Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][N:14]([C:22]([CH:24]2[CH2:31][C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:8][CH:7]=1.[Li+].[OH-]>O1CCCC1>[C:30]12[CH2:31][CH:24]([C:22]([N:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([O:32][CH2:33][CH3:34])[C:3]([OH:35])=[O:2])=[CH:11][CH:10]=3)=[O:23])[C:25]=1[CH:26]=[CH:27][CH:28]=[CH:29]2
Reactant: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)OC)cc1)C(=O)C1Cc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCN(CCc1ccc(CC(OCC)C(=O)O)cc1)C(=O)C1Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A solution of 3-(4-{2-[(bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl)-heptyl-amino]-ethyl}-phenyl)-2-ethoxy-propionic acid methyl ester (96 mg, 0.20 mmol) and 1 M LiOH (0.60 mmol, 0.60 mL) in tetrahydrofuran (3 mL) was allowed to stir at room temperature for 16 hours. 2 N HCL was then added until the solution had a pH<2. After dilution with twice its volume in water, the aqueous layer was extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-{2-[(bicyclo[4.2.0]octa-1(6),2,4-triene-7-carbonyl)-heptyl-amino]-ethyl}-phenyl)-2-ethoxy-propionic acid as a clear oil (56 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[K+].C1COCC1.Cl>CO.O>[NH2:1][C:2]1[C:11]([I:12])=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncc(C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.5 %

Procedure:
A solution of methyl 6-amino-5-iodonicotinate (723 mg, 2.6 mmol) and potassium hydroxide (729 mg, 13.0 mmol) in 40 mL methanol/H2O (3:1 ratio) was heated at 50° C. After 4 hours 10 mL THF was added and the reaction continued until 22 hours. The reaction was cooled to room temperature and concentrated HCl added until the solution was pH 4. The solution was concentrated to a volume of 15 mL and the resulting precipitate filtered, rinsed with H2O and 40% EtOAc/hexane to give the title compound as a white solid (443 mg, 65%).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([N:9]2[CH2:45][CH2:44][C:12]3[N:13]=[C:14]([C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[C:26]([CH3:43])=[CH:27][N:28]5S(C4C=CC(C)=CC=4)(=O)=O)[N:15]=[C:16]([N:17]4[CH2:22][CH2:21][NH:20][C@H:19]([CH3:23])[CH2:18]4)[C:11]=3[CH2:10]2)[N:6]([CH3:46])[N:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Br[CH2:57][C:58]([NH2:60])=[O:59].[OH-].[K+].[OH-].[NH4+].OS([O-])(=O)=O.[Na+]>CC#N.ClCCl.O>[CH:1]([C:4]1[CH:8]=[C:7]([N:9]2[CH2:45][CH2:44][C:12]3[N:13]=[C:14]([C:24]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:25]=4[C:26]([CH3:43])=[CH:27][NH:28]5)[N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20]([CH2:57][C:58]([NH2:60])=[O:59])[C@H:19]([CH3:23])[CH2:18]4)[C:11]=3[CH2:10]2)[N:6]([CH3:46])[N:5]=1)([CH3:3])[CH3:2]
Reactant: NC(=O)CBr
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN[C@H](C)C6)n4)CN(c4cc(C(C)C)nn4C)CC5)cccc32)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c[nH]c2cccc(-c3nc4c(c(N5CCN(CC(N)=O)[C@H](C)C5)n3)CN(c3cc(C(C)C)nn3C)CC4)c12
Temperature: 55 °C
Reaction time: 1.75 h

Procedure:
To a solution of (R)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-4-(3-methylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (78 mg, 0.122 mmol) in MeCN (2 mL) was added diisopropylethylamine (0.064 mL, 0.37 mmol) followed by 2-bromoacetamide (20 mg, 0.146 mmol). The mixture was heated to 55° C. and stirred for 105 minutes, then cooled to room temperature quenched with saturated aqueous NH4Cl. The mixture was diluted with dichloromethane and saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two additional times with dichoromethane and the organic layers were then combined, dried over Na2SO4, filtered and concentrated. The resulting residue was then dissolved in ethanol (2.1 mL) and placed in a microwave vial. The vial was charged with KOH (69 mg, 1.24 mmol) and 28% aqueous ammonium hydroxide (0.7 mL, 5.1 mmol), sealed and heated via microwave irradiation at 100° C. for 70 minutes. The mixture was then cooled to room temperature, diluted with dichloromethane and water and then neutralized with 1M aqueous NaHSO4. The resulting layers were separated and the organic layer was dried by passing through a phase separator. The eluent was concentrated and purified by reverse phase HPLC [10-55% MeCN/(0.1% NH4OH)water] to furnish (R)-2-(4-(6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-2-(3-methyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.3 Hz, 3 H) 1.16 (d, J=6.8 Hz, 6 H) 2.02 (s, 3 H) 2.59-2.66 (m, 1 H) 2.72-2.85 (m, 3 H) 2.89-3.00 (m, 3 H) 3.13 (d, J=16.2 Hz, 1 H) 3.20-3.26 (m, 1 H) 3.27-3.30 (m, 3 H) 3.56-3.64 (m, 5 H) 4.01 (s, 2 H) 5.73 (s, 1 H) 7.08-7.13 (m, 2 H) 7.13-7.16 (m, 1 H) 7.18-7.22 (m, 1 H) 7.26 (d, J=2.8 Hz, 1 H) 7.41 (dd, J=8.1, 1.0 Hz, 1 H) 10.90 (s, 1H); MS (ESI+) m/z 542.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:20]([Cu])#[N:21].CN(C)C=O.C(N)CN>O>[C:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:8]2=[O:11])=[CH:4][CH:3]=1)#[N:21]
Reactant: CCCCCCCCC1Cc2ccc(Br)cc2C1=O
Reactant: N#C[Cu]
Solvent: O
Solvent: NCCN
Solvent: CN(C)C=O
Product: CCCCCCCCC1Cc2ccc(C#N)cc2C1=O
Temperature: 160 °C
Reaction time: 6 h
Yield: 55.7 %

Procedure:
Subsequently, 150 g (4.7×10-1M) of 6-bromo-2-octyl-1-indanone, 62.3 g (7.0×10-1M) of CuCN and 800 ml of dimethylformamide (DMF) were placed in a 2 liter-reaction vessel, followed by stirring for 6 hours at 160° C. After the reaction, the reaction mixture was cooled and poured into 3 liter of water and 100 ml of ethylenediamine was added, followed by extraction with ethyl acetate. The organic layer was washed with water, followed by drying with anhydrous magnesium sulfate and distilling-off of the solvent to obtain a crude product. The crude product was purified by silica gel column chromatography (eluent: n-hexane/chloroform=1/1) to obtain 69.6 g of 6-cyano-2-octyl-1-indanone (Yield: 55%).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19](Cl)(=[O:21])=[O:20]>C([O-])(O)=O.[Na+].C(OCC)C>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([F:11])([F:23])[F:24])(=[O:21])=[O:20])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
Orcinol monohydrate (2.84 g. 20.0 mmol) and 2-trifluoromethylbenzenesulfonyl chloride (4.90 g, 20.0 mmol) were mixed in saturated NaHCO3 (70 mL) and diethyl ether (70 mL). The biphasic mixture was stirred vigorously at room temperature overnight. The reaction mixture was quenched with water (100 mL) and extracted into ethyl acetate (3×80 mL). The organic phase was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 2% ethyl acetate in dichloromethane) to give the title compound as a white solid (3.65 g, 55%). 1H-NMR (300 MHz, CDCl3) δ8.12 (d, J=8.0 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.80 (t, J=8.2 Hz, 1H), 7.69 (t, J=7.8 Hz, 1H), 6.55 (s, 1H), 6.48 (s, 1H), 6.39 (s, 1H), 5.11 (s, 1H), 2.23 (s, 3H).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][N:7]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]([C:14]2[C:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=23)=[N:8]1)([OH:4])=[O:2]
