Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[N:7]=[C:6]1[NH:20][C:21]1[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([C:16]([O:18][CH3:19])=[O:17])=[C:9]2[C:8]=1[N:7]=[C:6]1[N:20]([C:21]3[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=3[CH3:27])[CH2:2][CH2:3][CH2:4][N:5]21
Reactant: COC(=O)c1ccc(OC)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCCl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c2nc3n(c12)CCCN3c1c(C)nc(OC)nc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 89.2 %

Procedure:
A mixture of methyl 1-(3-chloropropyl)-4-methoxy-2-[(2-methoxy-4,6-dimethylpyrimidin-5-yl)amino]-1H-benzimidazole-7-carboxylate (878.9 mg, 2.03 mmol) and potassium carbonate (0.84 g, 6.08 mmol) in N,N-dimethylformamide (9.0 mL) was stirred at 70° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water (×3) and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The Precipitated pale yellow solid was collected by filtration, washed with diisopropyl ether to give the title compound (720.7 mg, 1.81 mmol, 89%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C@H:2]([OH:5])[CH2:3][CH3:4].CCN(CC)CC.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([O:5][C@@H:2]([CH3:1])[CH2:3][CH3:4])(=[O:16])=[O:15]
Reactant: CC[C@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)OS(C)(=O)=O
Temperature: 0 °C

Procedure:
An ice cold solution of (S)-2-butanol (888 mg) in DCM (15 ml) was treated with Et3N (1.26 ml) and followed by dropwise addition of methanesulfonyl chloride (0.52 ml). After 1 h the solution was washed with saturated sodium hydrogen carbonate solution (5 ml), water (2×5 ml), brine (5 ml), dried (MgSO4) and evaporated to give the title compound (D32)(1.01 g). 1H NMR δ (CDCl3): 4.74 (1H, m), 3.00 (3H, s), 1.67 (2H, m), 1.41 (1H, d, J=6.5 Hz), 0.99 (3H, t, J=7.5 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@H:6]([NH2:20])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].ClC([O:25][C:26]1C=CC=CC=1)=O.[N:32]1C=CC=CC=1.[OH-].[NH4+]>C1COCC1.CS(C)=O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C@H:6]([NH:20][C:26]([NH2:32])=[O:25])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(N)=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of (R)-3-amino-4-biphenyl-4-yl-butyric acid ethyl ester (200 mg, 0.625 mmol) in THF (10 ml) at 0° C. was added phenyl chloroformate (0.087 ml, 0.688 mmol) and pyridine (0.126 ml, 1.563 mmol). The mixture is stirred at 0° C. for 5 min then is warmed up to room temperature. LCMS monitored the reaction until it is complete. The reaction is extracted with EtOAc. The combined organic layer is washed with 1N HCl, H2O, sat. aq. NaHCO3 and brine and dried over anhydrous sodium sulfate, filtered and concentrated to give the crude residue. Next, to a solution of the obtained residue (0.252 g, 0.625 mmol) in DMSO (1.5 ml) at room temperature is added ammonium hydroxide (0.027 ml, 0.688 mmol). The reaction is stirred at room temperature. 30 min LCMS showed small desired product with big starting material so more ammonium hydroxide is added and the reaction is stirred at room temperature overnight until the reaction is complete. The reaction is extracted with EtOAc. The combined organic layer is washed with H2O, 1N HCl, H2O, 1 N NaOH and brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography (2% to 6% EtOH/DCM) to give (R)-4-biphenyl-4-yl-3-ureido-butyric acid ethyl ester (169 mg). HPLC retention time=1.04 minutes (condition B); MS (m+1)=327.
Reaction SMILES: C([O:3][C:4](=[O:38])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[C:18]([CH2:33][CH2:34][O:35][CH3:36])=[N:19][C:20]([C:23]3[CH:24]=[N:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[N:21][CH:22]=2)=[CH:11][C:10]=1[CH3:37])([CH3:7])[CH3:6])C.[Li+].[OH-]>C1COCC1.CO.CCOCC>[CH3:36][O:35][CH2:34][CH2:33][C:18]1[C:17]([CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:38])=[O:3])=[C:10]([CH3:37])[CH:11]=2)=[CH:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=2)[N:19]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)nc3)nc2CCOC)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1COc1ccc(OC(C)(C)C(=O)O)c(C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 52.2 %

