Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[O:26]1[C:28]([CH3:30])([CH3:29])[CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:27][C:28]([OH:26])([CH3:30])[CH3:29]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Reactant: CC1(C)CO1
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC(C)(C)O)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and 1,2-epoxy-2-methylpropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[O:33]1[C:37](B(O)O)=[CH:36][C:35]2[CH:41]=[CH:42][CH:43]=[CH:44][C:34]1=2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[O:33]1[C:34]2=[CH:44][CH:43]=[CH:42][C:41]2=[CH:35][CH:36]=[C:37]1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:14][C:12](=[O:13])[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(I)cc2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccccc2-c2ccc3cccc-3o2)cc1
Temperature: 125 °C
Reaction time: 0.1 h
Yield: 80 %

Procedure:
To 2-(4-tert-Butyl-phenyl)-N-(4-iodo-phenyl)-3-(4-nitro-phenyl)-propionamide (1056 mg, 2 mmol) in 8 ml 1,2-dimethoxyethane, 4 ml ethanol, and 2 ml water was added benzo[b]furan-2-boronic acid (972 mg, 6 mmol), bis(tri-o-tolylphosphine)palladium(II) dichloride (158 mg, 0.2 mmol), and sodium carbonate (1060 mg, 10 mmol). The reaction mixture was stirred at 125° C. for 6 min, filtered, and concentrated. Chromatography of the residue (20% ethyl acetate in hexane) afforded N-(4-Benzofuran-2-yl-phenyl)-2-(4-tert-butyl-phenyl)-3-(4-nitro-phenyl)-propionamide as a yellow foam (830 mg, 80%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:30]1[N:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][N:31]=1>C1COCC1>[CH3:37][O:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([N:3]2[C:4]3[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=3[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:2]2=[O:1])[N:35]=1
Reactant: COc1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccnc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
A mixture of tert-butyl (2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (200 mg, 0.806 mmol, described in Intermediate 4) and sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.69 mL, 1.69 mmol) in THF (0.5 mL) was stirred for 5 min, then 2-chloro-4-methoxypyrimidine (583 mg, 4.03 mmol) was added and argon was bubbled through the mixture for 5 min. The reaction mixture was heated at 130° C. for 10 min in a microwave reactor. The cooled mixture was partitioned between CHCl3 (10 mL) and saturated aqueous NaHCO3 (5 mL). The aqueous phase was extracted further with CHCl3 (10 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane::EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=357 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][NH:21][C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][N:34]([CH:36]([CH3:39])[C:37]#[N:38])[CH:35]=2)O1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:31]3[CH:32]=[N:33][N:34]([CH:36]([CH3:39])[C:37]#[N:38])[CH:35]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC(C#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(I)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(C(C)C#N)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine and 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile. LCMS (M+H)+=443.0/445.0. 1H NMR (300 MHz, DMSO-d6) δ: 9.39 (s, 1H), 8.66 (s, 1H), 8.27 (s, 1H), 7.42 (s, 1H), 7.00 (s, 1H), 5.91 (q, J=7.1 Hz, 1H), 3.96 (s, 6H), 1.88 (d, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]1([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[OH:15])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26]>O1CCCC1>[CH3:23][N:24]([CH3:28])[C:25]([O:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[N:8]=[CH:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:26]
Reactant: CN(C)C(=O)Cl
Reactant: Oc1cnccc1N=CN1CCOCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Oc1cnccc1N=CN1CCOCC1

Procedure:
A mixture prepared from 4-[[(4-morpholinyl)methylene]amino]-3-pyridinol (3.04 g), triethylamine (3.19 mL), dimethylcarbamyl chloride (2.04 mL) and tetrahydrofuran (121 mL) was refluxed for 1 hour, cooled, poured directly onto a silica column and eluted successively with ethyl acetate and 5% Et3N/ethyl acetate. Recrystallization from ethyl acetate (50 mL) and drying under high vacuum and refluxing acetone overnight yielded 3.04 g of fluffy needles, m.p. 127°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:43][CH2:44][CH2:45][CH2:46][OH:47]>O1CCCC1.O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:43][CH2:44][CH2:45][CH2:46][OH:47])=[O:19])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCCO)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
