Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH2:12](O)[CH:13]=[CH2:14].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:14]([O:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=1)[NH:9][CH:8]=[CH:7]2)[CH:13]=[CH2:12]
Reactant: Cc1cc(O)cc2cc[nH]c12
Reactant: C=CCO
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=CCOc1cc(C)c2[nH]ccc2c1
Temperature: 100 °C

Procedure:
7-Methyl-1H-indol-5-ol (5.2 g, 35.3 mmol) was dissolved in toluene (221 mL) and prop-2-en-1-ol (2.42 mL, 35.3 mmol) was added followed by cyanomethylenetributylphosphorane (21.32 g, 88 mmol). The reaction was heated at 100° C. After 1 hour the reaction was cooled to room temperature, concentrated and purified by silica gel flash chromatography (0:100 EtOAc:heptanes) to provide the title compound. MS (ESI+) m/z 188.15 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)nc23)CC1
Reaction time: 0.17 h
Yield: 87.1 %

Procedure:
A solution of 1.00 gm (4.3 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine in 85 mL pyridine was heated to 55° C. To this solution were added 0.57 mL (4.8 mMol) 4-fluorobenzoyl chloride and the resulting mixture was stirred for 30 minutes at which time an additional 0.10 mL 4-fluorobenzoyl chloride were added. After stirring for an additional 10 minutes the reaction mixture was concentrated under reduced pressure. The residue was treated with 50 mL cold 1N sodium hydroxide followed by 100 mL dichloromethane. The phases were separated and the aqueous phase was extracted 2×50 mL dichloromethane followed by 3×50 mL 3:1 chloroform:isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to radial chromatography (4 mm silica gel plate) eluting with dichloromethane containing 10-20% methanol and 1% ammonium hydroxide. Fractions containing product were combined and concentrated under reduced pressure. The residue was crystallized from aqueous ethanol to provide 1.32 gm (87%) of the title compound as ivory crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][C:6](=[O:8])[CH2:5][C:4]([CH3:10])([CH3:9])[P:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=1[CH:29]([CH3:31])[CH3:30].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:45](O)[CH2:46][OH:47]>>[CH3:32][C:2]1([CH3:1])[P:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][C:20]([CH:26]([CH3:28])[CH3:27])=[CH:19][C:18]=2[CH:29]([CH3:31])[CH3:30])[C:4]([CH3:9])([CH3:10])[CH2:5][C:6]2([O:47][CH2:46][CH2:45][O:8]2)[CH2:7]1
Reactant: OCCO
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC3(CC2(C)C)OCCO3)c(C(C)C)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A flask was charged with 3.75 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-tri-isopropylbiphenyl-2-yl)phosphinan-4-one (8.32 mmol, 1.0 equiv) and 0.16 g of p-toluenesulfonic acid monohydrate (0.84 mmol, 0.1 equiv). The atmosphere was purged with nitrogen and the flask was charged with 80 mL of nitrogen-sparged toluene. To this solution was added 4.6 mL of ethylene glycol (83 mmol, 10 equiv). The reaction flask was equipped with a Dean-Stark trap and warmed to an internal temperature of 110° C. for 2 h under nitrogen atmosphere. The distilled toluene was collected in the Dean-Stark trap. The reaction mixture was cooled to room temperature under nitrogen gas. The reaction was quenched with 1.6 mL of aqueous 10 wt % sodium carbonate solution and partitioned between 65 mL of heptane and 35 mL of water. The organic solution was washed twice with 20 mL portions of water, concentrated in vacuo with gentle heating and the residue was chased once with heptane. The concentrate was dissolved in 35 g of methanol. Seed crystals were added to induce crystallization, the solvent was removed in vacuo and 16 mL of methanol was added to the crystalline solid. The mixture was stirred overnight at room temperature and the crystalline product was isolated by filtration, washed with methanol and dried in vacuo at 50° C. to give 3.5 g of 7,7,9,9-tetramethyl-8-(2′,4′,6′-triisopropylbiphenyl-2-yl)-1,4-dioxa-8-phosphaspiro[4.5]decane (96 area % by HPLC, 82% yield).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:13]1([C:16]2[CH:21]=[CH:20][C:19]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[O:30]COCC[Si](C)(C)C)=[O:23])=[CH:18][CH:17]=2)[CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>C1COCC1>[CH:13]1([C:16]2[CH:17]=[CH:18][C:19]([C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][C:25]=3[OH:30])=[O:23])=[CH:20][CH:21]=2)[CH2:14][CH2:15]1
Reactant: C[Si](C)(C)CCOCOc1cnccc1C(=O)c1ccc(C2CC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(C2CC2)cc1)c1ccncc1O
Temperature: 65 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
p-Toluenesulfonic acid monohydrate (3.03 g, 15.9 mmol) was added to a solution of (4-cyclopropylphenyl)-[3-(2-trimethylsilylethoxymethoxy)pyridin-4-yl]methanone (1.96 g, 5.30 mmol) in THF (49 mL) and the mixture solution was stirred at 65° C. for one hour. The reaction mixture was cooled to room temperature and a saturated sodium hydrogencarbonate aqueous solution was added thereto and the mixture was extracted with ether, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled under reduced pressure, and the obtained residue was purified by silica gel flash column chromatography [developing solution=n-hexane:ethyl acetate (2:3)] to obtain the title product (1.10 g, 87%).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[N:19][N:18]=[N:17]2)[CH:8]=1.Cl>O1CCCC1>[F:24][C:21]([F:22])([F:23])[C:20]1[N:16]([C:9]2[CH:8]=[C:7]([CH:2]=[O:1])[C:15]3[O:14][CH:13]=[CH:12][C:11]=3[CH:10]=2)[N:17]=[N:18][N:19]=1
Reactant: FC(F)(F)c1nnnn1-c1cc(C2OCCCO2)c2occc2c1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1cc(-n2nnnc2C(F)(F)F)cc2ccoc12
Reaction time: 3 h
Yield: 75.4 %