Reactant: COC(=O)CCN1N=C(c2c(-c3ccccc3)nn3ccccc23)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCN1N=C(c2c(-c3ccccc3)nn3ccccc23)CCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
A mixture of 3-[2-(2-methoxycarbonylethyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (484 mg), 1N sodium hydroxide aqueous solution (2.1 ml) and methanol (5 ml) was stirred at room temperature for 1 hour. Methanol was evaporated in vacuo. To the residue, water (10 ml) was added and the solution was acidified with 5% hydrochloric acid and extracted with chloroform (20 ml×2). The combined extracts was washed with a saturated aqueous solution of sodium chloride (20 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (30:1) as an eluent to give 3-[2-(2-carboxyethyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (198 mg) as an oil. This free acid was dissolved in a mixture of 1N sodium hydroxide aqueous solution (0.547 mg) and ethanol (3 ml), and the solvent was evaporated in vacuo. The residue was triturated with 95% ethanol, collected by filtration, washed with acetone and dried to give powder of sodium salt of 3-[2-(2-carboxyethyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (129 mg).
Reaction SMILES: I[C:2]1([CH2:17][C:18]([OH:20])=[O:19])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3]1.C1CCCCC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:2]1([CH2:17][C:18]([OH:20])=[O:19])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3]1)([O-:32])=[O:28]
Reactant: O=C(O)CC1(I)OC2=CC=CC2=CC1c1ccccc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: C1=CCCCC1
Solvent: ClC(Cl)Cl
Product: O=C(O)CC1([N+](=O)[O-])OC2=CC=CC2=CC1c1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 2.2 g. (5.8 mmoles) of 2-iodo-3-phenyl-7-benzofuranacetic acid, 1 g. (5.8 mmoles) of cyclohexene and 175 ml. of chloroform is added 0.9 g. (10 mmoles) of dinitrogen tetroxide in 15 ml. of chloroform. The mixture is stirred for 20 hours, washed with water and made basic with sodium hydroxide. The chloroform layer is acidified with hydrochloric acid, washed with water twice and dried, then evaporated to provide 2-nitro-3-phenyl-7-benzofuranacetic acid, identical to the sample prepared in Example 2.
Reaction SMILES: [CH2:1]([N:8]1[C@H:13]([CH3:14])[CH2:12][O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][C@H:13]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1COCC(=O)N1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A solution of (R)-4-benzyl-5-methylmorpholine-3-one (3.0 g, 14.22 mmol) in THF (10 mL) was added dropwise at 0° C. to a solution of lithium aluminum hydride (1.0 M solution in THF, 28.5 mL, 28.5 mmol) in THF (10 mL). The ice bath was removed and the reaction mixture was heated at reflux for 18 h. The reaction was cooled in an ice-bath and excess hydride reagent was quenched by careful, dropwise addition of H2O (5 mL), 15% sodium hydroxide (5 mL) and H2O (15 mL). The resulting mixture was stirred at room temperature for 1 h and the reaction mixture was filtered through a pad of Celite and the pad rinsed with EtOAc (100 mL). The filtrate was washed with saturated brine solution, dried (Na2SO4), filtered and concentrated under reduced pressure to provide (R)-4-benzyl-3-methylmorpholine (2.66 g, 95%) as a red oil. 1H NMR and MS consistent.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=[O:10])[C:7](Cl)=O.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:21]#[N:22])[CH:19]=2)C=[CH:13]1>ClCCl>[CH:6]([C:7]1[C:15]2[C:20](=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[NH:12][CH:13]=1)=[O:10]
