Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42](O)=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26].Cl.[NH2:55][C@:56]1([C:61]([O:63][CH3:64])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:25]([O:29][C:30]([NH:32][C@@H:33]([C@H:45]([CH3:53])[CH2:46][CH:47]([CH3:52])[CH2:48][CH2:49][CH:50]=[CH2:51])[C:34]([N:36]1[CH2:40][C@H:39]([OH:41])[CH2:38][C@H:37]1[C:42]([NH:55][C@:56]1([C:61]([O:63][CH3:64])=[O:62])[CH2:58][C@H:57]1[CH:59]=[CH2:60])=[O:43])=[O:35])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCCC(C)C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
HATU (2.510 g, 6.60 mmol) was added to a solution of (2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (2.269 g, 5.5 mmol), (1R,2S)-methyl 1-amino-2-vinylcyclopropanecarboxylate HCl (1.172 g, 6.60 mmol), and Hunig's Base (3.84 ml, 22.00 mmol) in DCM (20 ml) and was stirred at RT for overnight. The reaction was washed with 1N HCl (3×) and then brine and evaporated on rotovap, then purified via silica gel chromatography to get the product (1R,2S)-methyl 1-((2S,4R)-1-((2S,3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate (2.68 g, 5.00 mmol, 91% yield) as a light orange foam. MS: MS m/z 558.16 (M++23).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12]C(C)(C)C)=O)[CH:5]=[N:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O.[NH2:24][C:25]1[N:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37](=[O:39])[CH3:38])[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[C:37]([N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)=[N:30][CH:29]=2)[CH2:36][CH2:35]1)(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)Cc1cnc(Cl)c(Cl)c1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3cnc(Cl)c(Cl)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 2-(5,6-dichloropyridin-3-yl)acetate 184-3 (130 mg, 0.49 mmol) and TFA (0.5 mL) in DCM (3 mL) was stirred at room temperature for 2 hours. The solvents were evaporated to dryness under high vacuum. The crude product, 2-(5,6-dichloropyridin-3-yl)acetic acid 184-4, was dissolved in DMF (3 mL). 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone (128 mg, 0.58 mmol) and DIEA (435 uL, 2.5 mmol) were added to the solution before O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (277 mg, 0.73 mmol). The mixture was stirred at room temperature overnight. The solvent was removed by rotary evaporation. The residue was purified by silica gel flash chromatography and eluted with 5% MeOH in CH2Cl2 to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(5,6-dichloropyridin-3-yl)acetamide 184-5. MS m/z 408.1 (M+1).
Reaction SMILES: Br[CH:2]1[CH:8](Br)[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4](=[O:22])[CH2:3]1.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[CH2:10]([N:5]1[CH2:6][CH:7]=[CH:8][CH:2]=[CH:3][C:4]1=[O:22])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCN1CCC(Br)C(Br)CC1=O
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CCCCCCCCCCCCN1CC=CC=CC1=O
Reaction time: 20 h
Yield: 177.4 %

Procedure:
A solution of 3.4 g (7.72 mmol) of 4,5-dibromo-1-dodecylazacycloheptan-2-one in 5.79 g (0.054 mol) of 2,6-lutidine was refluxed for 3 hours. After standing at room temperature for 20 hours, toluene was added, and the solution was filtered. The filtrate was concentrated in vacuo and distilled to give 3.8 g of a crude oil which was subjected to flash chromatography (silica gel; 3:1 petroleum ether/ether V/V) to yield pure product.
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[C:12]2[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=2)[C:15]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[O:16])[C@@H:6]([CH3:34])[CH2:5]1)[CH:2]=[CH2:3].Cl.[NH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].[OH-].[K+].C([BH3-])#N.[Na+]>C(O)C>[CH2:43]([O:42][C:40](=[O:41])[CH2:39][CH2:38][CH2:37][NH:36][CH:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[C:14]2[CH:24]=[CH:25][CH:26]=[C:12]([C@@H:11]([N:7]3[CH2:8][C@@H:9]([CH3:10])[N:4]([CH2:1][CH:2]=[CH2:3])[CH2:5][C@@H:6]3[CH3:34])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[CH:13]=2)[CH2:22][CH2:21]1)[CH3:44]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(=O)CC3)c2)C[C@H]1C
Reactant: CCOC(=O)CCCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(NCCCC(=O)OCC)CC3)c2)C[C@H]1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.4 %

