Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH:7]2[CH:8]3[CH2:22][CH2:21][CH:20]=[CH:19][C:9]3=[C:10]3[C:18]([CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]3=4)=[C:6]2[C:5](C)([CH3:23])[C:4]([CH3:26])([CH3:25])[C:3]1([CH3:28])[CH3:27].[CH2:30]([Li])CCC.CN1CCN(C)C1=O.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[C:51]2[CH:55]=[CH:54][CH:53]=[CH:52]2)=[CH:46][CH:45]=1>O1CCCC1.CCCCCC>[Cl:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]([C:56]2[CH:57]=[CH:58][C:59]([Cl:62])=[CH:60][CH:61]=2)([CH:51]2[CH:52]=[CH:53][CH:54]=[CH:55]2)[C:7]2([CH3:30])[C:6]3[C:5]([CH3:23])([CH:12]4[CH2:13][CH2:14][CH:15]=[CH:16][C:11]4=[C:10]4[C:18]=3[CH2:17][C:19]3[CH:20]=[CH:21][CH:22]=[CH:8][C:9]4=3)[C:4]([CH3:26])([CH3:25])[C:3]([CH3:28])([CH3:27])[C:2]2([CH3:1])[CH3:29])=[CH:48][CH:49]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc(C(=C2C=CC=C2)c2ccc(Cl)cc2)cc1
Reactant: CC1(C)C2=C3Cc4ccccc4C3=C3C=CCCC3C2C(C)(C)C(C)(C)C1(C)C
Solvent: CN1CCN(C)C1=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC12C(=C3Cc4ccccc4C3=C3C=CCCC31)C(C)(C(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)C1C=CC=C1)C(C)(C)C(C)(C)C2(C)C
Temperature: 0 °C

Procedure:
A reaction vessel equipped with a dropping funnel was charged with 40 ml of dehydrated tetrahydrofuran and 2.35 g (6.08 mmol) of octamethyloctahydrodibenzofluorene synthesized in Synthesis Example 2-1 under a nitrogen atmosphere. Then, 4.62 ml (7.30 mmol) of a 1.58 mol/L hexane solution of n-butyllithium was slowly added dropwise and while cooling this solution to 0° C., and the mixture was stirred. Then, 0.86 ml (7.90 mmol) of 1,3-dimethyl-2-imidazolidinone was added to the solution and the mixture was stirred for 30 minutes. Subsequently, the dropping funnel was charged with a solution prepared by dissolving 2.00 g (6.68 mmol) of 6,6-di{p-chlorophenyl}fulvene in 30 ml of dehydrated tetrahydrofuran. The solution was slowly added dropwise while cooling the solution to −78° C. The mixture was stirred for one day while returning the temperature thereof slowly to room temperature. This reaction solution was subjected to extraction with diethyl ether. The organic layer was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated brine. The organic phase collected by separation was dried over anhydrous magnesium sulfate and magnesium sulfate was separated by filtration. The filtrate was subjected to distillation under reduced pressure using a rotary evaporator to remove the solvent. The residue was purified by using a silica gel column and recrystallized from toluene to obtain a target product (yield 0.714 g (17%)). The target product was identified by 1H-NMR and FD-MS spectroscopy.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28]Br)[CH:22]=3)[O:20][C@@:6]1([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:7][O:8]2)(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:43]2[CH:58]=[CH:57][C:46]([O:47][C:48]3[CH:53]=[CH:52][C:51]([C:54](=[O:56])[CH3:55])=[CH:50][CH:49]=3)=[CH:45][CH:44]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>[Pd].O>[C:1]([O:4][C@H:5]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@:9]2([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:43]4[CH:44]=[CH:45][C:46]([O:47][C:48]5[CH:53]=[CH:52][C:51]([C:54](=[O:56])[CH3:55])=[CH:50][CH:49]=5)=[CH:57][CH:58]=4)[CH:22]=3)[O:20][C@@:6]1([CH2:30][O:31][C:32](=[O:34])[CH3:33])[CH2:7][O:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(Oc5ccc(C(C)=O)cc5)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 80 °C
Yield: 36.6 %

