Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][CH2:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:7]([C:17]([O:19]C)=[O:18])[CH2:6]1.[Li+].[OH-].Cl>C1COCC1.CO>[C:13]([O:12][C:10]([N:8]1[CH2:9][C@@H:5]([CH2:4][O:3][CH:2]([F:1])[F:21])[CH2:6][C@H:7]1[C:17]([OH:19])=[O:18])=[O:11])([CH3:16])([CH3:14])[CH3:15]
Reactant: COC(=O)[C@@H]1C[C@H](COC(F)F)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](COC(F)F)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.3 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 7.79 mmol) in a mixture of THF (39 mL) and MeOH (15.6 mL) was added LiOH (2.5 M aqueous, 15.6 mL, 38.9 mmol). The resulting solution was stirred at room temperature for 1 h. Upon completion by TLC the reaction mixture was acidified with aqueous HCl (1N). The desired product was extracted with CH2Cl2 (3×). The combined organic layers were dried over Na2SO4 and concentrated to provide (2S,4S)-1-(tert-butoxycarbonyl)-4-((difluoromethoxy)methyl)pyrrolidine-2-carboxylic acid (2.4 g, 99%). MS (ESI) m/z 294.96 [M−H]−. 1H-NMR: 400 MHz, (acetone-d6) δ (mixture of rotamers): 6.50 (t, 1H), 4.36-4.17 (m, 1H), 3.93 (d, 2H), 3.77-3.67 (m, 1H), 3.63-3.59 (m, 1H), 3.26-3.12 (m, 1H), 2.72-2.41 (m, 2H), 1.89-1.73 (m, 2H), 1.41 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])C.O.[OH-].[Na+]>CO>[C:11]([C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH3:15])[N:8]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1nc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid ethyl ester (1.08 g, 5.14 mmol, prepared as described in the previous step) was dissolved in MeOH (15 mL), and H2O (15 mL) and 2.5 M aqueous NaOH (5.00 mL, 12.5 mmol) was added. The resulting mixture was stirred at room temperature for 72 h, and then extracted with Et2O (2×10 mL). The aqueous layer was acidified to ca. pH 2 using 3 M aqueous HCl and extracted with DCM (3×20 mL). The combined organic extracts were dried over anhydrous MgSO4 and filtered, and the solvent was removed under reduced pressure to yield the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 6.80 (s, 1H), 4.15 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[Cl:13][C:14]1[C:15](F)=[CH:16][C:17]2[O:22][CH:21]([C:23]([F:26])([F:25])[F:24])[C:20]([C:27]([O:29]CC)=[O:28])=[CH:19][C:18]=2[CH:32]=1>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][C:15]1[C:14]([Cl:13])=[CH:32][C:18]3[CH:19]=[C:20]([C:27]([OH:29])=[O:28])[CH:21]([C:23]([F:25])([F:26])[F:24])[O:22][C:17]=3[CH:16]=1)[CH:6]=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc2cc(Br)ccc2c1
Solvent: O
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc4cc(Br)ccc4c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 6-bromo-2-napthol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 252.6–254.8° C. 1H NMR (acetone-d6/300 MHz) 8.19 (s, 1H), 8.04 (d, 1H, J=9.1 Hz), 7.93 (s, 1H), 7.87 (d, 1H, J=8.9 Hz), 7.75 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.55 (s, 1H), 7.43 (d, 1H, J=9.1 Hz), 6.72 (s, 1H), 5.83 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz). FABLRMS m/z 497 (M−H). ESHRMS m/z 496.9421 (M−H, Calc'd 496.9403). Anal. Calc'd for C21H11BrClF3O4 with 1.75 wt % H2O: C, 49.60; H, 2.38; Br, 15.71; Cl, 6.97. Found: C, 49.55; H, 2.03; Br, 15.56; Cl, 7.22.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[CH2:11][C@H:10]1[CH2:25][N:26]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[O:50][CH3:51])[CH2:27][C:28](=O)[CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=O)(C)(C)C.[C:52]([O:55][CH2:56][CH3:57])(=[O:54])C>>[CH2:56]([O:55][C:52]([N:12]1[CH2:13][CH2:14][N:9]2[C@H:28]([CH:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:27][N:26]([CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[O:50][CH3:51])[CH2:25][C@@H:10]2[CH2:11]1)=[O:54])[C:57]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(C)=O
Reactant: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Product: COc1ccccc1CN1C[C@@H]2CN(C(=O)OCc3ccccc3)CCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h

Procedure:
4N Hydrogen chloride in ethyl acetate solution (3 ml) was added to a solution of (2R)-2-[[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (160 mg) in ethyl acetate (3 ml) at room temperature. After being stirred for 2 hours, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved into dichloromethane (4 ml). Sodium triacetoxyborohydride (150 mg) was added to the stirred mixture and the whole was stirred at room temperature for 18 hours. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (3:4) as an eluent to give (6R,9aR)-6-benzhydryl-8-(2-methoxybenzyl)octahydropyrazino[1,2-a]pyrazine-2-carboxylic acid benzyl ester (108 mg) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])N[C:5]([C:9]2([O:13][CH2:14][CH2:15][CH2:16]O)[CH2:12][CH2:11][CH2:10]2)=[N:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl-].[CH2:24](N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:1][C:2]1[C:7](=[O:8])[CH:24]2[CH2:16][CH2:15][CH2:14][O:13][C:9]3([CH2:12][CH2:11][CH2:10]3)[C:5]2=[N:4][C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1nc(C2(OCCCO)CCC2)[nH]c(=O)c1O
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(O)C(=O)C2CCCOC3(CCC3)C2=N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
A cold (0° C.) solution of ethyl 5-hydroxy-2-(1-(3-hydroxypropoxy)cyclobutyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate (3.0 g, 9.6 mmol) in tetrahydrofuran (25 mL) was treated with methanesulfony chloride (3.30 g, 29 mmol) followed by dropwise addition of triethylamine (4.7 mL, 33.6 mmol). The reaction was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the mixture was dissolved in ethanol (50 mL) and dimethylformamide (25 mL). To the slurry was added potassium carbonate (1.36 g, 9.7 mmol) and the reaction was stirred at room temperature for 16 hours, followed by heating (80° C.) for 3 hours. The solvent was removed in vacuo. The crude product was diluted with ethyl acetate (50 mL) and washed with 1N hydrochloric acid (2×50 mL), extracted with ethyl acetate (2×25 mL) then brine ((50 mL). The solution was then dried (sodium sulfate), filtered and concentrated to give the title compound (0.534 g, 19%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ: 10.64 (1H, br s), 4.45 (2H, q, J=7.0 Hz), 4.38 (2H, br), 3.91 (2H, t, J=5.0 Hz), 2.81 (2H, br), 2.36-2.44 (2H, m), 1.87-1.97 (1H, m), 1.82-1.86 (2H, m), 1.67-1.75 (1H, m), 1.43 (3H, t, J=7.2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([O-:12])(=O)=[O:10].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9]([Cl:15])(=[O:12])=[O:10]
Reactant: O=S(=O)([O-])Cc1ccccc1Br
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=S(=O)(Cl)Cc1ccccc1Br
Temperature: 100 °C
Reaction time: 4 h
Yield: 50.1 %

Procedure:
To a suspension of crude sodium (2-bromophenyl)methanesulfonate (34 g) in toluene (500 mL) was added PCl5 (34 g, 0.16 mol). The resulting mixture was stirred at 100° Celsius for 4 hours before concentrating to dryness and pouring the residue onto crushed ice (150 g), stirring for 5 min, and extracting with DCM (3×50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to dryness to give (2-bromophenyl)methanesulfonyl chloride (16.8 g, 77%). 1H NMR (300 MHz, DMSO-d6) δ 7.62-7.45 (m, 2H), 7.29 (m, 1H), 7.18-7.01 (m, 1H), 3.97 (s, 2H).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:2].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Si:22]([O:29][C:30]1[CH:35]=[C:34]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[CH:33]=[CH:32][C:31]=1[C@H:44]1[CH2:49][CH2:48][C@H:47]([CH2:50][OH:51])[CH2:46][CH2:45]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O>[Si:22]([O:29][C:30]1[CH:35]=[C:34]([O:36][Si:37]([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:39])[CH3:38])[CH:33]=[CH:32][C:31]=1[C@H:44]1[CH2:45][CH2:46][C@H:47]([C:50]([OH:2])=[O:51])[CH2:48][CH2:49]1)([C:25]([CH3:26])([CH3:27])[CH3:28])([CH3:24])[CH3:23]
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](CO)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](C(=O)O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Reaction time: 24 h

Procedure:
Pyridinium dichromate (146 mg) was added to a stirred solution of cis/trans-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanol (50 mg) in N,N-dimethylformamide (1 ml) at room temperature under argon. After 24 hr, the reaction mixture was partitioned between water (20 ml) and diethyl ether (30 ml). The layers were separated and the aqueous layer was extracted with diethyl ether (2×30 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:9 v/v) to give the title compound as a cream solid (23 mg, 44%); m/z (ES+) 465 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(Cl)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