Procedure:
A solution of 133 mg (0.25 mmol) 2-{4-[4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid ethyl ester (example 101A]) in 1.5 ml of THF/MeOH (1:1) was cooled (0° C.) treated with 0.75 ml 1N LiOH and stirred for 15 h at RT. The reaction mixture was taken up in ether and washed with aqueous 10% KHSO4 solution and aqueous 10% NaCl. The organic phase was dried (Na2SO4) and evaporated. The crude product was suspended in ether (RT to 4° C.) and filtered to give 66 mg of the title compound as a white powder of mp. 140.5–141.5° C., dec.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:8]([O:21][CH3:22])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:23]N(C=NC=[N+](C)C)C.[Cl-].C(O)(=O)C.C([O-])(=O)C.[Na+]>O1CCOCC1>[OH:5][C:4]1[C:3]2[C:2](=[CH:10][C:9]([O:11][CH2:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:8]([O:21][CH3:22])[CH:7]=2)[N:1]=[CH:23][N:6]=1
Reactant: CN(C)C=NC=[N+](C)C
Reactant: COc1cc(C(N)=O)c(N)cc1OCCCN1CCOCC1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 77.7 %

Procedure:
A mixture of 2-amino-5-methoxy-4-(3-morpholinopropoxy)benzamide (4.57 g, 12.25 mmol) and Gold's reagent (2.6 g, 15.89 mmol) in dioxane (35 ml) was heated at reflux for 5 hours. Acetic acid (0.55 ml) and sodium acetate (1.0 g) were added to the reaction mixture which was heated at reflux for a further 3 hours. The mixture was cooled to ambient temperature and the volatiles removed by evaporation. The residue was adjusted to pH7 with 2M sodium hydroxide and then purified on a Diaion (trade mark of Mitsubishi) HP20SS resin column, eluting with methanol (gradient of 0 to 60%) in water. Concentration of the fractions by evaporation gave a precipitate which was collected by filtration and dried under vacuum over phosphorus pentoxide to give 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (3.04 g, 78%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[O:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[CH2:16]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C.[CH3:54][N:55]1[C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=2[N:57]=[C:56]1[CH:64]=O.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]2([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[O:20][C:19](=[O:21])[C:18]([CH2:64][C:56]3[N:55]([CH3:54])[C:59]4[CH:60]=[CH:61][CH:62]=[CH:63][C:58]=4[N:57]=3)=[C:17]([OH:22])[CH2:16]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1
Reactant: Cn1c(C=O)nc2ccccc21
Reactant: O=C1CC(=O)OC(CCc2ccc(OCC3CC3)c(Cl)c2)(C2CCCC2)C1
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cn1c(CC2=C(O)CC(CCc3ccc(OCC4CC4)c(Cl)c3)(C3CCCC3)OC2=O)nc2ccccc21

Procedure:
The title compound was prepared analogously to Example B(31), carbaldehyde where 6-[2-(3-Chloro-4-cyclopropylmethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione was substituted in place of 6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 1-methyl-2-formylbenzimidazole was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([CH:31]([CH3:33])[CH3:32])=[N:12]1)[C:6]#[N:7])=[O:2].C(C1C=C(C=CC=1N1C2=NC=CC(I)=C2C(C(C)C)=N1)C#N)=[O:35].Cl.CN1C=C(C2N=CNC=2)C=N1>>[CH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][C:19]([N:20]3[CH:24]=[C:23]([C:25]4[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=4)[N:22]=[CH:21]3)=[C:14]2[C:13]([CH:31]([CH3:33])[CH3:32])=[N:12]1)[C:6]([NH2:7])=[O:35])=[O:2]
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Reactant: CC(C)c1nn(-c2ccc(C#N)cc2C=O)c2nccc(I)c12
Agent: Cl
Agent: Cn1cc(-c2c[nH]cn2)cn1
Product: CC(C)c1nn(-c2ccc(C(N)=O)cc2C=O)c2nccc(-n3cnc(-c4cnn(C)c4)c3)c12
Yield: 17 %

Procedure:
According to Example 97(2), 3-formyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was prepared using compound (125a) instead of compound (97a) and using 4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazole hydrochloride instead of 4-phenyl-1H-imidazole and was used in the subsequent reaction without being purified. According to Example 1(7), compound (125) (the second stage yield: 17%) was prepared as a white solid using 3-formyl-4-{3-isopropyl-4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[O:11][CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].[C:16](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:16])[C:12](=[O:14])[O:11][CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2CCO1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN1C(=O)OCCc2cc([N+](=O)[O-])ccc21