Procedure:
To a mixture of (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (1.0 g, 1.77 mmol, Intermediate 2), 1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)phenyl)ethanone (899.0 mg, 2.66 mmol), Pd (dppf) Cl2 (72 mg, 0.09 mmol) and sodium carbonate (563.0 mg, 5.31 mmol) under nitrogen atmosphere, was added DMF and H2O (9 mL, 1:1). The reaction mixture was heated at 80° C. for 1 h. After the completion of the reaction, as confirmed by TLC, the solution was cooled to r.t. and filtered through celite. The solvent was evaporated in vacuo and the crude compound was diluted with ethyl acetate (200 mL). The organic layer was washed with water (3×30 mL), separated, dried over Na2SO4 and concentrated in vacuo to afford crude compound which was purified by column chromatography (silica gel, 1:4 EtOAc:Pet ether) to afford the title compound (450 mg, 36.6%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7](Cl)=[O:8].[CH2:13]([NH2:15])[CH3:14]>C1C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)/[CH:5]=[CH:6]/[C:7]([NH:15][CH2:13][CH3:14])=[O:8]
Reactant: O=C(Cl)/C=C/c1cccc(Cl)c1
Reactant: CCN
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCNC(=O)/C=C/c1cccc(Cl)c1

Procedure:
Trans 3-chlorocinnamoyl chloride (4.4 g) in dry benzene (75 ml) was allowed to react with an excess of ethylamine in dry ether (75 ml) according to the procedure of Example 2. Trans 3-chloro-N-ethylcinnamamide, m.p. 87°-88° C, was obtained which had NMR, IR, and elemental analysis consistent with this structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([O:8][CH3:10])=[CH:6][CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)nc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(Cl)nc1Cl
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 2,6-dichloropyridin-3-ol (16.3 g, 0.1 mol) and K2CO3 (41.4 g, 0.3 mol) in DMF (200 mL) were added MeI (21.3 g, 0.15 mol). The mixture was allowed to stir at 80° C. for 2 hours. The mixture was then diluted with water (200 mL) and extracted with EtOAc (200 mL×3). The organic layer was washed with brine (200 mL×3), dried over Na2SO4, filtered and the solvent was concentrated in vacuo to provide 2,6-dichloro-3-methoxypyridine (17.0 g, yield: 96.0%). 1H-NMR (CDCl3, 400 MHz) δ 7.12˜7.18 (m, 2H), 3.86 (s, 3H). MS (M+H)+: 178/180/182.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.CO[CH:9]([O:28][CH3:29])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:13][CH:12]=1.B(F)(F)F.CCOCC>ClCCl>[CH3:29][O:28][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][CH:16]=1)[C:5]#[N:6]
Reactant: C[Si](C)(C)C#N
Reactant: COC(Cc1ccc(OCCN(C)c2ccccn2)cc1)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(C#N)Cc1ccc(OCCN(C)c2ccccn2)cc1
Reaction time: 1.5 h

Procedure:
Trimethylsilyl cyanide (3.4 mL) was added dropwise to a solution of 1,1-dimethoxy-2-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]ethane (2.64 g) in dichloromethane (70 mL) at room temperature. The mixture was stirred during the addition of boron trifluoride etherate (0.3 mL), and stirring continued at room temperature for 1.5 hrs. prior to the addition of a further portion of boron trifluoride etherate (1 mL). After a further 2 hours the mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2×300 mL), water (2×300 mL) and brine (300 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound, a gum, which was used without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11](=[O:17])[C:10]([C:18]1[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[CH:25]=3)[N:22]=1)=[CH:9]2.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[ClH:1].[ClH:1].[ClH:1].[CH3:16][N:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)=[CH:15][CH:14]=2)[CH:9]=[C:10]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]4[CH:41]=[CH:40][C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=4)[CH:25]=3)[N:22]=2)[C:11]1=[O:17]
Reactant: CN1CCNCC1
Reactant: Cn1c(=O)c(-c2nnn(Cc3cccc(OCc4ccc5ccccc5n4)c3)n2)cc2cc(OCCCCl)ccc21
Product: CN1CCN(CCCOc2ccc3c(c2)cc(-c2nnn(Cc4cccc(OCc5ccc6ccccc6n5)c4)n2)c(=O)n3C)CC1
Product: Cl
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 269.7 %

