Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]3[CH2:43][CH2:42]3)=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:41]1([C:38]2[N:37]=[CH:36][C:35]([C:31]3[CH:30]=[C:29]([C:27]4[CH2:26][C:25](=[O:44])[NH:24][C:9]5[CH:10]=[C:11]([C:20]([F:22])([F:21])[F:23])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=5[N:7]=4)[CH:34]=[CH:33][CH:32]=3)=[CH:40][CH:39]=2)[CH2:42][CH2:43]1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccc(C4CC4)nc3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M148) (334 mg, 0.524 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (201 mg, 74%).
Reaction SMILES: [CH3:1][C:2](=[CH2:13])[CH2:3][N:4]1[C:11](=[O:12])[CH2:10][CH2:9][C@H:5]1[C:6]([OH:8])=O.ON1C2C=CC=CC=2N=N1.[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][NH2:33].Cl.CN(C)CCCN=C=NCC>ClCCl>[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[CH2:32][NH:33][C:6](=[O:8])[C@@H:5]1[CH2:9][CH2:10][C:11](=[O:12])[N:4]1[CH2:3][C:2]([CH3:1])=[CH2:13]
Reactant: NCc1ccc(F)cc1Cl
Reactant: C=C(C)CN1C(=O)CC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: C=C(C)CN1C(=O)CC[C@H]1C(=O)NCc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.5 %

