Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Br:15][C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[S:19][C:20]=1[Br:21]>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:22]([C:18]2[S:19][C:20]([Br:21])=[C:16]([Br:15])[CH:17]=2)=[O:23])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cc(Br)c(Br)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc(Br)c(Br)s2)C1

Procedure:
58.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 4,5-dibromothiophene-2-carboxylic acid to give (R)-3-{[(4,5-dibromo-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. White solid. MS 466.9 ([M−H]−)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=1>>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH:24]=[C:20]1[CH2:19][N:16]1[CH:11]([C:4]2[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: BrCc1cc2ccccc2o1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc2ccccc2o1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)benzofuran. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.83 min.; [M+H]+: 366.15 g/mol.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=3)[N:14]=[C:13]([CH3:22])[C:12]=2[CH3:23])=[C:4]([O:24][CH3:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1>>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[C:5](=[C:4]([O:24][CH3:25])[CH:3]=[C:2]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: COc1cc(Br)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: COc1cc(-c2cn[nH]c2)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12

Procedure:
Prepared according to procedure W using 4-(6-bromo-4-methoxy-1H-indol-1-yl)-6-chloro-2,3-dimethylquinoline (0.4 g, 0.962 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.3734 g, 1.92 mmol) to give 6-chloro-4-(4-methoxy-6-(1H-pyrazol-4-yl)-1H-indol-1-yl)-2,3-dimethylquinoline as a white solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.09 (2H, d, J=9.0 Hz), 7.81 (1H, s), 7.73 (1H, dd, J=8.9, 2.3 Hz), 7.39 (1H, d, J=3.2 Hz), 6.90-6.94 (2H, m), 6.80 (1H, dd, J=3.2, 0.5 Hz), 6.63 (1H, s), 4.00-4.06 (4H, m), 2.77 (3H, s), 2.06 (3H, s); Mass Spectrum (ESI) m/e=403.0 (M+1).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:15][NH:16][CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH3:15][N:16]([C@@H:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][C@H:18]1[N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:12](=[O:14])[CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CNC1c2ccccc2CCC1N1CCCC1
Reactant: O=C(O)Cc1cccc2ccccc12
Product: CN(C(=O)Cc1cccc2ccccc12)[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 54.9 %

Procedure:
Using the procedure of Step C of Example 1, 2.3 g of 1-naphthylacetic acid and 2 g of the product of Step B of Example 1 were reacted to obtain 5.3 g of crude product which was purified by chromatography on silica (methylene chloride 9-methanol 1). After crystallization from ethyl ether, 1.9 g of product melting at 117° C. were obtained which was crystallized from isopropyl ether to obtain 1.1 g of the expected product melting at 125° C.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]1[Br:10].[O-:11][CH2:12][CH3:13].[Na+]>C(O)C>[CH2:12]([O:11][CH2:2][N:3]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]1[Br:10])[CH3:13]
Reactant: CC[O-]
Reactant: ClCn1c(Br)nc(Cl)c1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOCn1c(Br)nc(Cl)c1Cl
Yield: 22.8 %

Procedure:
A mixture of 1.06 g of 1-chloromethyl-2-bromo-4,5-dichloroimidazole, 0.54 g of sodium ethoxide and 40 ml of ethanol was heated under reflux for 10 hours. The reaction mixture was then concentrated under reduced pressure to obtain an oily product. This product was purified by column chromatography on silica gel to obtain 0.25 g of 1-ethoxymethyl-2-bromo-4,5-dichloroimidazole.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][NH:8][C:7](=[O:11])[C:6]1=[O:12])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C=O)C>[CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([O:19][CH3:20])=[O:18])[C:7](=[O:11])[C:6]1=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCNC(=O)C1=O
Reactant: COC(=O)C(Br)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1CCN(C(C(=O)OC)c2ccccc2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86 %