Procedure:
A mixture of 2-nitro-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (0.7 g, 3.36 mmol), potassium carbonate (1.4 g, 10.1 mmol, 3 eq.), and iodomethane (0.42 mL, 6.7 mmol, 2 eq.) was stirred for 16 hours in DMF (10 mL). The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried (sodium sulfate) and concentrated to provide 2-nitro-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one: 1H NMR (300 MHz, CDCl3) δ 8.19 (dd, 1H), 8.13 (d, 1H), 7.28 (d, 1H), 4.55 (t, 2H), 3.43 (s, 3H), 3.10 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:9])[C:7]=1[CH3:8].C[C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][NH:16][C:17]2=[O:20])=[CH:13][CH:12]=1.[C:21](=O)([O-])[O-].[K+].[K+].CNCCNC>O1CCOCC1.[Cu]I>[Br:9][C:6]1[C:7]([CH3:8])=[C:2]([N:16]2[CH2:15][C:14]3[C:18](=[CH:19][CH:11]=[C:12]([CH3:21])[CH:13]=3)[C:17]2=[O:20])[CH:3]=[N:4][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2c(c1)C(=O)NC2
Reactant: Cc1c(Br)cncc1Br
Agent: [Cu]I
Agent: CNCCNC
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)CN(c1cncc(Br)c1C)C2=O
Temperature: 100 °C
Yield: 30.1 %

Procedure:
Step 2 A mixture of 3,5-dibromo-4-methylpyridine (2.00 g, 7.97 mmol), 6-methylisoindolin-1-one (1.173 g, 7.97 mmol), copper (I) iodide (0.076 g, 0.399 mmol), potassium carbonate (2.203 g, 15.94 mmol) and N1,N2-dimethylethane-1,2-diamine (0.070 g, 0.797 mmol) in 1,4-dioxane (20 mL) was heated at 100° C. for 15 h. The mixture was cooled to rt, filtered through Celite and washed with DCM. The filtrate was diluted with DCM (100 mL) and washed with water (10 mL) and brine (10 mL), then was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to give 2-(5-bromo-4-methylpyridin-3-yl)-5-methylisoindolin-1-one (760 mg, 30%). 1H NMR (400 MHz, chloroform-d) δ 8.68 (1 H, s), 8.42 (1 H, s), 7.84 (1 H, d, J=7.77 Hz), 7.37 (1 H, d, J=7.77 Hz), 7.34 (1 H, s), 4.73 (2 H, s), 2.50 (3 H, s), 2.35 (3 H, s). Mass spectrum m/z 317, 319 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4]Br)[CH3:2].[CH:10]1[C:11]([I:19])=[CH:12][C:13]([I:18])=[C:14]([OH:17])[C:15]=1[I:16].C(=O)([O-])[O-].[K+].[K+].IC1C=C(I)C=C(I)C=1OC(CC)C>CN(C=O)C>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:17][C:14]1[C:15]([I:16])=[CH:10][C:11]([I:19])=[CH:12][C:13]=1[I:18])[CH3:2]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCCCC(CC)CBr
Agent: CCC(C)Oc1c(I)cc(I)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1c(I)cc(I)cc1I
Reaction time: 20 h
Yield: 73.7 %

Procedure:
2-Ethyl-bromohexane (10.4 g, 53.0 mmol), triiodophenol (25.5 g, 54.0 mmol) and potassium carbonate (7.5 g, 54.3 mmol) were reacted in dry DMF (110 ml) at 77° C. as for 2-(2,4,6-triiodophenoxy)butane. After stirring for 20 hrs, the reaction was cooled, diluted with DMF, filtered through a pad of celite and evaporated in vacuo. The resulting residue was taken up in EtOAc (500 ml), washed with water (200 ml), 1N aqueous sodium hydroxide (200 ml), water (2×200 ml) and brine (200 ml), dried (Na2SO4), filtered and evaporated. Flash column chromatography (silica, hexanes) provided 2-ethyl-1-(2,4,6-triiodophenoxy)-hexane (22.8 g, 73.7%) as a clear viscous oil. Title Compound: 1H (300 MHz) and 13C (75 MHz) NMR spectra were consistent with the desired structure. Calculated for C14H19I3O: C, 28.79; H, 3.28; I, 65.19. Found: C, 29.13, H, 3.24; I, 65.05.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[NH2:19])=[O:5])[CH3:2].Cl.[CH3:21][C:22]1[CH:31]=[C:30]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH:7]1[NH:19][S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[C:22]([CH3:21])[CH:31]=2)=[CH:35][CH:36]=1)(=[O:41])=[O:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1N
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Temperature: 25 °C
Yield: 25.8 %