Procedure:
A 100 mL round bottom flask equipped with a magnetic stir bar was flushed with nitrogen and charged with 2.31 g (5 mmol, 1 eq) of 1-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)-methyl]-benzoyl}-4-piperidinone (Example 136), 1.41 g (8.4 mmol, 1.68 eq) of ethyl 4-aminobutyrate hydrochloride, 0.47 g (8.4 mmol, 1.68 eq) of potassium hydroxide, and 10 mL of ethanol. The reaction was stirred vigorously at room temperature under nitrogen for 2.5 hours. A solution of 0.32 g (5 mmol, 1 eq) of sodium cyanoborohydride in 5 mL of ethanol was added and the reaction was stirred overnight. The reaction was quenched by careful addition of 1 mL of saturated aqueous NH4Cl solution and stirred vigorously for 30 minutes and concentrated in vacuo. The residue was partitioned between 50 mL dichloromethane and water, and the aqueous solution was adjusted to pH=8-9 using saturated sodium bicarbonate solution. The organic layer was separated and dried over sodium sulfate/magnesium sulfate and the solvent was removed in vacuo, leaving 2.81 g of crude product as a viscous, amber-colored oil. Chromatography of this material on a pre-packed 4×15 cm Biotage® silica gel cartridge eluting with dichloromethane/ethyl acetate with 2% ammonium hydroxide yielded 1.57 g (53%) of 4-(1-{3-[(R)-((2S,5R)-4-Allyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-piperidin-4-ylamino)-butyric acid ethyl ester as an off-white foam. Calculated for C34H48N4O4 0.1 CH2Cl2: %C, 69.98; H, 8.30; N, 9.57. Found: %C, 70.07; H, 8.39; N, 9.65. 1H NMR (300 MHz, CDCl3): {tilde over (□)}{tilde over (□)}1{tilde over (□)}1m, 1H), 7.38-7.23 (m, 3H), 7.11 (t, J=7.9 Hz, 1H), 6.68-6.56 (m, 1H), 6.65 (t, J=7.9 Hz, 2H), 5.93-5.80 (m, 1H), 5.21-5.14 (m, 3H), 4.52 (br s, 1H), 4.14 (q, J=7.2 Hz, 2H), 3.67 (m, 1H), 3.36 (br d, 1H), 2.98-2.78 (m, 4H), 2.73-2.55 (m, 5H), 2.46 (m, 1H), 2.37 (t, J=7.2 Hz, 2H), 2.12 (dd, J=1, 9.3 Hz, 1H), 1.92 (m, 1H), 1.79 (quint, J=7.1 Hz, 2H), 1.26 (t, J=7.1 Hz, 3H), 1.15 (br d, J=5.6 Hz, 3H), 0.98 (d, J=6.2 Hz, 3H).
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)[N:12]=1.Br.[OH-].[Na+]>C(O)(=O)C>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]1[N:12]=[C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:21])=[O:2])[S:9][CH:10]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2OC)cs1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)CCCCc1nc(-c2ccccc2O)cs1
Yield: 90.7 %

Procedure:
Dissolve 5-[4-(2-methoxy-phenyl)-thiazol-2-yl]-pentanoic acid methyl ester (3.20 g, 10.5 mmol) in acetic acid (50 mL, glacial), add HBr (50 mL, 48% aqueous solution) and heat to reflux under N2 for 6 hours. Add additional HBr (20 mL, 48% aqueous solution) and heat at reflux under N2 overnight. Adjust to pH 4 with 5N NaOH solution, extract with EtOAc (×2), dry over MgSO4 and concentrate to get 2.64 grams of a light brown solid. Recrystallize from EtOAc/hexanes to afford the title compound (2.14 g, 74%). MS (IS) 278 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[CH:6]1)[CH3:2].[CH2:12]([Si:14](Cl)([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][O:11][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:12][CH3:13])[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOCn1cnc(CO)c1
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOCn1cnc(CO[Si](CC)(CC)CC)c1
Reaction time: 17 h