Reactant: N#Cc1ccc2cc[nH]c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMF (0.389 mL) was added dropwise to a solution of oxalyl chloride (0.440 mL) in dry dichloromethane (5 mL) at 0° C. The resulting solution was stirred at 0° C. for 10 min. A solution of 1H-indole-6-carbonitrile (D12) (0.650 g) in dry dichloromethane (5 mL) was added to the reaction mixture. The reaction mixture was warmed to RT and stirred at that temperature for 45 min. The solvent was evaporated. THF (50 mL) was added, followed by addition of aqueous NaOH (2 M, 50 mL) and water (200 mL). The biphasic mixture was allowed to stand for 10 min. EtOAc (300 mL) and water (100 mL) was added. The organic fraction was separated and was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 3-formyl-1H-indole-6-carbonitrile (D13) as a orange solid (604 mg). δH (DMSO-d6, 400 MHz): 7.59 (1H, dd), 8.05 (1H, d), 8.24 (1H, m), 8.56 (1H, s), 10.00 (1H, s), 12.62 (1H, br s). MS (ES): C10H6N2O requires 170; found 169.0 (M−H+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1.[Br:29][CH2:30][CH2:31]Br.O>C(#N)C>[Br:29][CH2:30][CH2:31][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:14]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)=[CH:16][CH:17]=1
Reactant: BrCCBr
Reactant: Oc1ccc(N(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Clc1ccc(N(c2ccc(Cl)cc2)c2ccc(OCCBr)cc2)cc1
Temperature: 25 °C

Procedure:
To a 250 mL rbf was added cesium carbonate (4.93 g, 15.14 mmol) and anhydrous acetonitrile (50 mL). A solution of 4-(bis(4-chlorophenyl)amino)phenol (69, 2.5 g, 7.57 mmol) in acetonitrile (25 mL) was added, and an immediate light purple colour was observed. 1,2-dibromoethane (7.11 g, 37.9 mmol) was added and the reaction was heated to reflux for 5 days. After cooling to RT, the reaction mixture was poured into water (250 mL), mixed well and separated. The aqueous portion was extracted with EtOAc (2×100 mL) and the combined organics were washed with water (2×250 mL), dried over MgSO4, filtered and solvent removed by rotary evaporation. Flash chromatography (2% EtOAc/hexanes) afforded 70 as a clear, colourless oil (1.42 g, 43%).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[S:20][C:18]=2[N:19]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Product: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7](Br)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:10]1([C:2]2[CH:8]=[C:7]([C:2]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:3]=3)[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1ccc(-c2ccccc2)cc1-c1ccccc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 163.1 %

Procedure:
2,4-dibromoaniline (10 mmol), benzeneboronic acid (24 mmol), tetrakis(triphenylphosphine)palladium(0) (1 mmol) and potassium carbonate (12 g) are put in a two-neck round-bottom flask and dissolved in toluene (30 mL) and H2O (10 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, toluene is removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering with dichloromethane and petroleum ether, 2,4-diphenylaniline (2.0 g) is yielded.
