Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:11]([NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][CH:28]=2)=[O:26])[CH:10]=1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=[O:43]>>[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH3:23])=[C:11]([NH2:24])[CH:10]=1.[O:37]=[C:36]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=[C:27]1[C:25]([OH:26])=[O:43]
Reactant: CCOc1ccccc1-c1ccc(CNC(=O)OC(C)(C)C)cc1NC(=O)c1c[nH]c2ccccc2c1=O
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccccc1-c1ccc(CN)cc1N
Product: O=C(O)c1c[nH]c2ccccc2c1=O

Procedure:
{2′-Ethoxy-2-[(4-oxo-1,4-dihydroquinoline-3-carbonyl)-amino]-biphenyl-4-ylmethyl }-carbamic acid tert-butyl ester (304) (40 mg, 0.078 mmol) was stirred in a CH2Cl2/TFA mixture (3:1, 20 mL) at room temperature for 1 h. The volatiles were removed on a rotary evaporator. The crude product was purified by preparative HPLC to afford 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (4-aminomethyl-2′-ethoxybiphenyl-2-yl)amine (163) as a tan solid (14 mg. 43%). 1H NMR (300 MHz, DMSO-d6) δ 12.87 (d, J=6.3 Hz, 1H), 11.83 (s, 1H), 8.76 (d, J=6.3 Hz, 1H), 8.40 (s, 1H), 8.26 (br s, 2H), 8.01 (dd, J=8.4 Hz, J=1.5 Hz, 1H), 7.75 (dt, J=8.1 Hz, J=1.2 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.24 (s, 2H), 7.15 (dd, J=7.5 Hz, J=1.8 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.02 (dt, J=7.5 Hz, J=0.9 Hz, 1H), 4.09 (m, 2H), 4.04 (q, J=6.9 Hz, 2H), 1.09 (t, J=6.9 Hz, 3H); HPLC ret. time 1.71 min, 10-100% CH3CN, 5 min gradient; ESI-MS 414.1 m/z (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[CH:32]1([N:37]=[C:38]=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1>O1CCOCC1>[CH:32]1([NH:37][C:38]([NH:16][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:28]([F:31])([F:29])[F:30])[CH:4]=2)([C:17]2[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([F:27])[CH:18]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:39])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Reactant: O=C=NC1CCCC1
Solvent: C1COCCO1
Product: O=C(NC1CCCC1)NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Yield: 67 %