The title compound was prepared as described in Example 76. To a solution of 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (0.200 g, 0.781 mmol) in tetrahydrofuran (5 mL) was added 1-hydroxybenzotriazole hydrate (0.316 g, 2.34 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.449 g, 2.34 mmol), 3-amino-1-propanol (0.178 mL, 2.34 mmol) and N,N-dimethylformamide (2 mL). The solution was stirred for 16 h at room temperature. Water (40 mL) was added and the solid was filtered and dried in a vacuum oven to give the title compound (0.192 g, 78% yield): 1H NMR (DMSO-d6) δ 13.45 (s, 1H), 8.59 (t, 1H), 8.53 (s, 1H), 8.08 (AB quartet, 2H), 7.91 (dd, 1H), 7.62 (d, 1H), 7.40 (t, 2H), 4.50 (t, 1H), 3.48 (q, 2H), 3.36 (q, 2H), 1.71 (pentet, 2H); ES-MS (m/z) 314 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:35]=[CH:34][C:6]([CH2:7][O:8][C:9]([C:11]2C(C3C=CC=C([N+]([O-])=O)C=3)C(C(OC(C)C)=O)=C(C)[NH:15][C:16]=2[CH3:17])=[O:10])=[CH:5][CH:4]=1>C(O)C>[F:1][C:2]([F:36])([F:37])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:10])/[CH:11]=[C:16](\[NH2:15])/[CH3:17])=[CH:34][CH:35]=1
Reactant: CC1=C(C(=O)OCc2ccc(C(F)(F)F)cc2)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC(C)C)=C(C)N1
Solvent: CCO
Product: C/C(N)=C/C(=O)OCc1ccc(C(F)(F)F)cc1
Yield: 76 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 3'-nitrobenzylideneacetoacetic acid isopropyl ester and 75 mmols of β-aminocrotonic acid 4-trifluoromethylbenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-isopropoxycarbonyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 4-trifluoromethylbenzyl ester of melting point 139° C (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=1.[O:22]1[CH2:27][CH2:26][CH:25]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:29]([NH:28][CH:25]3[CH2:26][CH2:27][O:22][CH2:23][CH2:24]3)=[O:30])[CH2:10][C:5]2=[C:4]([C:11]([NH2:13])=[O:12])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=1
Reactant: O=C(NC1CCOCC1)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1cccc(-c2c(C(N)=O)c3n(c2Cl)CCNC3)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cccc(-c2c(C(N)=O)c3n(c2Cl)CCN(C(=O)NC2CCOCC2)C3)c1
Temperature: 65 °C
Yield: 82.8 %

Procedure:
A suspension of 0.67 g (2.23 mmol) of 6-chloro-7-(3-cyanophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide, 0.712 g (2.67 mmol) of 4-nitrophenyl tetrahydro-2H-pyran-4-ylcarbamate and 0.616 g (1.12 mmol) of potassium carbonate in 10 ml of acetonitrile is heated at 65° C. for 1 hour 30 minutes. After cooling, the mixture is concentrated under reduced pressure, the residue is diluted with dichloromethane and the solution is washed with aqueous 1N sodium hydroxide solution. The organic phase is washed with water, dried over sodium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of 40 g of silica gel, eluting with a mixture of 2 to 5% methanol in dichloromethane, to give 0.79 g of 6-chloro-7-(3-cyanophenyl)-N2-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxamide in the form of a whitish powder after recrystallizing from 100 ml of ethanol, filtering off and drying under reduced pressure.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+].O>CN(C)C=O>[N:28]([CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4])=[N+:29]=[N-:30]
Reactant: COc1ccccc1CN(C(=O)CCl)c1ccccc1Oc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1CN(C(=O)CN=[N+]=[N-])c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A solution of 1.51 g of N-chloroacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline synthesized in the same manner as in Example 1 and 770 mg of sodium azide in 10 ml of dimethylformamide was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:4) to give 1.55 g of N-azidoacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: [Br:1]Br.[CH2:3]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)[CH:9]=[C:8]([Cl:16])[N:7]=1)[CH3:4].O.N>C(Cl)Cl>[CH2:3]([NH:5][C:6]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)[C:9]([Br:1])=[C:8]([Cl:16])[N:7]=1)[CH3:4]
Reactant: CCNc1nc(Cl)cc(NC2CC2)n1
Reactant: BrBr
Agent: N
Solvent: O
Solvent: ClCCl