Reaction SMILES: [ClH:1].[C:2]1([NH:8][C:9]([C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([C:19](=[NH:23])OCC)=[CH:15][N:14]3[CH:24]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](N)[CH2:26][NH2:27]>C(O)C>[ClH:1].[NH:27]1[CH2:26][CH2:25][N:23]=[C:19]1[C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:24]=[C:11]([C:9]([NH:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[N:12]=2)[CH:15]=1
Reactant: NCCN
Reactant: CCOC(=N)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccccc1)c1cn2cc(C3=NCCN3)ccc2n1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
A suspension of 296 mg of ethyl 2-phenylcarbamoylimidazo[1,2-a]pyridine-6-carboximidate hydrochloride (1:1) in 10 mL of ethanol is cooled to 0° C., followed by addition of 144 μL of ethylenediamine. The reaction mixture is refluxed for 16 hours and then stirred at room temperature for 60 hours. The precipitate is filtered off by suction and washed with ethanol and then recrystallized from methanol to give 64 mg of 6-(4,5-dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide hydrochloride (1:2) in the form of a white solid. The filtrate is concentrated to dryness and taken up in water. The insoluble matter is filtered off by suction, washed with methanol and then dried to give 99 mg of 6-(4,5-dihydro-1H-imidazol-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide hydrochloride (1:1) in the form of a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12].C([Li])CCC>C(OCC)C.C1COCC1>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([CH:9]([OH:14])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CC(O)c1cnc(Cl)nc1
Temperature: -78 °C
Yield: 38.2 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (5.0 g, 25.8 mmol) in diethyl ether (129 mL) and THF (129 mL) was added isovaleraldehyde (4.45 g, 51.7 mmol). The reaction mixture was cooled to −78° C., and n-butyllithium (15.4 mL of a 1.6 M solution in hexanes, 24.6 mmol) was added. The mixture was stirred for 30 m at −78° C. The reaction mixture was quenched by addition of saturated aqueous NH4Cl, and extracted with ethyl acetate (300 mL×3). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give 1-(2-chloropyrimidin-5-yl)-3-methylbutan-1-ol (1.98 g) as yellow oil. 1HNMR (400 MHz, CDCl3) δ 8.54 (s, 2H), 4.76-4.80 (m, 1H), 1.75-1.66 (m, 2H), 1.45-1.37 (m, 1H), 0.89 (d, J=6.35 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][S:13]([O-:15])=[O:14].[Na+]>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[S:13]([CH3:12])(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 130 °C
Yield: 74 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (10 g, 62.9 mmol) and sodium methanesulfinate (8.3 g, 69.1 mmol) in DMSO (60 mL) was heated at 130° C. for 8 hours. After cooling down to room temperature, the mixture was poured into ice-water. The whole was extracted with ethyl acetate (200 mL×2), the combined organic layer washed with water (80 mL), brine (80 mL), dried over MgSO4, and concentrated in vacuo. The residue was crystallized from hexane and triturated with hexane to give the subtitle compound (10.2 g, 74% yield).
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH:33]C)=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:35]([O:37]C)=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O.CO.O1CCCC1>[C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH:31]=[C:32]=[CH2:33])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:11]([C:35]([OH:37])=[O:36])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=C=CCOc1ccc(S(=O)(=O)N2Cc3ccccc3N(C(=O)c3ccccc3)CC2C(=O)O)cc1
Yield: 98.9 %

Procedure:
The procedure of Example 42 was followed using the product from Example 40 (270 mg, 0.521 mmol), lithium hydroxide (55 mg, 1.3 mmol) in water (0.4 ml), methanol (1 ml) and tetrahydrofuran (1 ml) to give 260 mg (99%) of the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=[O:5])[CH3:2].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:19]>C(OCC)(=O)C>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][C:13]([CH3:15])=[CH:12][CH:11]=2)[N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Nc1cc(C)ccc1C#N
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccccc2)c(N)c2ccc(C)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 2-(ethoxycarbonylamino)-4-methylbenzonitrile (step 1) and 2-bromoacetophenone. tlc: Rf=0.6 (25% ethyl acetate in hexanes)
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([O:11][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: Fc1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc(C(F)(F)F)cc1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluoro benzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([O:19]CC)=[O:18])[CH:6]=[CH:5][N:4]=[CH:3]1>Cl>[ClH:1].[N:2]1([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: CCOC(=O)Cc1ccccc1OCCn1ccnc1
Agent: Cl
Product: O=C(O)Cc1ccccc1OCCn1ccnc1

Procedure:
A solution of ethyl 2-[2-(1-imidazolyl)ethoxy]phenylacetate hydrochloride (3.5 g) in 5N hydrochloric acid (20 ml) was heated on a steam bath for 6 hours and then evaporated. The residue was crystallised from isopropanol to give 2-[2-(1-imidazolyl)ethoxy]phenylacetic acid hydrochloride, m.p. 146°-147°. Found: C, 54.69; H, 5.25; N, 9.80. C15H14N2O3.HCl requires: C, 55.22; H, 5.35; N, 9.91%.