Procedure:
1-(4-Fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (300 mg, 0.67 mmol) and cyclopentyl isocyanate (0.4 mL, 5.3 eq) were stirred in 1,4-dioxane (2 mL) at room temperature overnight. The reaction mixture was concentrated, and purified by flash chromatography (silica gel, hexanes/EtOAc) to give the racemic mixture of 1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea (250 mg, yield: 67%). The racemate (250 mg) was dissolved in 10% isopropanol in heptane, and was resolved by chiral prep HPLC using an AD column (10% isopropanol/heptane/0.1% DEA, isocratic) to give the fast eluting enantiomer 1 (110 mg) corresponding to (5)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, (analytical chiral HPLC (AD, 10% isopropanol/heptane/0.1% DEA, isocratic), retention time=4.85 min) and the slow eluting enantiomer 2 (105 mg) corresponding to (R)-1-cyclopentyl-3-(1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)urea, (analytical chiral HPLC (AD, 10% isopropanol/heptane/0.1% DEA, isocratic), retention time=14.11 min) LCMS (10-90% MeOH in H2O with 0.1% TFA in a 4-min run), retention time=4.33 min, 557.32 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.44 (m, 2H), 7.23-7.29 (m, 3H), 7.13-7.21 (m, 4H), 6.68-6.74 (m, 2H), 4.84 (s, 1H), 4.40 (s, br, 1H), 3.84-3.95 (m, 3H), 1.88-1.98 (m, 2H), 1.56-1.68 (m, 4H), 1.34 (d, J=6.36 Hz, 2 H).
Reaction SMILES: Cl.C(O[CH:5]=[CH:6][C:7]1[N:8]([C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:25])[C:23]=2[N:24]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])C.C([O-])([O-])=[O:27].[K+].[K+].CO>C1COCC1.C(Cl)Cl>[C:6]([C:7]1[N:8]([C:18]2[N:19]=[CH:20][N:21]=[C:22]([NH2:25])[C:23]=2[N:24]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])(=[O:27])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC=Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1nc2c(N)ncnc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1 M HCl (10 ml) was added to a solution of 8-ethoxyvinyladenosine (17k) (1.48 g, 4.37 mmol) in THF (40 ml) and the solution stirred at room temperature for 20 h. Aqueous K2CO3 was added to neutral pH and the mixture applied directly onto a flash chromatography silica gel column which was developed with 15% MeOH in CH2Cl2; yield 1.17 g (87%). 1H NMR: (300 MHz, DMSO-d6); δ 2.72 (3H, s, COCH3), 3.52-3.71 (2H, m, H-5′), 3.94-3.96 (1H, m, H-4′ el. H-3′), 4.10-4.23 (1H, m, H-3′ or H-4′), 4.94 (1H, m, H-2′), 5.11 (1H, d, J 4.4 Hz, 3′-OH), 5.24 (1H, d, J 6.1 Hz, 2′-OH), 5.56-5.59 (1H, m, 5′-OH), 6.76 (1H, d, J 6.5 Hz, H-1′), 7.87 (2H, s, NH2), 8.21 (1H, s, H-2). 13C NMR: (75 MHz, DMSO-d6); δ 27.9 (CH3), 62.3 (C-5′), 70.9/72.0 (C-2′, C-3′), 86.3/89.3 (C-4′, C-1′), 118.7 (C-5), 143.7/150.5/154.7/157.7 (C-6, C-8, C-2, C-4), 191.7 (CO).
Reaction SMILES: C([N:8]1C[CH2:10][CH:9]1[C:12](O)=O)(OC(C)(C)C)=O.C[N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.[Cl:22]C(OCC(C)C)=O.CO>C1COCC1>[ClH:22].[CH3:12][C:9]1[CH:10]=[C:20]([C@@H:21]2[CH2:18][CH2:17][NH:16]2)[O:19][N:8]=1
Reactant: CN1CCOCC1
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc([C@@H]2CCN2)on1
Product: Cl
Temperature: -10 °C

Procedure:
A 4.9 g (24.37 mmol) sample of 1-BOC-azetidine-2-carboxylic acid, from step a above, was dissolved in 35 mL of THF, and stirred under N2 at -10° C. To this solution was added 2.68 mL of NMM, and the mixture was stirred for 5 min. Next was added 3.16 mL (24.37 mmol) of isobutyl chloroformate, and the reaction was stirred for 20 min. To the reaction was next added 0.99 mL of methanol, and the stirred mixture was warmed to room temperature and stirred for 16 hr. The reaction was adjusted to an acidic pH and extracted with ethyl acetate. The solvent was removed, and the residue was purified on silica gel, eluting with 2:1 hexane:ethyl acetate to give 2.00 g of the title product. MS: 177 (M-C4H8 +NH4)+, 216 (M+H)+, 233 (M+NH4)+. 1H NMR (CDCl3) δ: 1.42 (s, 9H), 2.15-2.25 (m, 1H), 2.45-2.55 (m, 1H), 3.78 (s, 3H), 3.85-3.95 (m, 1H), 4.00-4.10 (m, 1H), 4.61 (dd, 1H, J=5, 10 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)(=[O:13])/[CH:10]=[CH:11]/[CH3:12].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:8][CH:11]([CH3:12])[CH2:10][C:9]2=[O:13]
Reactant: Oc1ccc(F)cc1
Reactant: C/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC1CC(=O)c2cc(F)ccc2O1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
11.2 G (0.1 mol) of para-fluorophenol and 17.2 g (0.2 mol) of crotonic acid were dissolved in 100 ml of polyphosphoric acid, and the solution was reacted with vigorously stirring at 120° C. for 8 hours. After cooling, the reaction solution was poured into 450 ml of iced 2N-sodium hydroxide solution, and the mixture was extracted with 500 ml of chloroform. The chloroform layer was washed with 2N-sodium hydroxide solution and with water, followed by drying over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from n-hexane in the amount of about ten times. There were thus obtained 5.8 g (yield : 32%) of the subject material, 6-fluoro-2-methyl-4- chromanone.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].CC(C)=O.C(OC(C)C)(C)C.[C:26]1([CH:32]([C:36]([O:38][CH:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])[C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.[OH-].[Na+]>[CH:39]([O:38][C:36]([CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:33]([NH:9][CH:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12)=[O:34])=[O:37])([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=C(Cl)C(C(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(C(=O)OC(c3ccccc3)c3ccccc3)c3ccccc3)[C@H]2SC1
Reaction time: 0.05 h