Procedure:
A mixture of crude 6-[3-chloropropyl]oxy-1-methyl-3-{2-[3-(2-quinolylmethoxy)benzyl]tetrazolyl}quinolin-2-one (180 mg, 0.317 mmol) and N-methylpiperazine (127 mg, 1.27 mmol) was stirred under an argon flow at a bath temperature of 120° C. for 90 minutes. The reaction mixture was concentrated under reduced pressure, and purified through silica gel chromatography (developer: chloroform-methanol (20:1)). Fractions containing the target compound were collected, and concentrated under reduced pressure, to thereby obtain the free base of the title compound (180 mg, 0.285 mmol) as yellow oily matter. The thus-obtained free base was dissolved in methanol (2 ml), and a solution of hydrochloric acid (4N) in ethyl acetate (285 μl, 1.14 mmol) was added thereto. The mixture was crystallized from a methanol-diethylether mixture, to thereby obtain the trihydrochloride; i.e., the title compound, as yellow needles (143 mg, 0.203 mmol, 64.1%).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:22])[CH2:17][O:18][CH2:19][CH:20]=[CH2:21])[CH3:14].[CH:23]([CH:25]=[CH2:26])=[O:24]>C1COCC1>[CH2:13]([O:15][C:16](=[O:22])[CH:17]([O:18][CH2:19][CH:20]=[CH2:21])[CH:23]([OH:24])[CH:25]=[CH2:26])[CH3:14]
Reactant: C=CC=O
Reactant: C=CCOCC(=O)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=CCOC(C(=O)OCC)C(O)C=C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under an atmosphere of argon, n-BuLi (3 mmol, 1.2 ml, 2.5 M in hexane) was added dropwise to a solution of diisopropylamine (281 mg, 2.78 mmol) in dry THF (20 ml) at −78° C. After stirring for 20-30 min, a solution of allyloxy-acetic acid ethyl ester (200 mg, 1.38 mmol) in THF (4 ml) was added and the mixture was stirred at −78° C. for 10 min. Acrolein (79 mg, 1.38 mmol) was added into the reaction mixture and stirring was maintained until all starting materials were consumed. The reaction was quenched by addition of EtOH (2 ml) and warmed to room temperature. The solution was diluted with EtOAc (60 ml), washed with H2O (20 ml×2), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17][C:18]3[NH:22][C:21]4[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=4[N:19]=3)[C:11]=2[CH3:27])[O:4][CH2:3]1.ClC1C=CC=C(C(OO)=[O:37])C=1.C(=O)([O-])O.[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:28])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:17]([C:18]3[NH:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)=[O:37])[C:11]=2[CH3:27])[O:4][CH2:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
The 2-(((4-((5,5-dimethyl-1,3-dioxan-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (599 mg, 1.5 mmol) obtained by the step (1e) was mixed with methanol (5 ml) and toluene (15 ml), and the mixture was cooled to −50° C. 3-chloroperbenzoic acid (358 mg, 1.35 mmol, as the content was regarded as 65%) dissolved in a solvent mixture of methanol and toluene was slowly added dropwise to the mixture, and stirred at −47° C. to −70° C. for 3 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over potassium carbonate, and the solvent was distilled off. The residue was purified with silica gel column chromatography (NH silica gel: 40 g, elution solvent: dichloromethane/heptane=7/3→methanol/dichloromethan=3/97 to 1/9). To the obtained product, heptane (20 ml) and diethyl ether (2 ml) were added, the precipitate was obtained by filtration. In this manner, the title compound (475 mg, yield: 76.2%) was obtained as a light orange solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:23][CH3:24])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][N:11]2[C:14]([O:16]C2C=CC=CC=2)=O)=[CH:6][CH:5]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([C:34]#[N:35])[CH:27]=1>>[C:34]([C:28]1[C:29]([C:32]#[N:33])=[CH:30][N:31]=[C:26]([NH:25][C:14]([N:11]2[C:12]3[C:7](=[CH:6][CH:5]=[C:4]([CH:3]([O:2][CH3:1])[O:23][CH3:24])[N:13]=3)[CH2:8][CH2:9][CH2:10]2)=[O:16])[CH:27]=1)#[N:35]
Reactant: COC(OC)c1ccc2c(n1)N(C(=O)Oc1ccccc1)CCC2
Reactant: N#Cc1cnc(N)cc1C#N
Product: COC(OC)c1ccc2c(n1)N(C(=O)Nc1cc(C#N)c(C#N)cn1)CCC2