Product: CCNc1nc(Cl)c(Br)c(NC2CC2)n1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of 6.4 g of bromine (0.04 mol) in 30 ml of methylene chloride is added dropwise over the course of one hour to a solution of 8.5 g (0.04 mol) of 2-ethylamino-4-cyclopropylamino-6-chloropyrimidine in 300 ml of methylene chloride, whilst cooling with ice. The solution is left to stand overnight at room temperature, 150 ml of water are then added and the mixture is brought to pH 9-10 with dilute ammonia solution. The organic phase is separated off, rinsed with water, dried over magnesium sulphate, filtered and evaporated. The evaporation residue (12 g), when recrystallised from methanol-water (1:1), gives 10.4 g of colourless crystals of melting point 100°-101°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC=C)=[CH:9][CH:8]=1)[CH3:2].CN(C)[C:28]1[CH:33]=CC=C[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:33][CH:28]=[CH2:29])[CH:8]=1)[CH3:2]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Product: C=CCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of 3-(4-allyloxyphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (475 mg, 1.39 mmol) in dimethylaniline (1.5 mL) was heated at reflux for 18 h. After cooling to ambient temperature, the reaction mixture was partitioned between ethyl acetate and 1N H2SO4. The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (100 mL SiO2, hexanes to 30% ethyl acetate/hexanes) to provide the desired product (343 mg, 72%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.23 (t, J=8.4 Hz, 2H), 7.02–6.96 (m, 3H), 6.83 (d, J=8.8 Hz, 2H), 6.72 (d, J=7.6 Hz, 1H), 6.05 (m, 1H), 5.16–5.09 (m, 2H), 4.21 (q, J=6.8 Hz, 2H), 3.38 (d, J=6.4 Hz, 2H), 3.25 (A of AB, J=13.6 Hz, 1H), 3.10 (B of AB, J=13.6 Hz, 1H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6](N1CCN(C2C=CC(F)=CC=2)CC1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH:45]=[C:46]([O:50][CH3:51])[C:47]=1[O:48][CH3:49].[ClH:58]>O1CCCC1>[ClH:58].[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:55]1[CH2:56][CH2:57][N:52]([C:44]2[CH:43]=[C:42]([O:41][CH3:40])[C:47]([O:48][CH3:49])=[C:46]([O:50][CH3:51])[CH:45]=2)[CH2:53][CH2:54]1)=[O:7]
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(N2CCN(C(=O)NCCN(C)C)CC2)cc(OC)c1OC
Yield: 56 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 2.4 g (0.015 mole) of 1,1'-carbonyldiimidazole, 13 g (0.015 mole) of unsym-dimethylethylenediamine and 3.8 g (0.025 mole) of 1-(3,4,5-trimethoxyphenyl)piperazine in a total volume of 100 ml of tetrahydrofuran gave an oil as residue. The hydroxhloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized from methanol-ethyl ether to yield 3.7 g (56%) of the title compound as a white solid, m.p. 205°-208° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5].[H-].[Na+].[CH2:26](Br)[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([O:14][CH2:26][CH3:27])[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(O)c(Cl)nc2n1C(=O)OC(C)(C)C
Reactant: CCBr
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCC)c(Cl)nc2n1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a solution of 1.0 g (2.93 mmol) 6-chloro-5-hydroxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 20 mL N,N-dimethylformamide was added 0.14 g (3.23 mmol) sodium hydride (60% dispersion in mineral oil). After 30 min., 0.44 mL (0.64 g, 5.87 mmol) ethyl bromide was added and the suspension stirred for 1 h. The reaction mixture was poured into 10% aqueous citric acid solution and extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:2) as eluant to give the product as a colourless crystalline solid (93.4%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]3[C:8]([N:9]=[C:10]4[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]4)=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Clc1c2c(nc3ccccc13)CCCC2
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1ccc(COc2ccc(-c3c4c(nc5ccccc35)CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 9-chloro-1,2,3,4-tetrahydro-acridine (282 mg, 1.30 mmol), 4-Benzyloxyphenyl boronic acid (443 mg, 1.94 mmol), tetrakistriphenylphosphine palladium (15 mg, 0.01 mmol), and 2 M aq Na2CO3 (0.97 mL, 1.94 mmol) was heated to 80° C. in 1,2-dimethoxyethane (2 mL) with vigorous stirring overnight in a sealed vial. The reaction mixture was cooled to room temperature and partitioned between EtOAc (50 mL) and H2O (10 mL). The aq. layer was extracted with EtOAc (25 mL). The combined organic layers were washed with sat. aq. NaCl (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was triturated with hexanes (50 mL) and to give a mixture of the desired product and starting chloride, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[CH:21]=[CH2:22]>C(O)C>[C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:9][CH2:10][N:11]([CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Reactant: C=CC(=O)OCC(C)C
Solvent: CCO