Procedure:
Following a procedure analogous to that of Goldman et al. (loc. cit.), 7-aminodesacetoxycephalosporanic acid (7-amino-3-methylceph-3-em-4-carboxylic acid; 74.9 g., 0.35 mole) is dissolved in well-stirred water (200 ml.) by the slow addition of sodium hydroxide (approximately 75 ml. of 4 N) to a pH of 7.5. To this solution is added 200 ml. of acetone. Keeping the temperature at 10° to 15° C., the isopropyl ether solution of 2-phenyl-2-benzhydryloxycarbonylacetyl chloride prepared above is added with continued strong stirring over 3 minutes. The pH is maintained near 6.5 by the addition of 4 N NaOH (about 160 ml.). Organic solvents are removed by evaporation in vacuo. The aqueous layer is diluted with an equal volume of ethyl acetate and the pH adjusted to 2. The ethyl acetate layer is separated, washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 7-(2-benzhydryloxycarbonyl-2-phenylacetamido)-3-methylceph-3-em-4 -carboxylic acid.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:20]([C:22]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:21].C(=O)(O)[O-].[Na+]>ClCCl.O1CCCC1>[C:20]([C:22]1([C:28]2[N:33]=[CH:32][C:31]([NH:34][C:35]([C:37]3[CH:38]=[N:39][N:40]([C:43]4[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][N:44]=4)[C:41]=3[CH3:42])=[O:36])=[CH:30][CH:29]=2)[CH2:23][CH2:24][N:25]([CH:3]2[CH2:2][O:1][CH2:4]2)[CH2:26][CH2:27]1)#[N:21]
Reactant: O=C1COC1
Reactant: Cc1c(C(=O)Nc2ccc(C3(C#N)CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(C3(C#N)CCN(C4COC4)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Reaction time: 6 h
Yield: 44.5 %

Procedure:
3-Oxetanone (316 mg) and sodium triacetoxyborohydride (112 mg) were added at room temperature to a solution of N-[6-(4-cyanopiperidin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (200 mg) described in Reference Example 169 in dichloromethane (20 ml) and tetrahydrofuran (20 ml), and stirred at the same temperature for eight hours. Further 3-oxetanone (316 mg) and sodium triacetoxyborohydride (112 mg) were added at room temperature and stirred at the same temperature for six hours. After completion of the reaction, a saturated aqueous solution of sodium bicarbonate was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated and the resulting residue was purified with silica gel column chromatography (chloroform/methanol) to give the titled compound (100 mg) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:7][CH:8]=1)#[CH:2].[CH:18]1([NH:21][C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](I)[CH:24]=2)[CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH:18]1([NH:21][C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]#[C:1][C:3]3[CH:8]=[N:7][C:6]([NH:9][CH2:10][CH2:11][N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[CH:5][CH:4]=3)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1I
Reactant: C#Cc1ccc(NCCN2CCOCC2)nc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1C#Cc1ccc(NCCN2CCOCC2)nc1
Temperature: 90 °C