Procedure:
From intermediate 3 and 6-aminopyridine-3,4-dicarbonitrile, reacted in an analogous manner to the preparation of intermediate 2. (UPLC-MS 1) tR 1.15 min, ESI-MS 379.1 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([OH:14])=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:22][CH2:21][C:18]3[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=3)=[C:10]([Br:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: OCCc1ccncc1
Reactant: CC(=O)N1CCc2cc(O)c(Br)cc21
Product: CC(=O)N1CCc2cc(OCCc3ccncc3)c(Br)cc21
Yield: 84 %

Procedure:
This was prepared from 1-acetyl-6-bromo-2,3-dihydro-1H-indol-5-ol (Tetrahedron 1973, 29(8), 1115) and 2-(4-pyridyl)ethanol (D65), following the procedure of Description 8a. This gave the title compound (84%), as a yellow solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)N>>[N:31]1[CH:32]=[CH:33][C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:30]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccncc1
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccncc1
Yield: 16 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazinopyridine according to the method described for Example 1 in 16% yield. MS: M=400.2 (M+H)+
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[H][H]>FC(F)(F)C(O)=O.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Yield: 56 %

Procedure:
A solution of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoyl)-L-glutamate in 30 mL of trifluoroacetic acid was hydrogenated at 55 psi of hydrogen in the presence of 1.0 g of 5% Pd/C at room temperature for 14 hours. The catalyst was removed by filtration, the filtrate evaporated under reduced pressure, and the residual solid partitioned between 100 mL of chloroform and 50 ml of 2N aqueous sodium carbonate. The organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent removed by evaporation to give a gum which was chromatographed on silica gel. Elution with chloroform:methanol (97:3) gave 0.25 g (56%) of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate; mp 215°-217° C.; NMR (CDCl3) delta 1.25, 1.35 (2t, 6H, J=6 Hz), 2.1-2.5 (m, 4H), 2.55 (s, 3H), 3.1 (s, 4H), 4.15, 4.25 (2q, 4H, J=6 Hz), 4.6-4.96 (m, 1H), 7.05 (s, 1H), 7.25, 7.75 (AB q, 4H, J= 9 Hz), 8.35 (d, 1H, J=3 Hz), 8.77 (d, 1H, J=3 Hz); IR (Nujol) 3200, 3150, 1725, 1675, 1630, 1605 cm-1. Anal.: Calc'd. for C27H31N5O7 : C, 60.32; H, 5.81; N, 13.03. Found: C, 59.98; H, 6.03; N, 12.92).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:18]=[C:2]([C:30]4[N:26]([C:23]5[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=5)[N:27]=[CH:28][CH:29]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[C:11]([F:17])[CH:12]=1
Reactant: OB(O)c1ccnn1-c1ccc(Cl)cc1
Reactant: Fc1cc(Cl)ccc1-n1cnc2ccc(Br)cc21
Product: Fc1cc(Cl)ccc1-n1cnc2ccc(-c3ccnn3-c3ccc(Cl)cc3)cc21