Procedure:
To a mixture of 2.89 g (10.62 mmol) of 3-amino-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester [WO 01/70673, Example 134] and 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride (4.0 g, 11.8 mmol) in CH2Cl2 (40 mL) at 0° C. was added saturated aqueous NaHCO3 (40 mL). The solution was allowed to warm to 25° C. over 19 h. The reaction was then diluted with CH2Cl2 (100 mL) and water (30 mL), the organic layer was washed with water (2×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by Biotage Flash 40M chromatography, eluting with 1:2 ethyl acetate-hexanes, to afford 3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester as a white solid (1.6 g, 25.8%). MS: 584 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([C:9]([CH2:13][CH3:14])([CH3:12])[CH2:10][CH3:11])C(OC)=O.[Li+].[Cl-].O>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:9]([CH2:13][CH3:14])([CH3:12])[CH2:10][CH3:11]
Reactant: CCC(C)(CC)C(C(=O)OC)C(=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCC(C)(CC)CC(=O)OC
Temperature: 170 °C
Yield: 67.7 %

Procedure:
Step B To a solution of 2-(1-ethyl-1-methyl-propyl)-malonic acid dimethyl ester (3 g, 14 mmol) in DMSO (30 mL) was added LiCl (1.2 g, 28 mmol) and H2O (0.25 mL, 14 mmol). The reaction mixture was heated at 170° C. for 3 h, then poured into a ice-water, extracted with ethyl acetate. The organic layer were separated, washed with water, brine, dried over MgSO4, and concentrated to give 3-ethyl-3-methyl-pentanoic acid methyl ester as a yellow oil (1.5 g, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20](O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@H:20]([O:10][C:8]2[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=Cc1ccc(O)cc1O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(C=O)c(O)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
In 40 ml of tetrahydrofuran were dissolved 1.38 g of 2,4-dihydroxybenzaldehyde, 1.87 g of (3R)-1-tert-butoxycarbonyl-3-hydroxypyrrolidine and 2.88 g of triphenylphosphone. The thus prepared solution was mixed with 1.91 g of diethyl azodicarboxylate and stirred at room temperature for 1 hour. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography, thereby obtaining 1.2 g of 4-[((3S)-1-tert-butoxycarbonyl-3-pyrrolidinyl)oxy]-2-hydroxybenzaldehyde in a viscous and oily form.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23](Cl)(Cl)=[O:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>ClCCl>[CH:41]1([NH:44][C:23]([N:20]2[CH2:19][CH2:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:12][CH:13]=3)[CH2:22][CH2:21]2)=[O:24])[CH2:43][CH2:42]1
Reactant: c1cc(N2CCNCC2)ccc1OCCCN1CCCCC1
Reactant: O=C(Cl)Cl
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(NC1CC1)N1CCN(c2ccc(OCCCN3CCCCC3)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-piperazine (D11) (150 mg, 0.49 mM) in dry dichloromethane (3 ml) was added drop wise a 20% solution of phosgene in toluene (0.5 ml; −2 eq) and the resulting mixture stirred for 1 hour. The solvent was removed by evaporation and the resulting white powder dissolved in dry dichloromethane (4 ml). Triethylamine (0.14 ml: 2 eq) was added followed by cyclopropylamine (0.1 ml; 3 eq) and the mixture stirred for 18 hours. The solvent was removed by evaporation in vacuo and the residue purified on a silica column eluting with 3% methanol in dichloromethane to afford the title compound as a white solid (155 mg) MS (ES+) m/e 387 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]1[N:18]=[C:17](I)[C:16]([Cl:20])=[C:15]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH3:26][N:27]1[C:35]2[C:30](=[CH:31][C:32](B(O)O)=[CH:33][CH:34]=2)[CH:29]=[CH:28]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]1[N:18]=[C:17]([C:32]2[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=2)[N:27]([CH3:26])[CH:28]=[CH:29]3)[C:16]([Cl:20])=[C:15]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CC(C)(C)OC(=O)c1c(OC(C)(C)C)nc(I)c(Cl)c1OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc2cc(-c3nc(OC(C)(C)C)c(C(=O)OC(C)(C)C)c(OC(C)(C)C)c3Cl)ccc21
Temperature: 80 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
A mixture of tert-butyl 2,4-di-tert-butoxy-5-chloro-6-iodonicotinate (103 mg, 0.2 mmol), 1-methyl-1H-indol-5-ylboronic acid (53 mg, 0.3 mmol), PdCl2dppf (16 mg, 0.02 mmol), aqueous K2CO3 (2.0 M×0.4 mL, 0.8 mmol) in acetonitrile (1.0 mL) was stirred at 80° C. for 3 h and then extracted with ethyl acetate. The organic layers were combined and dried over sodium sulfate, evaporated and purified by silica chromatography (0-5% ethyl acetate in hexanes) to give tert-butyl 2,4-di-tert-butoxy-5-chloro-6-(1-methyl-1H-indol-5-yl)nicotinate (103 mg, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][O:7][CH2:8][CH:9]([OH:20])[CH2:10][CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].[CH:21](=O)[CH2:22][CH3:23]>C1(C)C=CC=CC=1>[CH2:22]([CH:23]1[N:4]([CH2:5][CH2:6][O:7][CH2:8][CH:9]([OH:20])[CH2:10][CH2:11][CH2:12][CH:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:3][CH2:2][O:1]1)[CH3:21]
Reactant: CCC=O
Reactant: CCCC(CCC)CCCC(O)COCCNCCO
Solvent: Cc1ccccc1
Product: CCCC(CCC)CCCC(O)COCCN1CCOC1CC
Temperature: 25 °C
Yield: 100 %

