Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])C(F)(F)F)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]1[CH2:28][CH2:27][CH2:26]1.[OH-:29].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:16])=[O:29])=[CH:7][N:8]2[CH2:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Reactant: BrCC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(CC2CCC2)c2cc(Cl)ccc12
Temperature: 60 °C
Yield: 99 %

Procedure:
A mixture of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone (300 mg, 1.21 mmol), potassium carbonate (419 mg, 3.03 mmol), and (bromomethyl)-cyclobutane (0.21 mL, 1.82 mmol) in N,N-dimethylformamide (4 mL) in a sealed reaction vessel was heated at 60° C. for 16 h. At this time, the reaction was cooled to 25° C. and partitioned between water (30 mL) and ethyl acetate (30 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (6 mL), shaken, and separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a yellow solid. The resulting solid was treated with a 20% aqueous sodium hydroxide solution (7 mL) and was heated at 115° C. for 24 h. At this time, the reaction was cooled to 25° C. and was partitioned between water (75 mL) and ethyl acetate (75 mL). This solution was treated with a 1N aqueous hydrochloric acid solution (30 mL), shaken, and separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 6-chloro-1-cyclobutylmethyl-1H-indole-3-carboxylic acid (318 mg, 99%) as a yellow solid: mp 191-193° C.; EI-HRMS m/e calcd for C14H14ClNO2 (M+) 263.0713, found 263.0715.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12]>C(Cl)Cl.CCN(CC)CC>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@@H:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COCC(=O)Cl
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@](C)(CO)C(=O)O
Reaction time: 0.17 h
Yield: 16.7 %

Procedure:
Methoxy-acetyl chloride (7 mg, 30 μmol) was combined with a 0.4 mL solution of 0.075 M of (2S,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid (136 mg, 30 μmol) in DCM and Et3N (110 μL). The resulting mixture was stirred for 10 minutes. The solvent was evaporated and the residue was dissolved in AcOH and purified by preparative HPLC to yield the title compound (2.1 mg). MS m/z [M+H]+ calc'd for C22H26ClNO5, 420.15. found 420.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)CCC.O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:36]1[S:37][CH:38]=[CH:39][CH:40]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3cccs3)cc12
Yield: 45.4 %

Procedure:
A solution of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), tri-n-butyl(2-thienyl)tin (0.32 ml, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in tetrahydrofuran (20 ml) was refluxed for 12 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-thienyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.22 g, 45.8%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[C:3]=1[C:4]#[N:5].[S:22](Cl)(=[O:25])(=[O:24])[NH2:23]>C(#N)C>[NH2:5][C:4]1[C:3]2[C:6]([O:10][CH2:11][C@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[CH:7][CH:8]=[CH:9][C:2]=2[NH:1][S:22](=[O:25])(=[O:24])[N:23]=1
Reactant: NS(=O)(=O)Cl
Reactant: CCCC(=O)N1CCC[C@@H]1COc1cccc(N)c1C#N
Solvent: CC#N
Product: CCCC(=O)N1CCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 20 h
Yield: 35.8 %

