), H2O (2.7 mL) and dimethoxyethane (3.5 mL) and the resulting mixture was stirred at 140° C. for 25 min. After cooling to RT, the mixture was diluted with EtOAc (30 mL) and the organic solution was passed through a celite plug, then washed with brine (10 mL). The celite plug was then further washed with CH2Cl2 (50 mL) and the organic layer was washed with brine (20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 98:2) gave 4-((3′-amino-[1,1′-biphenyl]-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (3 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-((3′-amino-[1,1-biphenyl]-3-yl)methyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol dihydrochloride 10 as a yellow solid (43 mg, 69% yield).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C@@H:4]1[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:21])[CH2:6][CH2:5]1.O1CCO[CH2:24][CH2:23]1.C(OCC)(OCC)OCC.C(=O)([O-])O.[Na+]>C(O)C.N1C=CC=CC=1>[CH2:23]([O:21][C:7]1[CH2:6][CH2:5][C@H:4]2[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:3]2[C@@H:2]([CH3:1])[CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:20])[CH:8]=1)[CH3:24]
Reactant: C1COCCO1
Reactant: C[C@H]1C[C@]2(C)C(=O)CC[C@H]2[C@@H]2CCC3=CC(=O)CC[C@@H]3[C@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: CCOC1=CC2=CC[C@@H]3[C@H]([C@@H](C)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1

Procedure:
—Pyridinium p-toluenesulfonate (1.65 g) was added to a solution of (11β)-11-methylestr-4-ene-3,17-dione [van den Broek, A. J. et al, Steroids 30, 481 (1977); 16.86 g] in a mixture of ethanol (110 ml), dioxane (220 ml) and triethyl orthoformate (35.0 ml). After 4 h stirring at room temperature pyridine was added and the reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate. The product was extracted into ethyl acetate; the combined organic phases were washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure, to give (11β)-3-ethoxy-11-methylestra-3,5-dien-17-one (21.84 g). The product was used in the following step without further purification.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][C:14]([CH3:16])=[CH:13][C:12]=3[CH:17]=2)[CH2:4][CH2:3]1.ClC(OCC)=O.[OH-].[K+].O>C1(C)C=CC=CC=1.C(O)COCCO>[CH3:16][C:14]1[O:15][C:11]2[CH:10]=[CH:9][C:8]([CH:5]3[CH2:6][CH2:7][NH:2][CH2:3][CH2:4]3)=[CH:17][C:12]=2[CH:13]=1
Reactant: Cc1cc2cc(C3CCN(C)CC3)ccc2o1
Agent: CCOC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: OCCOCCO
Solvent: O
Product: Cc1cc2cc(C3CCNCC3)ccc2o1

Procedure:
7.3 g (0.03 mol) of 1-methyl-4-(2-methyl-5-benzofuranyl)-piperidine (c.f. Example 11) are stirred, together with 11.0 g (0.1 mol) of ethyl chloroformate, in 125 ml of toluene at 50°-55° for 15 hours. The solvent and excess ethyl chloroformate are distilled off under a waterpump vacuum at a bath temperature of 70°, the resulting residue is dissolved in toluene and the toluene solution is washed with water, 2 N sodium hydroxide solution, water, 2 N hydrochloric acid and water again. The toluene solution is then dried over sodium sulfate and evaporated to dryness under a waterpump vacuum. Crude ethyl 4-(2-methyl-2-benzofuranyl)-1-piperidinecarboxylate which remains as an oil can be further used directly. 9.1 g (0.03 mol) of the above crude ester and 15 g of solid potassium hydroxide are dissolved in 55 ml of diethylene glycol and 10 ml of water and the solution is refluxed for 15 hours in a nitrogen atmosphere. After cooling, the reaction mixture is diluted with 250 ml of toluene and the organic phase is separated off, washed with water and then extracted with 10% aqueous methanesulfonic acid solution. The acid extract is washed with toluene, rendered strongly alkaline in the cold with concentrated sodium hydroxide solution and extracted with chloroform. The chloroform solution is washed with water, dried over sodium sulfate and evaporated under a waterpump vacuum. The resulting oil is distilled under a high vacuum and gives 4-(2-methyl-5-benzofuranyl)-piperidine of boiling point 108°-111°/0.015 mm Hg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=1B(O)O>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=2[O:19][CH3:18])[CH:7]=[CH:6][C:5]=1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(c1ccccc1)c1ccc(Br)cc1F
Reactant: COc1ccc(C)cc1B(O)O
Product: COc1ccc(C)cc1-c1ccc(S(=O)(=O)c2ccccc2)c(F)c1