Product: CC(C)COC(=O)CCN1CCC(=C(c2ccccc2)c2ccccc2)CC1
Yield: 87.7 %

Procedure:
A solution of 20 (0.782 g, 3.14 mmol), isobutyl acrylate (0.56 mL, 3.89 mmol) and ethanol (5 mL) was shaken at 75° C. for 2 h, then evaporated to dryness to give 1.04 g of 11e as a viscous yellow oil that was used without further purification. The structure was confirmed by 1H NMR. (Propanoate esters 11b, 11c, and 11f were similarly prepared (see synthesis of cyclopentyl acrylate in the Scheme 6). Isopropyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate (11d). Sodium hydride (60% dispersion in mineral oil, about 15 mg) was added to a stirred solution of 11b (1.20 g, 3.5 mmol) in 2-propanol (15 mL). Although after 1 h there was no insoluble solid, TLC showed evidence of degradation to the acid 11a, and the mixture was then stirred for an additional 48 h. The mixture was concentrated, suspended in a small amount of 1:1 heptane:ethyl acetate, filtered to remove insoluble solid (323 mg, 11a) and purified by flash chromatography to yield 560 mg (43%) of 11d. The structures were confirmed by 1H NMR and LC/MS. (Propanoate ester 11f was similarly prepared (this represents a second method for preparing 11f).) Cyclopentyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate, oxalic acid salt (11f-Ox). A solution of oxalic acid (190 mg, 2.11 mmol) in ethanol (3 mL) was added in one aliquot to a stirred solution of 11f (885 mg, 2.26 mmol) in warm ethanol (5.5 mL). The mixture became solid after 10 seconds of stirring. The solid mass was broken up and after 1.5 h of stirring, the solid was collected by suction filtration and washed with ethanol. After drying, the oxalate salt 11f-Ox was obtained as white powder (961 mg, 96%). 1H NMR, MS, and elemental analyses were consistent with the structure of the product. (The oxalate salt of 11d was similarly prepared.) Ethyl 3-[4-(diphenylmethylidene)piperidin-1-yl]propanoate, HCl salt (11c-HCl). 2 M HCl/ether (1.45 mL) was added to a stirred solution of 11c (812 mg, 2.32 mmol) in isopropyl ether (40 mL). After stirring for 30 min, the resulting precipitate was filtered, washed with isopropyl ether, and recrystallized from boiling H2O (2 mL) to give 608 mg of the hydrochloride salt of 11c-HCl as a creamy white powder. The structure was confirmed by 1H NMR, MS, and elemental analysis. (The HCl salt of 11e was similarly prepared.)
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:6]=2[C:5]([OH:17])=[C:4]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[N:3]=1.C[C:26]([N:28](C)C)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.[Zn]>[C:26]([C:2]1[C:7]2[S:8][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:10][C:6]=2[C:5]([OH:17])=[C:4]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])[N:3]=1)#[N:28]
Reactant: CC(=O)N(C)C
Reactant: O=C(O)CNC(=O)c1nc(Br)c2sc(-c3ccccc3)nc2c1O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2nc(-c3ccccc3)sc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of [(4-bromo-7-hydroxy-2-phenyl-thiazolo[5,4-c]pyridine-6-carbonyl)-amino]-acetic acid (130 mg, 0.32 mmole), tris(dibenzylideneacetone)dipalladium(0)(15 mg, 0.02 mmole), 1,1′-bis(diphenylphosphino)ferrocene (18 mg, 0.04 mmole), zinc cyanide (23 mg, 0.19 mmole) and zinc (3 mg, 0.04 mmole) in dimethylacetamide (640 μl) was stirred at 120° C. for 3 h before it was cooled to room temperature, partitioned between ethyl acetate and 1N NaOH (50 ml). The aqueous layer was acidified with 5 N HCl (10 ml) to pH=2, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a C18 column with a gradient of water and acetonitrile in formic acid to give the title compound as a yellow solid (46 mg). MS: (+) m/z 355.22 (M+1), MS: (−) m/z 353.18 (M−1).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH2:14][OH:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O.CC([O-])=O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH:14]=[O:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn(Cc2ccccc2)nc1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cn(Cc2ccccc2)nc1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
To a solution of (1-benzyl-4-methyl-1H-pyrazol-3-yl)methanol (compound 268.2, 3 g, 14.8 mmol) in dichloromethane (100 mL) was added PDC (11.3 g, 30.1 mmol), molecular sieves (3 g) and NaOAc (300 mg) were added to the reaction mixture. The reaction mixture was stirred for 4 h at room temperature. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel chromatography with ethyl acetate/petroleum ether (1/10) as the eluent to yield 1 g (34%) of the title compound as a colorless oil.