Procedure:
To a solution of (R)-2-amino-6-((1-butyrylpyrrolidin-2-yl)methoxy)benzonitrile (84 mg, 0.29 mmol) (Example 176a) in acetonitrile (9 mL), was added sulfamoyl chloride (70 mg, 0.60 mmol). The reaction was stirred at rt for 20 h, and upon completion was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL), and 2N aqueous NaOH (4 mL) was added. The mixture was refluxed for 2 h, and upon completion was cooled to rt, neutralized with 1N HCl and stirred at 0° C. The resulting precipitate was collected by vacuum filtration to provide the desired product (38 mg, 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 0.89 (t, J=7.3 Hz, 3H), 1.54 (sext, J=7.3 Hz, 2H), 1.94 (m, 4H), 2.26 (t, J=7.3 Hz, 2H), 3.49 (m, 2H), 4.10 (m, 1H), 4.25 (m, 1H), 4.43 (m, 1H), 6.62 (d, J=8.2 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 7.45 (t, J=8.2 Hz, 1H), 8.08 (br s, 1H), 8.34 (br s, 1H), 10.93 (br s, 1H). MS 367 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[CH:35]([CH2:37][CH3:38])[CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:35]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:6][CH:7]=1)([CH2:37][CH3:38])[CH3:36]
Reactant: CCC(C)Br
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)CC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and 2-bromobutane (0.66 mL) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 48 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.85 g, 76%).
Reaction SMILES: [Br-].[F:2][C:3]([F:35])([F:34])[C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:5]=1[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:36]=[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](=[O:46])[N:38]1[CH2:47][CH2:48][CH2:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH:53]=O>>[F:35][C:3]([F:2])([F:34])[C:4]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[C:5]=1/[CH:6]=[CH:53]/[C:52]1[CH:51]=[C:50]([CH2:49][CH2:48][CH2:47][N:38]2[C:39](=[O:46])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37]2=[O:36])[CH:57]=[CH:56][CH:55]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2c(C(F)(F)F)cccc2C(F)(F)F)c1

Procedure:
2,6-Bis(trifluoromethyl)benzyltriphenylphosphonium bromide was coupled with phthalimide 29 following the method used in Example 46. Purification by flash chromatography (30% diethyl ether-hexanes) gave (E)-2-(3-(3-(2,6-bis(trifluoromethyl)styryl)phenyl)propyl)isoindoline-1,3-dione as an oil. Yield (0.227 g, 62%): 1H NMR (400 MHz, DMSO-d6) δ 8.09 (d, J=8.0 Hz, 2H), 7.78-7.84 (m, 4H), 7.75 (t, J=7.6 Hz, 1H), 7.28-7.38 (m, 3H), 7.27 (t, J=7.6 Hz, 1H), 7.19 (d, J=7.2 Hz, 1H), 6.57 (d, J=16.8 Hz, 1H), 3.62 (t, J=6.8 Hz, 2H), 2.64 (t, J=8.0 Hz, 2H), 1.88-1.96 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C.C1(C)C(S([N:39]=[N+:40]=[N-])(=O)=O)=CC=CC=1>CC#N>[N+:39](=[C:16]([C:15]([C:3]1[CH:4]=[C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][C:2]=1[F:1])=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:40]
Reactant: CCOC(=O)CC(=O)c1cc(CN2CCOCC2)ccc1F
Reactant: Cc1ccccc1S(=O)(=O)N=[N+]=[N-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=[N+]=[N-])C(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To a solution of ethyl 3-(2-fluoro-5-(4-morpholinylmethyl)phenyl)-3-oxopropanoate (Preparation 9, 5.00 g) and triethylamine (2.48 mL) in 50 mL CH3CN cooled to 0° C. is added toluenesulfonyl azide (3.51 g, prepared according to Org. Prep. Proc. Intl., 1981, 13, 112) in 10 mL CH3CN. The reaction is stirred at 0° C. for 15 min then at room temperature for 2 h. The reaction is concentrated (below 50° C.). 2N NaOH (25 mL) is added. The aqueous layer is extracted with CHCl3 (3×). The combined organic layers are washed, dried and concentrated to yield 4.68 g (86%) of the desired product as a yellow oil. Physical characteristics are as follows: 1H NMR (CDCl3) δ7.52, 7.44, 7.06, 4.24, 3.75, 3.55, 2.50, 1.24; MS (ESI+) for C16H18FN3O4 m/z 336.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[NH3:33]>O1CCOCC1>[NH2:33][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]=[C:17]3[CH:19]=[CH:20][N:21]([CH3:22])[C:16]3=[CH:15][C:14]=2[N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH3:12])[N:5]=1
Reactant: N
Reactant: Cc1nc(S(C)(=O)=O)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)c1C#N
Solvent: C1COCCO1
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 6 h
Yield: 17 %