Procedure:
7-([1,3]-Dioxan-2-yl)-5-(5-trifluoromethyl-tetrazol-1-yl)-benzofuran (160 mg) was dissolved in tetrahydrofuran (30 ml) and dilute hydrochloric acid (20 ml; 2M). The reaction mixture was heated to reflux and stirred for a total of 3 h, cooled and concentrated in vacuo. The residue was taken up in chloroform (40 ml), and the organic phase washed with 8% sodium bicarbonate solution (3×20 ml), dried and concentrated in vacuo. The crude material was purified by FCC eluted with dichloromethane-hexane (1:1) to dichloromethane-hexane (2:1) to give the title compound (100 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(N)c([N+](=O)[O-])c2)ccn1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture containing 4-amino-3-nitrophenol (1 eq) and potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added (4-chloro(2-pyridyl))-N-methylcarboxamide (1 eq) and potassium carbonate (1.2 eq) and stirred at 90° C. for 3 days. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered, and concentrated in vacuum to give brown solid. Purification on silica gel (2% triethyl amine/50% ethyl acetate in hexane) gave 4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carbox-amide as an orange solid. The product gave satisfactory NMR. HPLC, 3.39 min; MS: MH+=289.
Reaction SMILES: C(N(CC)CC)C.[SH:8][CH2:9][C:10]([NH2:12])=[O:11].[CH2:13](Br)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O>C(O)C>[C:16]1([C:14]2[NH:12][C:10](=[O:11])[CH2:9][S:8][CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(=O)CS
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C1CSC=C(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (4.55 g) is added to a solution of 2-mercaptoacetamide (8.00 g, Reference compound No. 40-1) in ethanol (70 ml), then phenacyl bromide (17.5 g) is added to the mixture, and the whole is stirred for four hours. The reaction mixture is concentrated under reduced pressure, water and 0.1 N hydrochloric acid are added to the resulting residue, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure. The resulting residue is suspended in ethanol (200 ml), p-toluenesulfonic acid monohydrate (catalytic amount) is added to the suspension, and the mixture is refluxed for five days. The reaction mixture is cooled to room temperature to precipitate crystals. The crystals are filtered off and washed with ethanol to give the titled reference compound (11.6 g).
Reaction SMILES: [C:1]([C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[NH:18][CH:19]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>[Ni].C(O)C>[CH2:1]([C:15]1[CH:16]=[C:17]([C:20]([O:22][CH3:23])=[O:21])[NH:18][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)c1c[nH]c(C(=O)OC)c1
Agent: [Ni]
Solvent: CCO
Product: CCCCCCCCCCCCCc1c[nH]c(C(=O)OC)c1
Temperature: 30 °C
Yield: 91.8 %