Procedure:
5-Ethynyl-N-(2-morpholinoethyl)pyridin-2-amine (0.54 g, 2.36 mmol), N-cyclopropyl-3-iodo-4-methylbenzamide (0.71 g, 2.36 mmol), and triethylamine (0.49 mL, 3.54 mmol) were dissolved in dioxane (10 mL) before these were sparged with nitrogen for 15 min.; palladium dichloro-bis-triphenylphosphine (83 mg, 0.12 mmol) and copper (I) iodide (45 mg, 0.24 mmol) were added before the reaction mixture was heated to 90° C. for 6 h. The reaction mixture was diluted with 100 mL EtOAc, washed with 50 mL saturated, aqueous NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow oil. MS (ES+): 406 (M+H)−.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([C:16]([F:19])([F:18])[F:17])[C:4]=1[C:5](Cl)=[O:6].[CH3:20][C:21]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)([CH3:30])[CH:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:30][C:21]([N:31]1[CH2:32][CH2:33][CH2:34][CH2:35]1)([CH3:20])[CH:22]([NH:29][C:5](=[O:6])[C:4]1[C:8]([C:16]([F:19])([F:18])[F:17])=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=1[S:2][CH3:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)Cl
Reactant: CC(C)(C(N)c1ccccc1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC(c1ccccc1)C(C)(C)N1CCCC1
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 2-(methylthio)-4,6-bis(trifluoromethyl)benzoyl chloride D55 (60 mg; 0.19 mmol) in dry DCM (1 ml) was treated with (+)-[2-methyl-1-phenyl-2-(1-pyrrolidinyl)propyl]amine D6 (60 mg, 0.27 mmol) followed by triethylamine (5drops) and left overnight at room temperature. The volatile components were removed under reduced pressure and the residue chromatographed on silica gel. Elution with 0-80% ethyl acetate in pentane gave the title product as an oil (80 mg, 85%). 1H NMR (CDCl3) δ: 0.94 (3H, s), 1.00 (3H, s), 1.69 (4H, overlapping m), 2.54 (3H, s), 2.62 (2H, m), 2.72 (2H, m), 4.78 (1H, s), 7.25-7.45 (6H, overlapping m), 7.68 (1H, s), 7.72 (1H, s). Mass Spectrum (Electrospray LC/MS): Found 505 (MH+) C24H26F6N2OS requires 504. Ret time 2.24 min.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4][NH:3][CH2:2]1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:18]([O:17][C:15]([CH:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4]1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C1CNCCc2c1[nH]c1ccccc21
Reactant: OB(O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1CN(c2ccccc2)CCc2c1[nH]c1ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 7.9 %

Procedure:
The mixture of ethyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (520 mg, 2 mmol), cupric acetate (728 mg, 4 mmol), phenyl boronic acid (490 mg, 4 mol) and pyridine (0.35 mL, 4 mmol) in dry DCM (20 mL) was stirred at ambient temperature for 3 days. The mixture was filtered though a pad of celite. The filtrate was concentrated in vacuo and then purified by chromatography on silica gel eluting with EtOAc-Hexane (7:93) to give the title compound (53 mg); 1H-NMR (CDCl3): δ 8.66 (1H, s), 7.42 (1H, d), 7.26-7.18 (4 h, m), 7.10-7.00 (2H, m), 7.69 (2H, m), 6.67 (1H, t), 5.22 (1H, m), 4.40-4.18 (3H, m), 4.04-4.01 (1H, m), 3.98-3.88 (1H, m), 3.58-3.52 (1H, m), 3.22-3.15 (1H, m), 3.08-3.02 (1H, m), 1.27 (3H, t); MS (ES): 335 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17](I)=[C:12]2[CH:11]=[N:10]1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:13]2=[N:14][CH:15]=[CH:16][C:17]([B:22]([OH:23])[OH:21])=[C:12]2[CH:11]=[N:10]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1cccc(F)c1-n1ncc2c(I)ccnc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: OB(O)c1ccnc2c1cnn2-c1c(F)cccc1F
Temperature: 85 °C