Procedure:
(S)-4-Methyl-6-((1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (15 mg, 0.033 mmol) in dioxane (2 mL) was combined with ammonia in dioxane 0.5 M (0.198 mL, 0.099 mmol) to give a yellow solution, which was stirred for 6 hours at room temperature. The product was purified by LC/MS using a 20-45% CH3CN gradient in H2O with 0.035% formic acid. The pure fractions were combined and lyophilized to give a formic acid salt of the title compound as a white solid (2 mg, 17%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34-1.47 (m, 3 H), 2.17-2.28 (m, 3 H), 2.70-2.85 (m, 2 H), 2.96-3.13 (m, 2 H), 3.67-3.92 (m, 8 H), 5.82-5.97 (m, 1 H), 6.45-6.59 (m, 1 H), 6.87-6.98 (m, 2 H), 7.52-7.62 (m, 1 H), 7.82-7.91 (m, 1 H); ESI-MS m/z [M+H]+ calc'd for C20H24N8O3S, 393.4; found 393.4.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C@@H:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:13]([O:1][C:2]1[CH:12]=[CH:11][C:5]([C@@H:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)[C@H](O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)[C@H](O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
(R)-4-Hydroxymandelic acid (2.02 g) was dissolved in N,N-dimethylformamide (24 ml), and benzyl bromide (3.57 ml) and potassium carbonate (3.65 g) were added to the solution at room temperature with stirring. After reaction for 12 hours, ice-water was poured into the reaction mixture and the resulting precipitates were collected by filtration. The precipitates were suspended in methanol (24 ml) and 1N aqueous sodium hydroxide solution (12 ml) was added to the suspension under ice-cooling with stirring. After reaction at room temperature for 2 hours, 1N hydrochloric acid (12 ml) was added to the reaction mixture under ice-cooling with stirring. Collection by filtration of the resulting precipitates gave (R)-4-benzyloxymandelic acid (2.43 g) having a melting point of 161-163° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.CC(O)(C)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])=[CH:21][CH:20]=1.CCN(CC)CC>[Cl-].[Cl-].[Zn+2].ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])=[CH:21][CH:20]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(N)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
ZnCl2 (1.0 M in Et2O; 3.27 mL, 3.27 mmol) was added to a stirred solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (620 mg, 2.86 mmol) in a 1:1 t-BuOH:DCE mixture (120 mL) at room temperature. After stirring for 20 minutes tert-butyl 1-(4-aminophenyl)ethylcarbamate (0.643 g, 2.72 mmol) (prepared according to Bioorganic and Medicinal Chemistry Letters, 14(7), 1751-1755; 2004) followed by Et3N (455 μL, 3.27 mmol) was added and the resulting mixture stirred at room temperature overnight. The volatiles were evaporated to dryness and the resulting residue purified by silica gel column chromatography (CombiFlash Rf, SiO2 cartridge, 0-10% EtOAc in cyclohexane) to give the title compound A63 (480 mg, 42%); 1H NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 7.56 (m, 1H), 7.56 (d, J=8.61 Hz, 2H), 7.33 (d, J=8.61 Hz, 2H), 4.81 (m, 2H), 1.46 (m, 12H). LCMS-B: rt 8.47 min; m/z 417 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](I)=[CH:7][C:6]([C:10](=[O:26])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][C:4]=1I.[CH:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[CH:28]([C:30]1[CH:31]=[C:32]([C:4]2[CH:5]=[C:6]([C:10](=[O:26])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:7]=[C:8]([C:4]3[CH:3]=[CH:8][CH:7]=[C:6]([CH:10]=[O:26])[CH:5]=3)[C:3]=2[O:2][CH3:1])[CH:33]=[CH:34][CH:35]=1)=[O:29]
Reactant: COc1c(I)cc(C(=O)NCCCCCCCCc2ccccc2)cc1I
Reactant: O=Cc1cccc(B(O)O)c1
Product: COc1c(-c2cccc(C=O)c2)cc(C(=O)NCCCCCCCCc2ccccc2)cc1-c1cccc(C=O)c1