Procedure:
To a solution of 1-butylpiperazine-2,3-dione (1.6 g, 9.1 mmol) in DMF (12 ml) at 0° C. was added sodium hydride (0.25 g, 10.4 mmol). After stirring for 20 min, methyl α-bromophenylacetate (1.6 ml, 10.0 mmol) was added to the reaction. The reaction was warmed to rt and allowed to stir for 18 h. The reaction was quenched with water, diluted with EtOAc, washed with 3M LiCl, water, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via flash chromatography (silica) to yield methyl (4-butyl-2,3-dioxopiperazin-1-yl)(phenyl)acetate (86%).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2][C:3]([O:5]C1C=CC([N+]([O-])=O)=CC=1)=O.[NH:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25].O>CN(C=O)C>[NH:1]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:2][C:3]([N:22]1[CH2:29][CH2:28][CH2:27][C@H:23]1[C:24]([OH:26])=[O:25])=[O:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
Boc-Gly-ONp (50 g, 0.17 mol.) and proline (20.7 g, 0.175 mol.) were dissolved in 300 ml DMF. 20 ml TEA and 30 ml water were added while stirring the solution. The stirring was continued overnight and TLC analysis showed no more starting materials. The solvents were removed under reduced pressure and the resulting mixture was dissolved in 250 ml saturated Na2CO3. The aqueous solution was extracted by 3×100 ml ethyl acetate to remove p-nitrophenol. Then, after chilling to 0° C., the aqueous solution was acidified to about pH=3 by addition of concentrated HCl slowly (vigorously swirling the solution at the same time). The product was extracted from the aqueous phase by 3×150 ml ethyl acetate. The organic phase was combined and washed by saturated NaCl (brine) 3×20 ml, and dried using Na2SO4. TLC analysis showed there was still p-nitrophenol in the solution. The ethyl acetate was removed under reduced pressure and column chromatography (elution solvents: E/H, 2:1) was carried out to obtain the pure product Boc-Gly-Pro-OH (white solid, 41.2 g, 88%). TLC Rf=0.25 (CMA, 85:15:3). FAB-MS, observed (M+H)+ =273. 1H-NMR (360 MHz, DMSO-d6, 20° C.) δ 12.55 (s, 1H, carboxyl), 6.79 (s, NH-major), 6.44 (s, NH-minor), 4.50 (dd, 0.25H, Pro-α-minor), 4.20 (dd, 0.71H, Pro-α-major), 3.81-3.62 (m, 1.7H, Gly-α-major), 3.47-3.33 (m, 2.5H, Pro-δ and Gly-α-minor), 2.25-2.00 (m, 1.2H, Pro-β), 1.96-1.60 (m, 2.7H, Pro-β and Pro-γ), 1.36 (s, 9H, Boc-CH3)b.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH:31]=5)=[CH:22][CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>COC1C=CC(CN2C=C(B3OC(C)(C)C(C)(C)O3)C=N2)=CC=1.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]5[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]5)=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: CN1CC=C(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Agent: [Pd+2]
Agent: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Agent: [OH-]
Product: CN1CCC(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 7.7 %

Procedure:
Using similar reaction conditions as described in step-ii of example-82, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.280 mmol) was reduced with palladium hydroxide (50 mg) in ethyl acetate/ethanol 5/5 mL to afford 10 mg (6.0% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.627-8.621 (d, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.77-7.73 (m, 3H), 7.45-7.42 (d, 2H), 7.38-7.33 (m, 1H), 7.13-7.00 (m, 3H), 5.44 (s, 2H), 3.67-3.63 (d, 2H), 3.22-3.15 (t, 2H), 3.03-2.94 (m, 4H), 2.20-2.00 (m, 4H). MS: m/z=466.7 (M+1), HPLC: 95.92% in method B.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.O[C@@H]1CCNC1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:30]3[CH2:31][CH2:32][CH:28]([OH:27])[CH2:29]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: OC1CCNC1
Agent: O[C@@H]1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCC(O)C3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with (R)-3-hydroxypyrrolidine. A yellow solid 94 was obtained (0.0385 g, 87%). 1H-NMR (CDCl3, 400 MHz) δ 2.13–2.31 (m, 2H), 3.83 (s, 3H), 3.88–3.95 (m, 4H), 4.74 (m, 1H), 6.79 (s, 1H), 6.92 (d, J=6.6 Hz, 1H), 7.01–7.07 (m, 3H), 7.45–7.53 (m, 3H), 7.86 (s, 1H), 8.14 (d, J=7.0 Hz, 1H); MS (APCI) m/z 447 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[I:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([I:24])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(I)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (300 mg), 4-iodobenzoyl chloride (520 mg) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (4 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with saturated aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])[CH2:2][CH3:3].[CH:10](OC)(OC)OC.OS(O)(=O)=O>>[CH3:9][O:8][C:6](=[O:7])[CH:5]=[C:1]([O:4][CH3:10])[CH2:2][CH3:3]
Reactant: COC(OC)OC
Reactant: CCC(=O)CC(=O)OC
Agent: O=S(=O)(O)O
Product: CCC(=CC(=O)OC)OC
Reaction time: 8 h