Procedure:
The compound (520 mg) obtained in (2) was dissolved in dichloromethane (30 mL), followed by addition of triethylsilyl chloride (1.12 mL), TEA (1.16 mL) and DMAP (catalytic amount) under stirring, and the stirring was continued for 17 hours. The reaction solution was diluted with water, and extracted with chloroform. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→80%) using silica gel column (product name: SNAP Cartridge KP-Sil 50 g, manufactured by Biotage, Ltd.) to afford the title compound (665 mg).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH:7]([OH:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)c1ccc(Br)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1ccc(Br)s1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of ethyl 2-(5-bromothiophen-2-yl)-2-oxoacetate (2.5 g, 9.5 mmol) in tetrahydrofuran (50 mL) was added sodium triacetoxy borohydride (2.5 g, 11.8 mmol, 1.2 eq). After stirring for 1 hour at 60° C., the reaction mixture was diluted with ethyl acetate, washed (brine), dried (Na2SO4), filtered and concentrated to provide ethyl 2-(5-bromothiophen-2-yl)-2-hydroxyacetate (2.5 g, 99.24%). 1H NMR (400 MHz, DMSO-d6): δ 1.19 (t, J=7.0 Hz, 3H), 4.11-4.16 (m, 2H), 5.34 (d, J=5.6 Hz, 1H), 6.50 (d, J=6.0 Hz, 1H), 6.91 (d, J=4.0 Hz, 1H), 7.09 (d, J=4.0 Hz, 1H).
Reaction SMILES: C(O)(=O)C.[NH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10]2.[CH:17]([N:20]([CH:23]([CH3:25])[CH3:24])CC)([CH3:19])C.N1C=CC=C1C=O.N1CCCC1>C(O)C>[NH2:5][CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10]2=[CH:25][C:23]1[NH:20][CH:17]=[CH:19][CH:24]=1
Reactant: NCc1ccc2c(c1)CC(=O)N2
Reactant: CCN(C(C)C)C(C)C
Agent: O=Cc1ccc[nH]1
Solvent: C1CCNC1
Solvent: CCO
Solvent: CC(=O)O
Product: NCc1ccc2c(c1)C(=Cc1ccc[nH]1)C(=O)N2
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Alternatively, a solution of 5-aminomethylindolin-2-one acetate salt (220 mg, 1 mmol) in ethanol (10 mL) was treated with diisopropylethylamine (DIEA) (3 mL). After 20 minutes, 2-pyrrolecarboxaldehyde (95 mg, 1 mmol) and pyrrolidine (0.05 mL) were added and the reaction mixture was stirred at 60° C. for 3 hours. Concentration of the solvent gave an oil which was purified by reverse phase HPLC (acetonitrile/water) to afford 5-aminomethyl-3-[(pyrrol-2-yl)methylene]indolin-2-one; as a trifluoroacetate salt (70 mg); 1H NMR (400 MHz, DMSO-d6) δ 3.98 (m, 2H), 6.36 (m, 1H), 6.84 (brs, 1H), 6.88 (d, 1H), 7.22 (d, 1H), 7.34 (s, 1H), 7.62 (s, 1H), 7.68 (s, 1H), 8.20 (brs, 2H), 11.00 (s, 1H) ppm.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH:12]1([CH2:17][CH2:18][C:19](O)=[O:20])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:1]1[C:10]2[C:5](=[C:6]([NH:11][C:19](=[O:20])[CH2:18][CH2:17][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cccc2ncccc12
Reactant: O=C(O)CCC1CCCC1
Product: O=C(CCC1CCCC1)Nc1cccc2ncccc12
Yield: 24.1 %

Procedure:
Prepared according to the method of example 18, using 5-quinolinamine (250 mg) and cyclopentanepropanoic acid (270 mg). Purification (HPLC, Symmetry—0.1% aqueous trifluoroacetic acid/acetonitrile) followed by recrystallisation from methanol/ethyl acetate gave the title compound as a colourless solid (112 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[CH:29]=[O:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]3[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=3[CH:10]=2)=[CH:22][C:21]=1[CH:29]=[O:30]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Reactant: O=Cc1cc(B(O)O)ccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)c(C=O)c2)cc2c1c(C)cn2C(C)C
Temperature: 110 °C
Reaction time: 4 h
Yield: 98.3 %