Procedure:
The title compound was prepared as a solid (0.479 g, 75%) from 2,6-diiodo-4-(8-phenyl-octylcarbamoyl)phenyl methyl ether using 3-formylbenzeneboronic acid and a procedure similar to step 3 of Example 93; 1H NMR (DMSO-d6) δ 1.21–1.35 (m, 8H), 1.46–1.60 (m, 4H), 2.47–2.58 (m, 2H), 3.13 (s, 3H), 3.21–3.32 (m, 2H), 7.09–7.19 (m, 3H), 7.21–7.30 (m, 2H), 7.54 (t, J=7.5 Hz, 2H), 7.94–8.03 (m, 6H), 8.17 (s, 2H), 8.61 (t, J=5.6 Hz, 1H), 10.14 (s, 2H); mass spectrum [(+) ESI], m/z 548 (M+H)+, 570 (M+Na)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[C:14]1([C:20]2([O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=3)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[C:11]([N:23]1[CH2:22][CH2:21][C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([O:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=2)[CH2:25][CH2:24]1)=[O:13]
Reactant: FC(F)(F)c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(C1CCc2ccccc2O1)N1CCC(Oc2ccc(C(F)(F)F)cc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.89 g (5.5 mmol) of 1,1-carbonyldiimidazole and 11 ml of dry tetrahydrofuran is added dropwise to a solution of 0.89 g (5.0 mmol) of 3,4-dihydro-2H-1-benzopyran-2-carboxylic acid and 5.5 ml of dry tetrahydrofuran at 20°-25° C. in the course of 1 hour. The reaction solution is then stirred at room temperature for a further 2 hours. A solution of 1.93 g (6.0 mmol) of 4-phenyl-4-(4-trifluoromethyl-phenoxy)-piperidine is then added dropwise at 25° C. in the course of 1 hour. After 18 hours at room temperature, the reaction solution is stirred into a mixture of 220 ml of 5% strength sodium chloride solution, 13 ml of 1 molar hydrochloric acid and 110 ml of toluene for working up. The aqueous phase is extracted once more with 55 ml of toluene. The combined organic phases are then washed with 55 ml each of 0.1 molar hydrochloric acid, followed by 1% strength sodium bicarbonate solution and then water. The organic phase is dried with sodium sulphate and concentrated to dryness.
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.Cl[C:11]1C(F)=CC=C(F)[C:12]=1CN.[Cl:21][C:22]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:23]=1[CH2:24][NH2:25]>>[Br:9][C:5]1[N:6]=[C:7]2[N:25]([CH2:24][C:23]3[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:22]=3[Cl:21])[CH2:11][CH2:12][NH:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1c(F)ccc(F)c1Cl
Reactant: NCc1cc(Cl)ccc1Cl
Product: Clc1ccc(Cl)c(CN2CCNc3ncc(Br)nc32)c1

Procedure:
7-bromo-1-(2,5-dichlorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine was prepared from 2-amino-3,5-dibromopyrazine as described in Example 1 by replacing 2-chloro-3,6-difluorobenzylamine in step 1 with 2,5-dichlorobenzylamine.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[CH:8]=O.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:14]1([N:20]2[C:24]3([CH2:25][CH2:26][N:27]([CH2:8][C:7]4[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=4[C:2]4[S:1][CH:5]=[CH:4][N:3]=4)[CH2:28][CH2:29]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: O=Cc1ccccc1-c1nccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1NCN(c2ccccc2)C12CCN(Cc1ccccc1-c1nccs1)CC2