Procedure:
The subtitle compound was prepared by the method of example 2 step (ii) using the product of example 2 step (i) and (2-methoxy-5-methylphenyl)boronic acid.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[C:12](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:34])=[O:5])[CH2:3][CH2:2]1.Br[C:36]1[N:37]=[N:38][N:39]([CH3:41])[CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:1]1([C:4]([N:6]2[C:15]3[C:10](=[C:11]([O:25][C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=4[C:28]#[N:29])[C:12]([C:36]4[N:37]=[N:38][N:39]([CH3:41])[CH:40]=4)=[CH:13][CH:14]=3)[CH2:9][CH2:8][C@@H:7]2[CH3:34])=[O:5])[CH2:3][CH2:2]1
Reactant: C[C@H]1CCc2c(ccc(B3OC(C)(C)C(C)(C)O3)c2Oc2ccccc2C#N)N1C(=O)C1CC1
Reactant: Cn1cc(Br)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: C[C@H]1CCc2c(ccc(-c3cn(C)nn3)c2Oc2ccccc2C#N)N1C(=O)C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
A mixture of (S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile (0.050 g, 0.11 mmol), 4-bromo-1-methyl-1H-1,2,3-triazole (0.025 g, 0.15 mmol), cesium carbonate (0.110 g, 0.34 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.10 g, 0.01 mmol) in 1,4-dioxane (10 mL) and water (3 mL) was stirred overnight at 80° C. The reaction mixture was cooled to room temperature and filtered through a short pad of Celite. The filtrate was concentrated and purified via preparative thin layer chromatography (eluting with 25% ethyl acetate-petroleum ether) to afford (S)-2-(1-(cyclopropanecarbonyl)-2-methyl-6-(1-methyl-1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydroquinolin-5-yloxy)benzonitrile (0.006 g, 13%) as a white solid. MS (ESI, pos. ion) m/z 414 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 0.75-0.82 (m, 1H), 0.88-1.05 (m, 2H), 1.15-1.25 (m, 3H), 1.28-1.35 (m, 1H), 1.45-1.55 (m, 1H), 1.97-2.05 (m, 1H), 2.15-2.25 (m, 1H), 2.27-2.45 (m, 1H), 2.60-2.75 (m, 1H), 4.09 (s, 3H), 4.75-4.85 (m, 1H), 6.58 (d, J=8.40 Hz, 1H), 7.17 (t, J=8.00 Hz, 1H), 7.45-7.51 (m, 1H), 7.57 (d, J=8.40 Hz, 1H), 7.78 (d, J=1.20 Hz, 1H), 8.03-8.07 (m, 2H). MS (ESI, pos. ion) m/z 414 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[C:15]([NH:17][C:18](SC)=[N:19][CH2:20][CH2:21][O:22][CH3:23])#[N:16]>>[C:15]([NH:17][C:18]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[O:9][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=1)=[N:19][CH2:20][CH2:21][O:22][CH3:23])#[N:16]
Reactant: COCCN=C(NC#N)SC
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: COCCN=C(NC#N)NCCSCc1ccc(CN(C)C)o1
Yield: 41.3 %

Procedure:
A mixture of 2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethanamine (2.14 g) and N-cyano-N'-(2-methoxyethyl)carbamimidothioic acid, methyl ester (1.73 g) was heated on a steam bath for 6.5 hr. Vacuum was applied occasionally to remove methanethiol. The crude product was purified by chromatography (silica gel/methanol) to give N-cyano-N'-[2-[[[5-(dimethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N"-(2-methoxyethyl)guanidine (1.4 g). Analysis Found: C, 50.51; H, 7.20; N, 19.41, C15H25N5O2S.H2O requires: C, 50.42; H, 7.50; N, 19.60%.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].CN1CCOCC1.C(O)(C(F)(F)F)=O.[NH2:28][C@H:29]([C:31]([NH:33][C@H:34]([C:36]([NH:38][CH2:39][CH2:40][CH2:41][Br:42])=[O:37])[CH3:35])=[O:32])[CH3:30]>C1COCC1.CCOC(C)=O.CN(C=O)C>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:28][C@H:29]([C:31]([NH:33][C@H:34]([C:36]([NH:38][CH2:39][CH2:40][CH2:41][Br:42])=[O:37])[CH3:35])=[O:32])[CH3:30])=[O:6])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)NCCCBr
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)NCCCBr
Temperature: 25 °C

Procedure:
To a cold (−15° C.) solution of Boc-Ala-OH (118 mg, 0.63 mmol) and NMM (103 μl, 1.03 mmol) in THF (8 mL) was added ECF (61 μl, 0.64 mmol) and stirred vigorously. After 2 min. a solution of the TFA salt of Ala-Ala-NH(CH2)3—Br (270 mg, 0.69 mmol) in a mixture of THF:DMF (4 mL: 2 mL) was added to it followed by NMM (170 μL, 1.7 mmol) and stirred for further 30 minutes. The mixture was warmed to r.t. and stirred for 6 h. The solvent was removed under reduced pressure to give a residue which was diluted with EtOAc and washed with saturated citric acid, saturated NaHCO3 and the organic layer was dried over Na2SO4 and concentrated under vacuum to give a residue, which was purified by silica gel flash column chromatography (EtOAc:Hexanes—9:1) to give the desired product as a solid (m.p.—decomposed at 192° C.) in moderate yields (137 mg, 54%). TLC (MeOH:DCM—1:9; Rf—0.44).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]#[C:23][CH:24]([O:26][C:27](=[O:30])[CH2:28][CH3:29])[CH3:25])[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>C(Cl)(Cl)Cl>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([CH2:22][CH2:23][CH:24]([O:26][C:27](=[O:30])[CH2:28][CH3:29])[CH3:25])[CH:16]=[CH:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc2cc(C#CC(C)OC(=O)CC)ccc2c1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1ccc2cc(CCC(C)OC(=O)CC)ccc2c1
Yield: 98.5 %

Procedure:
In the same manner as above, 1.2 g (yield 98.5%) of 6-decyloxy-2-(3-propionyloxy-1-butyl)naphthalene, [α]D20 =-12.8° (c=1, chloroform), is obtained from 1.2 g (3 mmol) of optically active 6-decyloxy-2-(3-propionyloxy-1-butynyl)naphthalene.