Procedure:
Crude 1-(2-methyl-2-propen-1-yl)-5-oxoproline (˜0.075 g, ˜0.41 mmol, prepared as described below) was dissolved in dichloromethane (5 ml) and to this was added 1-Hydroxybenzotriazole (0.061 g, 0.45 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.068 g, 0.43 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.087 g, 0.45 mmol). The mixture was then stirred at room temperature for 24 hrs. The mixture was diluted with more dichloromethane then washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and evaporated to give a brown residue which was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-(2-methyl-2-propen-1-yl)-5-oxoprolinamide (0.018 g) as a white solid. LC/MS [M+H]+=325.1, retention time=2.40 minutes.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)=[CH:2]1.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)=[CH:2]1
Reactant: COc1ccc(C(NCCc2c[nH]c3ccccc23)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(NCCc2c[nH]c3ccccc23)c2cccc(N)c2)cc1
Yield: 22.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[2-(1H-indol-3-yl)ethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine (2.33 g) [prepared as described in step (a) above] in ethanol (50 ml), nickel chloride hexahydrate (2.76 g) and sodium borohydride (878 mg) were reacted, to afford the title compound (484 mg) as a pale yellow oil.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[CH2:13][CH2:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH2:1]([NH:4][S:15]([CH:14]=[CH2:13])(=[O:17])=[O:16])[CH:2]=[CH2:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: C=CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCNS(=O)(=O)C=C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled, 0° C., solution of allylamine (1.926 g, 33.7 mmol) and triethylamine (12.789 mL, 92.0 mmol) in anhydrous methylene chloride (50 mL) was slowly added a solution of 2-chloroethanesulfonyl chloride (5.000 g, 30.7 mmol) in methylene chloride (10 mL). The resulting mixture was allowed to warm to room temperature and stirred for 4 hrs. The mixture was successively extracted with 1 N aqueous hydrochloric acid (2×), water, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to give a yellow liquid. 1H NMR (300 MHz, CDCl3) δ 6.57-6.48 (dd, 1H, J=9.9, 16.8 Hz), 6.28-6.22 (d, 1H, J=16.8 Hz), 5.96-5.92 (d, 1H, J=9.6 Hz), 5.90-5.77 (m, 1H), 5.30-5.29 (m, 1H), 5.24-5.17 (m, 1H), 4.44 (br s, 1H), 3.69-3.64 (tt, 2H, J=1.5, 6.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:22][C@@H:21]([C:23]3[CH:34]=[CH:33][C:26]4[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=4[CH:24]=3)[O:20][C:19]2=[O:35])=[CH:12][CH:11]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]5[CH:3]=[C:2]([NH:1][C:39](=[O:41])[CH3:40])[CH:38]=[CH:37][CH:36]=5)=[CH:15][CH:14]=4)[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(COCCOc2ccc(CCN3C[C@@H](c4ccc5c(c4)COC(C)(C)O5)OC3=O)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of (5R)-3-[2-(4-{2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one {Example 1 xii)} (100 mg), acetic anhydride (21 μL) and N,N-diisopropylethylamine (67 μL) in DCM (2 mL) was stirred at room temperature under nitrogen for 20 h. The solution was then diluted in DCM, washed with 2M HCl, NaHCO3 and brine, dried (MgSO4) and concentrated in vacuo to give the title compound (136 mg). LCMS RT=3.24 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:12]O.N1C=CC=CC=1.P(Br)(Br)[Br:21]>ClCCl>[Br:21][CH2:12][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:3]=1[O:2][CH3:1]
Reactant: BrP(Br)Br
Reactant: COc1c(CO)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(CBr)cccc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
A solution of 14.7 g of (2-methoxy-3-nitro-phenyl)-methanol dissolved in 140 ml of dichloromethane and 5.5 ml of pyridine was cooled in an ice bath and slowly added 6.48 ml of phosphorus tribromide. After 45 minutes at 5° C., the reaction mixture was diluted with dichloromethane, washed with water, dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (5:95) giving 7.3 g of 1-bromomethyl-2-methoxy-3-nitrobenzene as a yellow solid. ##STR158##
Reaction SMILES: [CH2:1]([N:8]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([OH:31])=O.C(N)C1C=CC=CC=1>>[CH2:1]([NH:8][C:29]([C:28]1[S:27][C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:45])([F:46])[F:47])=[CH:40][CH:39]=3)[C:33]2=[O:48])=[N:25][C:24]=1[CH3:23])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 44 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with benzylamine, the title compound was obtained as a white powder in 44% yield: mp 127-128° C.; 1H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.1 Hz, 2H), 7.41-7.26 (m, 7H), 5.90 (t, J=5.7 Hz, 1H), 4.55 (d, J=5.7 Hz, 2H), 4.51 (s, 2H), 4.09 (t, J=8.1 Hz, 2H), 3.46 (t, J=8.1 Hz, 2H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 157.2, 155.4, 152.8, 139.6, 137.9, 130.2, 128.8, 128.5, 127.8, 127.6, 125.8, 122.1, 117.5, 47.6, 44.0, 42.1, 41.9, 17.0 MS (ES+) m/z 475.0 (M+1).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]1[CH2:26][O:25][CH:24]2[CH:9]([C@@H:10]([C@@H:22]([CH2:27][CH2:28][CH:29]([OH:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:8]1>[O-2].[O-2].[O-2].[Cr+6].C(Cl)Cl>[CH2:7]1[CH2:26][O:25][CH:24]2[CH:9]([C@@H:10]([C@@H:22]([CH2:27][CH2:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:23]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:8]1
Reactant: CCCCCC(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 8.7 g. of dry pyridine in 140 ml. of dry methylene chloride, stirred in a tap water bath is treated with 5.5 g. of dry chromium trioxide. The resulting deep red suspension is stirred at ambient temperature for 15 minutes. A solution of 3.78 g. of ethyl-9-ethylenedioxy-15-hydroxy-prostanoate (Example 55) in 15 ml. of methylene chloride is added, all at once, to the suspension. A black, tarry deposit is formed immediately. After stirring for 15 minutes at ambient temperature, the methylene chloride solution is decanted from the tarry deposit which is triturated with several portions of ether. The combined organic phases are washed with 5% aqueous sodium hydroxide, water, ice-cold 5% aqueous hydrochloric acid, saturated sodium bicarbonate solution, and saturated sodium chloride solution, dried with anhydros magnesium sulfate and taken to dryness to give 3.29 g. (88%) of a viscous oil; λ max 5.78 and 5.86 μ (carbonyl groups).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:29])[N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[C:30](Cl)(=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[C:13](=[O:29])[C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:30](=[O:39])[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.2 %

Procedure:
Triethylamine (0.5 g, 5.0 mmol) was added slowly to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and p-anisoyl chloride (0.5 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was stirred with 1N HCl (30 mL) for 1 hour then filtered. The solid was slurried with hot ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methoxy-benzamide (0.6 g, 71%) as a white solid: mp 193-195° C.; 1H NMR (DMSO-d6) δ 2.06-2.10 (m, 1H), 2.50-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.83 (s, 3H, OCH3), 4.93 (d, J=5.7 Hz, 2H, CH2), 5.14-5.21 (dd, J=5.4 and 12.7 Hz, 1H, CH), 7.04 (d, J=8.8 Hz, 2H, Ar), 7.69-7.86 (m, 3H, Ar), 7.89 (d, J=8.7 Hz, 2H, Ar), 9.01 (t, J=5.7 Hz, 1H, NH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.94, 38.25, 48.87, 55.36, 113.57, 121.80, 126.10, 127.06, 129.15, 131.51, 133.00, 134.77, 139.63, 161.75, 166.08, 166.99, 167.56, 169.85, 172.77; Anal. calcd. for C22H19N3O6+0.34H2O: C, 61.81; H, 4.64; N, 9.83. Found: C, 61.77; H, 4.54; N, 9.63.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][OH:6])[CH3:2].[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[O:22][CH3:23]>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:6][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[O:22][CH3:23])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCOC(CO)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(N)cc1OC)OCC
Reaction time: 18 h