Procedure:
To a 10 mL flask containing 1-[2-(2-hydroxy-ethylamino)-ethoxy]-6-propyl-nonan-2-ol (510 mg, 1,76 mmol, 1 eq.) in toluene (3 mL) was added dropwise at room temperature propionaldehyde (0,14 mL 1,85 mmol, 1,05 eq., d=0,798) before heating to reflux with a Dean-Stark trap for 2h. The reaction was cooled to room temperature and concentrated to afford the title compound as 2 stereoisomers (50:50) (580 mg, 100% yield). 1H NMR (CDCl3, 400 MHz) d?(ppm): 4,09-4,03 (m, H); 3,92-3,81 (m, 2H); 3,81-3,73 (m, H); 3,73-3,50 (m, 2H+2H); 3,35-3,21 (m, 2H); 2,92-2,74 (m, 2H); 2,72-2,63 (m, H); 2,62-2,52 (m, H); 1,69-1,14 (m, 15H+2H); 0,96 (m, 3H); 0,87 (t, J=7,0 Hz, 6H). 13C NMR (CDCl3, 129,9 MHz) d?(ppm): 98,0; 97,9; 78,1; 75,7; 70,6 (2C); 70,2 (2C); 64,2 (2C); 53,2; 53,1; 52,6 (2C); 36,9 (2C); 36,0 (2C+2C); 33,7 (2C); 33,6; 33,5; 26,9; 26,8; 22,7 (2C); 19,8 (2C+2C); 14,5 (2C+2C); 9,2 (2C).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19](Br)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27](B(O)O)[CH:26]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([C:27]5[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=5)[CH:20]=4)[CH:15]=3)=[O:13])[CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc2cc(-c3cccnc3)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1 (a). 6-Bromo-naphthalene-2-carboxylic acid quinolin-7-ylamide, Example 32(b), (67 mg, 0.18 mmol) reacted with 3-pyridine boronic acid (24 mg, 0.2 mmol, Fluorochem) to give the title compound as a brown amorphous solid. MS (ESI, pos. ion) m/z: 376 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([O:9][C:5]1[CH:6]=[C:7]([F:8])[C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(F)c(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(OCc2ccccc2)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-bromo-2,5-difluoro-phenol (41, 0.90 g, 0.0043 mol, prepared as described in Example 15, Scheme 3) in N,N-dimethylformamide (30.0 mL) were added sodium hydride (0.21 g, 60% in mineral oil, 0.0052 mol) and benzyl bromide (0.563 mL, 0.00474 mol). The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% ethyl acetate in hexane to give a white solid (47, 0.84 g, 65.0%).