Procedure:
To a mixture of methyl propionylacetate (104 g. 0.8 mole) and trimethyl orthoformate 98% (95.3 g, 0.88 mole) was added dropwise 1 ml of concentrated H2SO4 at room temperature and it was allowed to stir overnight. After neutralization with excess anhydrous K2CO3, the solution was filtered and distilled to yield the title ester, b.p. 55° C. (0.55 mm).
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:16]2[N:12]([N:13]=[C:14]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([Cl:27])[C:20]=3[CH3:28])[C@H:15]2[O:17][CH3:18])[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(OCC)(=O)C>[Cl:27][C:21]1[C:20]([CH3:28])=[C:19]([C:14]2[C@@H:15]([O:17][CH3:18])[C@@H:16]3[C@@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[N:13]=2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@@H]1C(c2ccc(C#N)c(Cl)c2C)=NN2CC[C@H](O)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-((3S,3aR,4S)-4-(tert-butyldimethylsilyloxy)-3-methoxy-3a,4,5,6-tetrahydro-3H-pyrrolo[1,2-b]pyrazol-2-yl)-2-chloro-3-methylbenzonitrile (400 mg, 0.954 mmol) in THF (10 mL) at 0° C. was added tetra butyl ammonium fluoride (1.9 mL, 1.909 mmol, 1M solution in THF) and the reaction mixture was stirred at room temperature for 3 h. Once the starting material had disappeared (monitored by TLC), reaction mixture was diluted with ethyl acetate and the organic layer was washed with water, brine, dried over Na2SO4 and concentrated to get the crude product. The product was purified by column chromatography over silica gel using 2% MeOH in DCM as solvent to provide the title compound. The absolute stereochemistry was confirmed by X-ray crystallography.
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[CH3:11][C:12]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])[CH:13]=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH3:4][NH:6][CH2:13][C:12]([CH3:11])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CC(C)=CCC(C)(C=O)c1ccccc1
Agent: CN
Agent: Cl
Agent: [BH3-]C#N
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CNCC(C)(CC=C(C)C)c1ccccc1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Methylamine hydrochloride (500 mg, 7.41 mmol), triethylamine (1.00 mL, 725 mg, 7.17 mmol), and 3 Å molecular sieve pellets (1.05 g) were added to a stirred solution of 2,5-dimethyl-2-phenylhex-4-enal (500 mg, 2.47 mmol) in 5.0 mL of methanol at RT. After 1 h, the mixture was cooled in an ice bath and acetic acid (0.29 mL, 0.30 g, 5.1 mmol) was added followed by sodium cyanoborohydride (310 mg, 4.93 mmol). The mixture was allowed to slowly come to RT and stirred 16 h before being diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (30 mL) and saturated aqueous sodium chloride (30 mL). The aqueous layers were extracted with ethyl acetate (30 mL) and the combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with 5% methanol in ethyl acetate to give 415 mg the title compound. 1H NMR (400 MHz, CD3OD): δ 7.36-7.28 (m, 4H), 7.18 (t, 1H, J=7 Hz), 4.88 (t, 1H, J=7.5 Hz), 2.87 (d, 1H, J=12 Hz), 2.66 (d, 1H, J=12 Hz), 2.39 (dd, 1H, J=14, 7.5 Hz), 2.30 (dd, 1H, J=14, 8 Hz), 2.27 (s, 3H), 1.59 (s, 3H), 1.54 (s, 3H), 1.34 (s, 3H). Mass spectrum (NH3 /CI): m/z=218 (M+1).
Reaction SMILES: [BH4-].[Na+].[CH:3]1([O:9][CH:10]([O:12][C@H:13]([CH3:21])[C:14](OCC(C)C)=[O:15])[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CO.O>C1(C)C=CC=CC=1>[CH:3]1([O:9][CH:10]([O:12][C@H:13]([CH3:21])[CH2:14][OH:15])[CH3:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(C)COC(=O)[C@@H](C)OC(C)OC1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(OC1CCCCC1)O[C@H](C)CO
Yield: 88.7 %