Procedure:
To a solution of 2,2-diethoxyethanol (50 mmol, 6.71 g) was added 60% sodium hydride (50 mmol, 2.0 g) and the solution was stirred for 10 minutes at which point a solution of 2-chloro-5-nitroanisole (50 mmol, 9.38 g ) in DMF was added dropwise. The reaction mixture was stirred for 18 h. The DMF was removed by rotary evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated. The principal component was purified by silica gel column chromatography. The product was subjected to reduction over 18 h using 1 atm hydrogen and 10% Pd on carbon. After the reaction took up a theoretical amount of hydrogen the catalyst was removed by filtration.
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:21])[NH:9][CH:10]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[CH2:11]O)(C)(C)C>C1COCC1>[F:20][C:15]1[CH:14]=[C:13]([CH:10]2[CH2:11][O:21][C:8](=[O:7])[NH:9]2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(c2ccc(F)c(F)c2)CO1

Procedure:
To a well stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) at room temperature was added a solution of [1-(3,4-difluorophenyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (5.0 g, 18.3 mmol) in 20 mL THF via a dropping funnel at room temperature. The resulting suspension was stirred for 3 hours and then quenched carefully with 10 mL of water. The biphasic mixture was extracted with 100 mL of Et2O, washed with brine, filtered, and the solvent was removed in vacuo. The gummy residue thus obtained was purified by column chromatography over silica gel (Rf=0.15, 3:2 hexane-EtOAc) to obtain 4-(3,4-difluorophenyl)-oxazolidin-2-one as a white flaky solid (2.8 g, 77%). M.P. 81-83° C.; 1H NMR δ 4.13 (dd, J=6.6 Hz, J=8.7 Hz, 1 H), 4.73 (t, J=8.7 Hz, 1 H), 4.94 (dd, J=6.6 Hz, J=8.7 Hz, 1 H), 6.08 (br, s, 1 H), 7.03-7.23 (m, 3 H). The enantiomers were separated by using Chiralcel OD column (4.6×250 mm) using 80% hexane/20% isopropyl alcohol/0.1% diethylamine as the eluting system under isothermal conditions (U.V. 254 nM). The retention times for the two isomers were 16.19 min and 20.08 min respectively. First isomer: [α]D=+62.9 (c=0.67, acetone); Analysis calculated for C9H7NO2F2: C, 54.28; H, 3.54; N, 7.03. Found: C, 54.16; H, 3.44; N, 6.96. Second isomer: [α]D=−56.9 (c=0.75, acetone); Analysis calculated for C9H7NO2F2: C, 54.28; H, 3.54; N, 7.03. Found: C, 54.31; H, 3.46; N, 6.98. The first isomer was used in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[NH:29]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]1>>[CH3:28][N:2]([CH3:1])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:29]4[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31][CH2:30]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: OC1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCC(O)CC4)cn3)nc2n1C1CCCC1