Sulfur trioxide pyridine complex (720 mg, 4.5 mmol) was added to a solution of 3-[3-(2,5-dichlorophenylsulfonyloxy)-5-methylphenoxy]propanol (580 mg, 1.5 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.3 mL, 4.2 mmol) in anhydrous dichloromethane (15 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (50 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (530 mg, 91%). 1H-NMR (300 MHz, CDCl3) δ 9.84 (s, 1H), 7.96 (s, 1H), 7.56 (s, 2H), 6.63 (s, 1 H), 6.58 (s, 1H), 6.50 (s, 1 H), 4.22 (t, J=6.0 Hz, 2H), 2.88 (t, J=6.1 Hz, 2 H), 2.27 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16]C(C)(C)C)=O)[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.F[C:22](F)(F)C(O)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:22])[CH2:10][CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccnc2F)CC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cccnc2F)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl 4-(2-fluoropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.69 g, 9.67 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (7.45 mL, 97 mmol) and stirred at RT for 2 h. The reaction was concentrated in vacuo, and the residue was partitioned between CH2Cl2 and aqueous saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to give a golden yellow oil. A solution of the crude golden yellow oil in CH2Cl2 (10 mL) was cooled to 0° C. and added acetic anhydride (4.5 mL, 48.3 mmol). The reaction was gradually allowed to warm to RT and stirred for 16 h. The reaction was diluted with CH2Cl2 and washed with aqueous saturated NaHCO3 solution; the aqueous layer was back-extracted with CH2Cl2 (1×). The organic extracts were combined, dried (MgSO4), and concentrated in vacuo. Flash column chromatography (20% to 80% EtOAc/Hexanes) afforded 1-(4-(2-fluoropyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone as a colorless oil. [M+1]=221.1.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16](O)=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:53][CH:54]([C:57]1[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=1)[CH2:55][OH:56]>ClCCl>[F:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([NH:53][CH:54]([C:57]3[CH:62]=[CH:61][C:60]([F:63])=[C:59]([F:64])[CH:58]=3)[CH2:55][OH:56])=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Reactant: NC(CO)c1ccc(F)c(F)c1
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 3.4 %

Procedure:
100 mg (0.31 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid, 111 mg (0.35 mmol) of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) and 159 mg (1.57 mmol) of 4-methylmorpholine were initially charged in 2.0 ml of dichloromethane. After 10 min at RT, 142 mg (0.35 mmol) of 2-amino-2-(3,4-difluorophenyl)-ethanol were added and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and acetonitrile/methanol/water was added. A solid precipitated out, and this solid was filtered off and purified by chromatography on silica gel (mobile phase: dichloromethane:THF=10:1→5:1). The combined product fractions were concentrated and then triturated with acetonitrile, and the solid was filtered off and washed with methanol. This gave 39 mg of the target compound (26% of theory, purity 95%). After some time, the filtrate produced more solid; this gave another 5 mg of the target compound (3.3% of theory, purity 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[O:34]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N-]=C=O>CN(C=O)C.C(O)(=O)C>[O:34]1[CH:38]=[CH:37][C:36]([CH2:39][N:11]2[CH2:12][CH2:13][CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:9]([CH2:8][N:7]([C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[C:6](=[O:33])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[CH:35]1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [N-]=C=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(Cc2ccoc2)CCC1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a mixture of 13.3 mg of tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate, 3.4 mg of 3-furaldehyde, 0.050 mL of acetic acid, and 0.5 mL of DMF was added 75 mg of MP-Triacetoxyborohydride (Argonaut Technologies, USA) at room temperature, followed by stirring overnight. To the reaction mixture was added 50 mg of PS-Isocyanate (Argonaut Technologies, USA) at room temperature, followed by stirring for 2 hours, and the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl {[1-(3-furylmethyl)-4-phenylpiperidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate as a crude product. To 0.5 mL of a methanol solution of the obtained crude product was added 0.5 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (column: registered trademark SunFire, Waters, particle diameter of 5 μm, inner diameter of 19 mm, and length of 100 mm), flow rate: 25 ml/min., column temperature: 20° C., methanol—a 0.1% aqueous formic acid solution) to obtain 4.9 mg of (1R)—N-{[1-(3-furylmethyl)-4-phenylpiperidin-3-yl]methyl}-1-(1-naphthyl)ethaneamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]=[O:11])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18].[CH2:21]([Mg]Br)[CH3:22]>C(OCC)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([CH:10]([OH:11])[CH2:21][CH3:22])[C:7]([C:12]([F:15])([F:14])[F:13])=[CH:6][C:5]=1[NH:16][C:17](=[O:19])[CH3:18]