Procedure:
8.4 g (0.204 mole) of sodium borohydride was suspended at room temperature in a solution of 47.9 g (0.17 mole) of the isobutyl (R)-(+)-2-(1-cyclohexyloxyethoxy)propionate (obtained in Reference Example 7) dissolved in 170 ml of toluene. Thereto was dropwise added slowly 41.3 ml (1.02 mole) of methanol with stirring, so that the internal temperature of the reaction system could be kept at 40° C. After the completion of the dropwise addition, the resulting mixture was stirred at room temperature for 7 hours to give rise to a reaction. To the reaction mixture was added 50 ml of water, followed by stirring for 0.5 hour. The organic layer was separated. The water layer was subjected to extraction with 50 ml of toluene. The two organic layers were combined and washed with 50 ml of water and 50 ml of a saturated aqueous sodium chloride solution in this order. The washed solution was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent, whereby was obtained 30.5 g (yield: 88.7%) of an oily title compound (diastereomixture).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH2:12][CH2:13][CH2:14][N:15]=1.O.[OH-].[Na+]>CO.C(O)(=O)C>[Br:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[CH:11]1[CH2:12][CH2:13][CH2:14][NH:15]1
Reactant: Fc1ccc(C2=NCCC2)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Fc1ccc(C2CCCN2)c(Br)c1
Temperature: 25 °C
Yield: 71 %

Procedure:
Add sodium tetrahydroborate (146 mg, 3.7 mmol) to a solution of 5-(2-bromo-4-fluorophenyl)-3,4-dihydro-2H-pyrrole (420 mg, 1.73 mmol) in methanol-acetic acid (saturated; 10 mL) mixture at −40° C. After warming up to RT, add water (10 mL) and make the solution basic with a NaOH solution (2 N). Extract the solution with DCM, wash the organic solution with aqueous saturated sodium chloride, dry over potassium carbonate, and remove the organic solvent to give the title compound (300 mg, 71%). MS (ES) m/z 236 [M+1]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]([C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)=[O:16])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[O:26]=[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]1[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]([C:17]3[CH:25]=[C:24]4[C:20]([CH:21]=[CH:22][NH:23]4)=[CH:19][CH:18]=3)=[O:16])[N:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc2cc[nH]c2c1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2)cn1)c1ccc2cc[nH]c2c1
Temperature: 130 °C

Procedure:
A mixture of N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)-1H-indole-6-carboxamide prepared above, 2-hydroxypyridine 1-7 (130 mg, 1.37 mmol), 8-hydroxyquinoline (30 mg, 0.21 mmol) and K2CO3 (246 mg, 1.78 mmol) in DMSO (2 mL) was degassed before being charged with CuI (43 mg, 0.23 mmol). The mixture in a sealed tube was heated at 130° C. overnight. It was then purified by HPLC to give the title compound (50 mg). MS 410.1 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][CH2:5]1.[C:27](Cl)(=[O:31])[O:28][CH2:29][CH3:30]>>[CH2:29]([O:28][C:27]([N:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:4]1([CH2:3][O:2][CH3:1])[CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])[CH2:8][CH2:9]1)=[O:31])[CH3:30]
Reactant: COCC1(Nc2ccccc2)CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N(c1ccccc1)C1(COC)CCN(C(=O)OCc2ccccc2)CC1
Temperature: 110 °C
Yield: 83.5 %