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.2 g, 0.529 mmol) and piperidin-4-ol (56 mg, 0.556 mmol) gave 7-cyclopentyl-2-[5-(4-hydroxy-piperidin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide is obtained as a white solid (25 mg, 10%) [following purification by preparative LCMS and further purification by SiO2 chromatography, eluting with 0-7% (2N NH3 in MeOH/EtOAc). MS (ESI) m/z 464.3 (M+H)+ (method B).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]Br)[CH:5]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][N:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19]([CH:16]3[CH2:17][CH2:18][N:13]([CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:12])[CH2:14][CH2:15]3)=[CH:20]2)[CH:30]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: c1cncc(Cn2cc(C3CCNCC3)c3ccccc32)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc(CN2CCC(c3cn(Cc4cccnc4)c4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution containing 1.2 g (52 mmol) of 3-bromomethyl-benzoic acid methyl ester in 10 mL of anhydrous dichloromethane was added dropwise over a solution of 1.5 g (5 mmol) 3-piperidin-4-yl-1-pyridin-3-ylmethyl-1H-indole and 0.8 mL (55 mmol) of triethylamine in 35 of anhydrous dichloromethane. After stirring at room temperature for 5 hours, the crude mixture was washed with water, saturated solution of sodium hydrogencarbonate and water. The organic phase was dried and the solvent was removed under reduced pressure. The crude mixture was purified by flash chromatography over silica gel affording 0.95 g (43% of yield) of 3-[4-(1-pyridin-3-ylmethyl-1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid methyl ester. This ester was dissolved in 15 mL of methanol and hydrolised with NaOH 1N at room temperature for 12 hours. The crude mixture was neutralised with HCl 1N and then the solvent was removed under reduced pressure. The solid residue was washed with water and dichloromethane and the corresponding acid (0.6 g, 77% of yield) was isolated by filtration.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1ccc(C#Cc2ccccc2)cc1)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(C#Cc2ccccc2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(4-phenylethynyl-phenyl)-propionic acid to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:11]=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.[CH3:27][O:28][C:29]1[C:30](=O)[C:31](=[O:35])[C:32]=1[O:33]C>CO>[CH3:27][O:28][C:29]1[C:32](=[O:33])[C:31](=[O:35])[C:30]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:11]=1
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COc1ccc(C(NCCCc2ccccc2)c2cccc(N)c2)cc1
Solvent: CO
Product: COc1ccc(C(NCCCc2ccccc2)c2cccc(Nc3c(OC)c(=O)c3=O)c2)cc1

Procedure:
In a similar manner to that described in Example (1c), a solution of 3-[(4-methoxyphenyl)-(3-phenylpropylamino)methyl]phenylamine (2.02 g) [prepared as described in step (b) above] in methanol (40 ml) and 3,4-dimethoxy-3-cyclobutene-1,2-dione were reacted, to afford the title compound (1.82 g) as yellow foamy solid.
Reaction SMILES: [C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH:20]=[O:21])[CH:10]=2)[NH2:2]>CO.[Pd].[H][H]>[C:1](=[O:23])([O:3][CH2:4][CH:5]1[C:17]2([OH:19])[O:18][N:12]([CH2:13][CH:14]3[CH:16]2[NH:15]3)[C:11]2[C:6]1=[C:7]([OH:22])[CH:8]=[C:9]([CH2:20][OH:21])[CH:10]=2)[NH2:2]
Reactant: NC(=O)OCC1c2c(O)cc(C=O)cc2N2CC3NC3C1(O)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)OCC1c2c(O)cc(CO)cc2N2CC3NC3C1(O)O2
Yield: 74.5 %

Procedure:
A solution of 4-formyl-6,9-dihydroxy-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (140 mg) in methanol (10 ml) was subjected to catalytic reduction for 120 minutes using 10% palladium on carbon in hydrogen gas under atmospheric pressure at room temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo to give 6,9-dihydroxy-4-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-8-ylmethyl carbamate (105 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1)#[N:18].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:9]3)=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)#[N:18]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: COC(=O)CC1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)CC1CCc2ccc(OCc3ccc(C#N)cc3)cc2C1
Yield: 93 %

Procedure:
In 50 ml of 2-butanone, 1.2 g of methyl 7-hydroxy-1,2,3,4-tetrahydronaphthalene-2-acetate and 1.60 g of 4-cyanobenzyl bromide were dissolved, 1.51 g of potassium carbonate was added, and the mixture was refluxed by heating for 12 hours. Most of the solvent was distilled off under reduced pressure. The concentrated residue was mixed with water and extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography using a mixture, ethyl acetate:n-hexane=1:3, as a developer to yield 1.7 g of the entitled compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](Br)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].O.CCOC(C)=O.Cl.[CH3:32][N:33]1CCCC1=O>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:32]#[N:33])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1nc(Br)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a mixture of 1-bromo-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (2.0 g, 5.34 mmol) in 16.2 mL of N-methylpyrrolidone was heated in a 130° C. oil bath for 2 h. After cooled, the reaction mixture was poured into a mixture of 100 mL of water (containing 5% conc. NH4OH) and EtOAc (100 mL). It was vigorously stirred at room temperature for 30 min, then was acidified by conc. HCl solution until two phases became clear. Organic layer was washed with water, brine and dried over MgSO4. It was filtered and concentrated. Crude product was triturated with MeOH and white solid was collected to provide the title compound 1.20 g (3.75 mmol) in 70% yield. LC-MS ESI+: 321.31 (M+1)+.