Procedure:
The title compound, white solid (23 mg, 18%), MS (ISP) m/z=423.4 [(M+H)+], mp 158° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-2-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate M) (100 mg, 307 μmol) and 1-(4-chloro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate D) (82.1 mg, 369 μmol).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH:11](O)[CH:12]([OH:14])[CH3:13])[N:3]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O:27]C(C)C)(C)C>CCO>[CH2:16]([NH:23][C:5]1[N:4]([CH2:11][CH:12]([OH:14])[CH2:13][OH:27])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(O)C(O)n1nc(Br)c([N+](=O)[O-])c1Br
Reactant: CC(C)OC(C)C
Reactant: NCc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1c(Br)nn(CC(O)CO)c1NCc1ccccc1
Yield: 42 %

Procedure:
A mixture of 1-(3,5-dibromo-4-nitropyrazol-1-yl)-propane-1,2-diol (3-4) (31 g, 898 mmol), EtOH (420 ml) and benzylamine (138 g, 1.26 mol) was refluxed for 1.5 hours. The reaction medium was concentrated to the maximum under reduced pressure. 100 ml of DCM were added to the residue. The organic phase was washed with dilute acid (5×50 ml). The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The brown oil obtained was treated with diisopropyl ether at 0° C. to give the 3-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propane-1,2-diol (14.1 g, 42%) in the form of a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.[Mg+].[C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:23])[CH2:19]C([O-])=O>O1CCCC1>[O:14]=[C:12]([C:11]1[CH:10]=[CH:9][C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:16][CH:15]=1)[CH2:19][C:18]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C(O)c1ccc(Oc2ccccn2)cc1
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Agent: [Mg+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccc(Oc2ccccn2)cc1)OCc1ccccc1
Temperature: 25 °C

Procedure:
To 4-(pyridin-2-yloxy)benzoic acid (20 g, 92.9 mmol) in tetrahydrofuran (300 ml) was added N,N′-carbonyldiimidazole (16.6 g, 102 mmol), and the mixture was heated under reflux for 1 hr. After cooling the reaction solution to room temperature, monobenzyl malonate magnesium salt (21 g, 51.2 mmol) was added, and the mixture was heated under reflux for 2 hrs. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the objective substance (20.6 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1.Cl[C:19]1[CH:20]=[C:21]2[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]2[C:23](=[O:25])[N:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:19]3[CH:20]=[C:21]4[N:28]([CH3:29])[C:27]([CH3:31])([CH3:30])[CH2:26][N:22]4[C:23](=[O:25])[N:24]=3)=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2cncc(Cl)c2)c(F)c1
Product: CN1c2cc(OCc3ccc(Oc4cncc(Cl)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and 7-chloro-1,2,2-trimet-hyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2].C(N(CC)CC)C.[C:40]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH:45]=[CH:44][C:43]([C:46](Cl)=[O:47])=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([N:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:46]([C:43]1[CH:44]=[CH:45][C:40]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[CH:41][CH:42]=1)=[O:47])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)N(Cc1ccccc1)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
A sample of 2-benzylamino-4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid ethyl ester (490 mg, 1.10 mmol) was dissolved in 10 mL of methylene chloride followed by addition of triethylamine (0.31 mL, 2.21 mmol) and biphenyl-4-carbonyl chloride (287 mg, 1.33 mmol). The reaction was allowed to stir at room temperature for 12 hours then partitioned between additional methylene chloride (50 mL) and 0.1 N HCl (50 mL). The organic phase was dried over sodium chloride, then concentrated under reduced pressure to yield 687 mg (100%) of an oil. HPLC RT1=7.65 min; 1H NMR (400 MHz, CDCl3) δ 7.60-7.20 (m, 14H), 6.77-6.46 (m, 4H), 4.91-4.45 (m, 2H), 4.19-3.66 (m, 7H), 2.78-2.12 (m, 2H), 1.49 (s, 6H), 1.25-1.22 (m, 6H).