Procedure:
A mixture of 14.2 parts of (phenylmethyl) 4-(methoxymethyl)-4-(phenylamino)-1-piperidinecarboxylate and 170.2 parts of ethyl carbonochloridate is stirred and refluxed for 16 hours in an oil-bath at 110° C. The reaction mixture is evaporated and the residue is dissolved in 225 parts of trichloromethane. The solution is washed twice with water, dried, filtered and evaporated. The residue is dissolved in methylbenzene and the latter is evaporated again, yielding 14.2 parts (83.5%) of (phenylmethyl) 4-[(ethoxycarbonyl)phenylamino]-4-(methoxymethyl)-1-piperidinecarboxylate as a residue.
Reaction SMILES: NC1C2C(=O)C=C(C(OCC)=O)[O:11]C=2C=CC=1.[CH2:18]([S:20]([C:22]1[C:31]2[C:26](=[C:27]([CH2:40][CH2:41][CH3:42])[C:28]3[O:35][C:34]([C:36]([O-:38])=[O:37])=[CH:33][C:32](=[O:39])[C:29]=3[CH:30]=2)[N:25]=[C:24]([C:43]([O-:45])=[O:44])[CH:23]=1)=[O:21])[CH3:19].[Na+:46].[Na+]>>[CH2:18]([S:20]([C:22]1[C:31]2[C:26](=[C:27]([CH2:40][CH2:41][CH3:42])[C:28]3[O:35][C:34]([C:36]([O-:38])=[O:37])=[CH:33][C:32](=[O:39])[C:29]=3[CH:30]=2)[N:25]=[C:24]([C:43]([O-:45])=[O:44])[CH:23]=1)(=[O:11])=[O:21])[CH3:19].[Na+:46].[Na+:46]
Reactant: CCCc1c2nc(C(=O)[O-])cc(S(=O)CC)c2cc2c(=O)cc(C(=O)[O-])oc12
Reactant: CCOC(=O)c1cc(=O)c2c(N)cccc2o1
Agent: [Na+]
Product: CCCc1c2nc(C(=O)[O-])cc(S(=O)(=O)CC)c2cc2c(=O)cc(C(=O)[O-])oc12

Procedure:
The product (ii) of section (a) above was hydrolysed in the same manner as in (b) above to afford the sub-title compound (0.12 g).
Reaction SMILES: C([C:7]1([CH2:26]CCCCC)[C:19]2[CH:18]=[C:17](B(O)O)[CH:16]=C[C:14]=2[C:13]2[C:8]1=[CH:9][C:10](B(O)O)=[CH:11][CH:12]=2)CCCCC.Br[C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[N:37][CH:38]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.C1(C)C=CC=CC=1>[N:37]1[CH:38]=[C:33]([C:11]2[CH:10]=[CH:9][C:8]3[C:7]4[C:19](=[CH:18][C:17]([C:33]5[CH:34]=[CH:35][C:36]([C:39]6[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=6)=[N:37][CH:38]=5)=[CH:16][CH:26]=4)[C:14]([CH2:26][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])([CH2:12][CH2:13][CH2:14][CH2:19][CH2:18][CH3:17])[C:13]=3[CH:12]=2)[CH:34]=[CH:35][C:36]=1[C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1
Reactant: Brc1ccc(-c2cccnc2)nc1
Reactant: CCCCCCC1(CCCCCC)c2cc(B(O)O)ccc2-c2ccc(B(O)O)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCCCCC1(CCCCCC)c2cc(-c3ccc(-c4cccnc4)nc3)ccc2-c2ccc(-c3ccc(-c4cccnc4)nc3)cc21
Temperature: 25 °C
Yield: 32.8 %

Procedure:
Into a flask, 0.6 g of 9,9-dihexyl-fluorene-2,7-diboronic acid, 0.5 g of 5-bromo-2,3′-bipyridine, 115 mg of Pd(PPh3)4, 1.27 g of tripotassium phosphate, and 20 ml of toluene were put, and the solution was stirred at reflux temperature for 6.5 hours under argon atmosphere. After heating, the reaction liquid was cooled to room temperature, and washed by a saturated sodium chloride aqueous solution. The organic layer was concentrated in an evaporator, and the concentrates were purified by activated alumina column chromatography. The concentrates were recrystallized in a heptane/ethyl acetate mixed solvent, and thus 150 mg of 2,7-bis(2,3′-bipyridine-5-yl)-9,9-dihexylfluorene was obtained.