Procedure:
To a glass pressure vessel was added methyl 6-bromo-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (500 mg, 1.612 mmol), 4-fluoro-3-formylbenzeneboronic acid (375 mg, 2.233 mmol), Potassium phosphate (1.1 g, 5.18 mmol), dioxane (12 mL) and water (3 mL). The reaction was purged with N2 and charged with PdCl2(dppf)-CH2Cl2 adduct (120 mg, 0.147 mmol). The reaction was capped and stirred at 110° C. for 4 hr. LCMS showed that the reaction was complete. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. Purification by silica gel chromatography (Analogix, SF25-60g, 0 to 50% EtOAc in hexanes) gave the product methyl 6-(4-fluoro-3-formylphenyl)-3-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (560 mg, 1.585 mmol, 98% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=10.30 (s, 1H), 8.24-8.13 (m, 2H), 8.10 (d, J=1.5 Hz, 1H), 7.75 (d, J=1.8 Hz, 1H), 7.57-7.46 (m, 2H), 4.98 (quin, J=6.6 Hz, 1H), 3.91 (s, 3H), 2.31 (s, 3H), 1.46 (d, J=6.6 Hz, 6H). MS(ES)+ m/e 354.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:30]([O:37][CH2:38][CH2:39][CH2:40]O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C(Cl)(Cl)Cl.CO>[CH2:30]([O:37][CH2:38][CH2:39][CH2:40][O:24][C:23]([C:18]1([C:20]([O:22][CH2:40][CH2:39][CH2:38][O:37][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: OCCCOCc1ccccc1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCCCOCc1ccccc1)(C(=O)OCCCOCc1ccccc1)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 38 %

Procedure:
The title compound was prepared as a yellow gum from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 3-benzyloxy-propanol according to the procedure of Example 1; yield: 38%; Rf =0.52 (9/1 CHCl3 /MeOH); 1H NMR (300 MHz, CDCl3): δ 1.32 (d, 3H), δ 2.00 (m, 4H), δ 2.75 (m, 1H), δ 3.30 (s, 2H), δ 3.50 (m, 4H), δ 4.40 (br m, 12H), δ 5.49 (s, 1H), δ 6.68-6.85 (m, 3H), δ 7.24-7.40 (m, 13H), δ 7.43 (s, 1H); MS (ES) m/z (relative intensity): 518 (M+ -HCl, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH3:24])=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:25])=[C:7]2[C:12](=[C:13]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([CH3:24])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(C)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 56.3 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-3-methyl-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (170 mg, 0.42 mmol), 3-tributylstannanyl-pyridine (0.2 mL, 0.63 mmol), and PdCl2(PPh3)2 (59 mg, 0.084 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1M HCl was added with stirring until pH was about 3. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes+2% AcOH) to give 95 mg of the title compound. MS: (+) m/z 402.14 (M+1).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH2:15][CH2:14]1)=[O:12].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:16]1[CH2:17][CH2:18][N:13]([C:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:12])[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C(c1cc([N+](=O)[O-])ccc1F)N1CCN(c2ccccc2F)CC1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccccc2F)CC1

Procedure:
The title compound was prepared according to the procedure described for example 1 from (2-Fluoro-5-nitro-phenyl)-[4-(2-fluoro-phenyl)-piperazin-1-yl]-methanone and morpholine (87%, yellow solid, MS (m/e): 415.2 (M+H, 100%)
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O.C(N(CC)CC)C.CCCP(=O)=O.[CH:33]([C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][CH:42]=1)[NH2:39])([CH3:35])[CH3:34]>CN(C1C=CN=CC=1)C.ClCCCl>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:39][C:38]1[CH:40]=[CH:41][CH:42]=[C:36]([CH:33]([CH3:35])[CH3:34])[CH:37]=1)=[O:16]
Reactant: O=C(O)c1cccc(N2CCc3ccncc3C2)c1
Reactant: CC(C)c1cccc(N)c1
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1cccc(NC(=O)c2cccc(N3CCc4ccncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 59.3 %