Procedure:
To a 48 mL pressure bottle containing Intermediate 74A (1.19 g, 3.24 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.35 g, 13.86 mmol), potassium acetate (1.36 g, 13.86 mmol), and anhydrous DMSO (12.5 mL). The reaction mixture was purged with argon and treated with PdCl2(dppf).CH2Cl2 (56 mg, 0.077 mmol). The reaction mixture was heated to 85° C. for 1 h, then at 105° C. for 1 h to give conversion to the desired product. LC/MS (Condition B): ret. T=2.7 min, (M+H)+ 276.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]CC1CO1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[N:34]1([CH:40]2[CH2:45][CH2:44]NCC2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[OH2:46]>CN(C)C=O>[OH:46][CH:45]([CH2:40][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH:39]1[CH:6]1[CH2:5][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:44][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Reactant: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCCCC1C1CCNCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and 4-piperidinopiperidine (45 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (49 mg, yield 91%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][C:16]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)([CH2:19][OH:20])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][C:16]([CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)([CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(C2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methane sulfonyl chloride (1.8 mL, 23.0 mmol) is added to a stirred solution of 4-cyclohexyl-4-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester, 3, (3.42 g, 11.48 mmol) and triethylamine (4.8 mL, 2.8 mmol) in dichloromethane (30 mL) at 0° C. The reaction mixture is then allowed to warm to room temperature and stir for 1 hour. The reaction is quenched with a saturated solution of NaHCO3 and the resulting mixture is extracted twice with dichloromethane (50 mL). The organic layers are combined, dried, filtered and concentrated in vacuo to yield the desired product in quantitative yield. The material is used for the next step without need for purification.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21]([O:23][C:24](Cl)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([N:2]1[CH2:7][CH2:6][C:5]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)=[O:25])[CH3:22]
Reactant: CN1CCC(Oc2ccccc2)(c2ccccc2)CC1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCC(Oc2ccccc2)(c2ccccc2)CC1

Procedure:
9.0 g of 1-methyl-4-phenoxy-4-phenylpiperidine are added in portions of 100 ml of chloroformic acid ethyl ester at 80° C.; severe foaming is observed during this addition. When the addition has ended, the mixture is boiled under reflux for 3 hours, excess chloroformic acid ethyl ester is distilled off in vacuo, and 120 ml of water and 15 ml of concentrated ammonia are added to resulting solid residue. This mixture is stirred thoroughly, and the precipitate is filtered off and rinsed with water. The 1-ethoxycarbonyl-4-phenoxy-4-phenylpiperidine (m.p. 117° to 118° C., from ethanol) thus obtained is boiled under reflux with a solution of 15 g of potassium hydroxide in 150 ml of n-butanol for 4 hours; after cooling, 300 ml of water are added to the solution, and the obtained mixture is extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate and concentrated. The title compound remains as a brownish oil. The hydrochloride melts at 192° C. (from ethanol).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Zn](CC)CC.CN([C@@H](C1C2C(=CC=CC=2)C=CC=1)C1C2C(=CC=CC=2)C=CC=1O)[C@H](C1C=CC=CC=1)C.[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[CH:50]=[O:51]>C1(C)C=CC=CC=1>[Cl:47][C:48]1[CH:55]=[CH:54][CH:53]=[CH:52][C:49]=1[C@@H:50]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:51]
Reactant: O=Cc1ccccc1Cl
Reactant: OB(O)c1ccccc1
Agent: CC[Zn]CC
Agent: C[C@@H](c1ccccc1)N(C)[C@@H](c1cccc2ccccc12)c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: O[C@H](c1ccccc1)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 10 h
Yield: 91.1 %

Procedure:
PhB(OH)2 (122 mg, 1.0 mmol) and ZnEt2 (334 μL, 3.25 mmol) in toluene (1 mL) is charged to a 10 mL flask under a nitrogin atmosphere. This mixture is heated to 60° C. and stirred for 10 h with a magnetic stirrer. Then the mixture is cooled to 0° C. and the title compound of Example 1, 1-{(S)-[methyl-((S)-1-phenyl-ethyl)-amino]-naphthalen-1-yl-methyl}-naphthalen-2-ol (16.7 mg, 0.04 mmol) in toluene (0.5 mL) and DiMPEG (100 mg, 0.05 mmol) in toluene (0.5 mL) are added. After stirring for additional 15 min, the solution is cooled to −15° C. and 2-chlorobenzaldehyde (70.0 mg, 0.5 mmol) in toluene (1 mL) is added. After stirring 15 h at −15° C., the reaction is quenched with 1 N hydrochloric acid (HCl, 2 mL) and the mixture is extracted with ethyl acetate (EtOAc, 5 mL), dried over anhydrous sodium sulfate (Na2SO4) and the solvent is removed in vacuo. The purification of the residue by flash chromatography (EtOAc/hexane, 1:10) gives (R)-(2-chlorophenyl)phenylmethanol in about 96.9% ee and about 91.1% yield (the ee value is determined by HPLC using a Chiralcel OB-H column).