Procedure:
To a mixture of 2-(2-thiazolyl)benzaldehyde (200 mg, 1.06 mmol) and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (0.232 mg, 1.00 mmol) in 1,2-dichloroethane (20 mL) was added sodium triacetoxyborohydride (376 mg, 1.79 mmol). The resultant mixture was stirred at room temperature for 18 h, quenched with aqueous NaHCO3 (50 mL) and extracted with CHCl3 (2×50 mL). The organic solution was dried over Na2SO4, filtered and concentrated. The crude product was dissolved in 1:1 CHCl3:CH3OH (30 mL) and treated with 2 mL of 1 N HCl in Et2O. The HCl salt was precipitated by addition of Et2O, collected by filtration and dried in the vacuum oven at 60° C. for 18 h to yield the product as an amorphous solid.
Reaction SMILES: [Si]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[S:18])[CH3:16])[NH:13][C:12]1=[O:26])[CH3:10])(C(C)(C)C)(C)C.CO.Cl[Si](C)(C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@H:15]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)=[S:18])[CH3:16])[NH:13][C:12]1=[O:26])[CH3:10]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Agent: C[Si](C)(C)Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
(3S ,4S)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (1.29 g, 3.0 mmol) is dissolved in toluene (10 ml), and thereto are added methanol (2 ml) and chlorotrimethylsilane (0.1 ml). The mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate (50 ml), washed several times with brine, dried over magnesium sulfate, and evaporated to remove the solvent to give (3S,4S)-3-[(1R)-1-hydroxyethyl]-4-[(1R)- 1-p-chlorophenylthiocarbonylethyl]-2-azetidinone (627 mg).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([OH:13])[CH:6]=1.C[O:16][C:17](=O)[CH2:18][C:19]1[O:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)=[N:22][N:23]=1.N1CCCCC1>C1C=CC=CC=1.C(#N)C>[F:1][CH2:2][CH2:3][N:4]([CH3:14])[C:5]1[CH:6]=[C:7]2[C:8]([CH:9]=[C:18]([C:19]3[O:20][C:21]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)=[N:22][N:23]=3)[C:17](=[O:16])[O:13]2)=[CH:11][CH:12]=1
Reactant: CN(CCF)c1ccc(C=O)c(O)c1
Reactant: COC(=O)Cc1nnc(-c2cccs2)o1
Solvent: CC#N
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: CN(CCF)c1ccc2cc(-c3nnc(-c4cccs4)o3)c(=O)oc2c1
Yield: 18.6 %

Procedure:
40 mg (ca. 0.2 mmol) crude 4-[(2-Fluoro-ethyl)-methyl-amino]-2-hydroxy-benzaldehyde and 30 mg (0.13 mmol) (5-thiophen-2-yl-[1,3,4]oxadiazol-2-yl)-acetic acid methyl ester are dissolved under argon in 4 mL benzene and 2 mL acetonitrile, treated with 0.03 mL (2 eq.) piperidine and heated to reflux for 1 h. The reaction mixture is allowed to reach room temperature, evaporated, and the residue column chromatographed (silica gel, AcOEt/petroleum ether 1:1). The fluorescent, yellow product is triturated in diisopropylether, then dried under high vacuum to yield 9 mg (19%) desired product as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12](=[O:15])[CH:13]=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])[O:17][CH2:18][CH3:19].O.[C:23]1(C)C=CC(S(O)(=O)=O)=C[CH:24]=1>C1(C)C=CC=CC=1>[CH2:23]([O:14][CH:13]([O:17][CH2:18][CH3:19])[C:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([F:1])[CH:11]=1)=[O:15])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1ccc(C(=O)C=O)cc1F
Reactant: CCOC([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(OCC)C(=O)c1ccc(C(=O)OC)c(F)c1

Procedure:
A mixture of methyl 2-fluoro-4-(oxoacetyl)benzoate (6.0 g, 0.028 mol), ethyl orthoformate (12.0 mL, 0.071 mol), and p-toluenesulfonic acid monohydrate (200 mg) in toluene (60 mL) was heated under reflux for 4 h. After cooling, the reaction mixture was concentrated under reduced pressure to give the desired product which was used in the next step without further purification.