Procedure:
To a mixture of 3-(3,4-dihydro-2,7-naphthyridin-2(1H)-yl)benzoic acid (15.0 mg, 0.059 mmol), triethylamine (0.016 mL, 0.12 mmol) and catalytic DMAP in 1.0 mL 1,2-dichloroethane at rt was added propylphosphonic anhydride solution (50 wt % in EtOAc, 0.046 mL, 0.077 mmol). After 8 min at rt, 3-isopropylaniline (0.015 mL, 0.106 mmol) was added and the reaction stirred at rt for 18 hours. Then additional 3-isopropylaniline (0.015 mL) and propylphosphonic anhydride solution (0.030 mL) was added and the reaction continued for an additional 3 hours. The reaction was quenched into brine/dilute aqueous Na2CO3 solution, extracted with EtOAc, the EtOAc layer washed with H2O, brine/dilute aqueous Na2CO3 solution, dried with anhydrous Na2SO4 and rotary evaporated to an oil. The oil was chromatographed eluting with CHCl3/EtOAc to give the title compound as a light yellow solid (13 mg, 57%). 1H NMR (CDCl3) δ: 8.42 (s, 1H), 8.38 (d, J=5.0 Hz, 1H), 7.94 (s, 1H), 7.55-7.57 (m, 2H), 7.47 (ddd, J=8.1, 2.2, 1.2 Hz, 1H), 7.34-7.40 (m, 1H), 7.29 (t, J=7.8 Hz, 1H), 7.21-7.26 (m, 1H), 7.08-7.14 (m, 2H), 7.01-7.05 (m, 1H), 4.46 (s, 2H), 3.63 (t, J=5.9 Hz, 2H), 2.85-3.02 (m, 3H), 1.27 (d, J=7.0 Hz, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7](Cl)(=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH2:31])[CH2:26]2)=[O:24])=[CH:21][CH:20]=1.[Cl-].[Na+]>ClC1C=CC=CC=1>[Cl:18][C:19]1[CH:33]=[CH:32][C:22]([C:23]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:7]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:26]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: O=C(N[C@@H]1CCCN(C(=O)c2ccc(Cl)cc2)C1)OCc1ccccc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 40.7 %

Procedure:
Potassium carbonate (0.15 g) and benzyl chlorocarbonate (0.18 g) were added to the aqueous solution of (R)-1-(p-chlorobenzoyl)-3-aminopiperidine obtained in Example 14 (amount: 3 g). The mixture was stirred at 15° C. for 3 hours, and chlorobenzene (3 ml) and sodium chloride (0.5 g) were added. The mixture was stirred at 90° C. for 10 minutes. The water layer was removed, and the solvent was evaporated under reduced pressure to obtain the title compound as yellow oil (0.16 g, yield: 35%).
Reaction SMILES: CS(O)(=O)=O.[CH2:6]1[O:24][C:9]2([CH2:14][CH2:13][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:15]O)[CH2:11][CH2:10]2)[O:8][CH2:7]1.[C-:25]#[N:26].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH2:6]1[O:24][C:9]2([CH2:14][CH2:13][C:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)([CH2:15][C:25]#[N:26])[CH2:11][CH2:10]2)[O:8][CH2:7]1
Reactant: [C-]#N
Reactant: OCC1(Cc2ccccc2)CCC2(CC1)OCCO2
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CCC1(Cc2ccccc2)CCC2(CC1)OCCO2

Procedure:
A mixture of 18.6 g. (0.055 M) of 4-benzyl-4-hydroxymethylcyclohexan-1-one ethylene ketal methanesulfonate (2) (prepared as in Preparation 30) and 18 g. of potassium cyanide in 180 ml. of hexamethylphosphoramide is heated for about 17 hours in an oil bath at about 145° C. The resulting gel is allowed to cool, diluted to 800 ml. with water and extracted with benzene. The organic layer is washed with water and brine and evaporated to dryness. The residue is chromatographed on 1 l. of silica gel and eluted with 25% ethyl acetate in Skellysolve B and the fractions found similar by TLC pooled to give 4-benzyl-4-(cyanomethyl)cyclohexan-1-one ethylene ketal (3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].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.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:23]=[CH:22][CH:21]=[C:18]([C:19]#[N:20])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: N#Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C#N)c2)CC1

Procedure:
To a dry flask containing 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.0 g; 1.2 eq) and 3-bromobenzonitrile (3.79 g; 1.0 eq) in dry toluene (80 mL) was added BINAP (390 mg; 0.03 eq), palladium acetate (94 mg; 0.02 eq) and sodium tert-butoxide (2.8 g; 1.4 eq).