Reactant: CC[Mg]Br
Reactant: COC(=O)c1cc(C=O)c(C(F)(F)F)cc1NC(C)=O
Solvent: CCOCC
Product: CCC(O)c1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
A solution of 2-acetylamino-5-formyl-4-trifluoromethyl-benzoic acid methyl ester (840 mg, 2.90 mmol) in dry diethyl ether (29 mL) was cooled to 0° C. and a solution of ethylmagnesium bromide (1M in THF, 5.8 mL, 5.8 mmol) was added dropwise. The mixture was stirred for 1 h at 0° C. and the reaction was quenched by adding aqueous ammonium chloride solution. This mixture was extracted once with EtOAc and the organic phase was then washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel 60, hexanes/EtOAc 80:20→70:30) to furnish 2-acetylamino-5-(1-hydroxy-propyl)-4-trifluoromethyl-benzoic acid methyl ester (262 mg, 0.82 mmol, 28%) as a white solid, m.p. 120-122° C., ESI-MS: m/z 320 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])[CH3:12].C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([N:17]2[CH2:18][CH2:19][N:14]([C:11](=[O:13])[CH3:12])[CH2:15][CH2:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 100 °C
Yield: 53.9 %

Procedure:
To a mixture of 5-bromo-2-nitropyridine (406 mg, 2 mmol) and 1-acetylpiperazine (256 mg, 2 mmol) in toluene (5 mL) is added Cs2CO3, then Pd2(dba)3 (74 mg, 0.08 mmol) and BINAP (100 mg, 0.16 mmol) are added. The mixture is degassed, and heated at 100° C. for 16 hours. Then the mixture is cooled down to room temperature, diluted with EtOAc, and filtered through celite. The filtrate is concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=0.7:99.3 to 6:93) to give 270 mg of the title compound as yellow solid.
Reaction SMILES: Br[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:10][C@H:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])[C:3]=1[C:4]#[N:5].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C=O)C>[N:21]([C:2]1[N:9]=[CH:8][CH:7]=[C:6]([NH:10][C@H:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:12])[C:3]=1[C:4]#[N:5])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](CCc1ccccc1)Nc1ccnc(Br)c1C#N
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](CCc1ccccc1)Nc1ccnc(N=[N+]=[N-])c1C#N
Yield: 87.7 %

Procedure:
Prepared according to the methods above using (S)-2-bromo-4-((4-phenylbutan-2-yl)amino)nicotinonitrile (76.1 mg, 0.230 mmol), sodium azide (30.0 mg, 0.461 mmol) and ammonium chloride (24.65 mg, 0.461 mmol) in DMF (1.0 mL) at 100° C. for 2.5 hours to give the desired product as a yellow oil (59 mg). LC/MS (291/293, [M−H]−/[M+H]+).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:36]2[CH:35]=[CH:34][C:33]([F:32])=[CH:38][C:37]=2[F:39])[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: OB(O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1-c1ccc(F)cc1F
Yield: 83.4 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.244 mmol) in DME (5 ml)/2M Na2CO3 (0.428 ml, 0.855 mmol) was treated with 2,4-difluorophenylboronic acid (77 mg, 0.489 mmol) and Pd[PPh3]4 (28 mg, 0.0244 mmol) at 90° C. overnight. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as solid (90 mg, 82%). MS m/e 443.38 (M+H+)
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[NH:3]1.CC(C)([O-])C.[K+].Br[CH2:21][CH2:22][CH2:23][Cl:24]>CN(C=O)C>[Cl:24][CH2:23][CH2:22][CH2:21][N:3]1[C:2]([CH3:13])([CH3:1])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4]1(=[O:12])=[O:11]
Reactant: CC1(C)NS(=O)(=O)c2ccccc21
Reactant: ClCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)c2ccccc2S(=O)(=O)N1CCCCl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 5.9 g (3 mmol) of 3,3-dimethyl-2,3-dihydro-1,2-benzoisothiazole 1,1-dioxide in 150 ml of DMF at room temperature was, after addition of 3.7 g (3.3 mmol) of potassium t-butoxide, heated under nitrogen to 80° C. Then 14.2 g (9 mmol) of 1-bromo-3-chloropropane were rapidly added and the mixture was stirred at 100° C. for 30 min. Pouring into ice-water was followed by extraction with ether, and the organic phases were washed with water, dried with sodium sulfate and then evaporated so that the product resulted as crystals which could be filtered off with suction. 6.7 g (82%) of substance were obtained. Melting point 107° C.