Procedure:
Into a mixture of 150 ml of Raney nickel (activated type, produced by Aldrich Co.), which had been washed with water and then ethanol, and 750 ml of ethanol, was added 15.06 g (37.9 mmol) of dithioethyleneketal of methyl 4-tridecanoylpyrrole-2-carboxylate obtained in Synthesis Example 2. The mixture was refluxed for 30 minutes and cooled to about 30° C. After removing Raney nickel, the mixture was evaporated. The residue was recrystallized from ethanol to obtain 10.70 g of methyl 4-tridecylpyrrole-2-carboxylate as white crystals. The yield was 91.8% and the melting point was 80° to 82° C.
Reaction SMILES: [NH2:1][C:2](=[N:23][OH:24])[CH:3]([N:11]([CH3:22])[C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:4]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5]1.[CH2:25]([O:27][C:28]([C:30]#[C:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:29])[CH3:26]>CCO>[NH2:1][C:2](=[N:23][O:24]/[C:31](=[CH:30]/[C:28]([O:27][CH2:25][CH3:26])=[O:29])/[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:3]([N:11]([C:12]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:21])[CH3:22])[CH:4]1[CH2:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CN(C(=O)OCc1ccccc1)C(C(N)=NO)C1CCC(CO)C1
Solvent: CCO
Product: CCOC(=O)/C=C(/ON=C(N)C(C1CCC(CO)C1)N(C)C(=O)OCc1ccccc1)C(=O)OCC
Temperature: 23 °C
Reaction time: 48 h
Yield: 63.3 %

Procedure:
To benzyl 2-amino-2-(hydroxyimino)-1-(3-(hydroxymethyl)cyclopentyl)ethyl(methyl)carbamate (0.800 g, 1.78 mmol) in EtOH (40 mL) was added diethylacetylenedicarboxylate (0.428 ml, 2.67 mmol). The reaction mixture was stirred at 23° C. for 2 days. The solvent was removed in vacuo and the crude material purified on a Silica gel column (Biotage flash chromatography system), eluted with a gradient of ethyl acetate:hexane (1:5) to (1:1) to afford 0.570 g (52% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.33-7.42 (5 H, m), 5.17-5.25 (3 H, m), 4.12-4.40 (4 H, m), 3.55 (2 H, m), 2.83-2.94 (4 H, m), 2.70-2.75 (1 H, m), 2.17-2.09 (2 H, m), 1.82-2.00 (3 H, m), 1.21-1.342 (7 H, m). LCMS (+ESI, M+H+) m/z 506.
Reaction SMILES: [C:1]1(=O)O[C:4](=[O:5])[CH:3]=[CH:2]1.CC(C)=O.CCC[CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:4]([O:5][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:2][CH3:1]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCC
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCCCOCCCC

Procedure:
Maleic anhydride can be reacted with amines to form the corresponding maleamic acid derivative. Suitably, a maleic anhydride containing polymer is reacted in solution or suspension with an amine in inert or non-reactive solvents, such as acetone, heptane, benzene or dibutylether, to provide the desired maleamic derivative.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.O.[NH2:19][NH2:20]>C(O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:10]2[CH2:9][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[NH:20][N:19]=2)[CH:13]=1
Reactant: O=C(/C=C/c1ccccc1O)c1cccnc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Oc1ccccc1C1CC(c2cccnc2)=NN1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (2E)-3-(2-hydroxyphenyl)-1-pyridin-3-ylprop-2-en-1-one (12.5 g, 55.6 mmol), hydrazine monohydrate (6.00 mL, 123 mmol), and ethanol (160 mL) was allowed to stir at 80° C. overnight. The reaction mixture was filtered over a pad of celite and washed with MeOH and DCM. The resulting filtrate was concentrated to give 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (12.5 g, 94%) as a light grey solid. 1H NMR (400 MHz, d6-DMSO, HCl salt) δ: 9.52-9.67 (bs, 1H), 8.78 (s, 1H), 8.45-8.51 (m, 1H), 7.97 (d, 1H), 7.61 (s, 1H), 7.38 (t, 1H), 7.26 (d, 1H), 7.07 (t, 1H), 6.81 (d, 1H), 6.76 (t, 1H), 5.04 (t, 1H), 3.44 (dd, 1H), and 2.76 (dd, 1H). LCMS: (FA) ES+ 240.2, ES-238.5.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:17][CH2:18][C:19]([OH:21])=[O:20]>CCO.O>[N+:8]([C:7]1[C:2]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C(O)CNc1ncccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2-Chloro-3-nitropyridine (5 g, 31.5 mmol) was dissolved in EtOH (125 ml), added potassium carbonate (4.35 g, 31.5 mmol) and to this mixture glycine (4.73 g, 6.3 mmol) in 25 ml water was added and refluxed for overnight. The reaction mixture cooled to 0° C. to obtain the solid. Then EtOH was removed on rotavapour and acidified with 2N HCl and solid filtered and dried on vacuum to obtain the title compound quantitatively as a yellow solid.
Reaction SMILES: C(=O)([O-])OCC[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([O:31][C:32]2[CH:33]=[CH:34][C:35]([N:38]([CH2:5]/[CH:6]=[CH:7]/[C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=3)[S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCS(=O)(=O)Nc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: N#Cc1cccc(/C=C/CCCOC(=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCS(=O)(=O)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a suspension of [3-(3-cyanophenyl)-2-(E)-propenyl]ethyl carbonate (1.04 g) and N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]ethanesulfonamide (1.15 g) in tetrahydrofuran (9 ml) were added tris(dibenzylideneacetone)palladium chloroform complex (0.077 g) and triphenylphosphine (0.039 g) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/ethyl acetate=8/1 as an eluant to give the desired compound (1.57 g, yield quantitative) as a pale yellow oil.
Reaction SMILES: [ClH:1].[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][C:12](=[NH:16])OCC)=[N:3]1.[CH2:17](N)[CH2:18][NH2:19].Cl>C(O)C>[ClH:1].[NH:19]1[CH2:18][CH2:17][N:16]=[C:12]1[CH2:11][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:2][N:3]=1
Reactant: CCOC(=N)Cc1noc2ccccc12
Reactant: NCCN
Agent: Cl
Solvent: CCO
Product: c1ccc2c(CC3=NCCN3)noc2c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
In ethanol (10 ml) was dissolved ethyl 1,2-benzisoxazole-3-acetimidate hydrochloride (2.0 g) and thereto was added ethylenediamine (0.6 g) under ice-cooling and the mixture was allowed to stand at 5°C overnight. To the mixture was added ethanolic hydrochloric acid and the precipitated crystallines were separated by filtration and recrystallized from ethanol to give the desired compound (1.85 g). m.p. 223° to 228°C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:19])[C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1)=[O:6].[CH3:20]I.Cl>O1CCCC1>[O:19]=[C:14]([CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5]([OH:4])=[O:6])=[CH:8][CH:9]=1)[CH3:20])[C:15]([OH:17])=[O:16]
Reactant: CI
Reactant: COC(=O)C(=O)Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C(=O)C(=O)O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 3N aqueous solution of sodium hydroxide (20 ml; 60 mmoles) was added to 4.82 g (20 mmoles) of methyl p-methoxycarbonylphenylpyruvate, and the mixture was stirred at room temperature for 30 minutes. Then, 50 ml of tetrahydrofuran and 3.0 ml of methyl iodide were added, and the mixture was reacted at room temperature for 12 hours. After the reaction, the reaction mixture was acidified with 1N of hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a yellowish white solid of 2-oxo-3-(p-hydroxycarbonylphenyl)butanoic acid. 3N sodium hydroxide (5.5 ml) was added to the resulting solid, and the mixture was concentrated under reduced pressure, and then ether was added. Sodium 2-oxo-3-(p-hydroxycarbonylphenyl)butanoate (4.18 g; yield 88 %) which precipitated was isolated by filtration.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([Cl:13])[CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=2)[CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:13][C:7]1[CH:8]=[C:9]([OH:12])[CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([F:21])[CH:15]=1)[CH:3]=[C:2]2[C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1
Reactant: Oc1cc(Cl)c2nc(-c3ccc(O)c(F)c3)cc(Br)c2c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(-c3ccc(O)c(F)c3)nc3c(Cl)cc(O)cc23)cc1
Yield: 97 %

Procedure:
This compound was prepared from 45a using 4-methoxyphenylboronic acid according to method P. Orange solid; Yield: 97%; mp 140–142° C.; 1H-NMR (400 MHz, DMSO-d6) δ 3.87 (s, 3H), 7.09 (dd, J=8.8, 8.8 Hz, 1H), 7.11 (d, J=2.7 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.51 (d, J=2.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.93(s, 1H), 8.02 (dd, J=8.5, 1.7 Hz, 1H), 8.14 (dd, J=13.1, 2.1 Hz, 1H), 10.21 (s, 1H), 10.27 (s, 1H); 19F-NMR (400 MHz, DMSO-d6) δ −136.48 (dd, J=13.0, 9.7 Hz); MS (ESI) m/z 394/396 ([M−H]−), 396/398 ([M+H]+); Anal. Calcd for C22H15ClFNO3: C: 66.76, H: 3.82, N: 3.54. Found: C: 66.05, H: 4.01, N: 3.19.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:16]=3)=[CH:11][CH:10]=2)[S:3]1.[H][H]>CO.O1CCOCC1.[Pd]>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH:16]=3)=[CH:13][CH:14]=2)[S:3]1
Reactant: [H][H]
Reactant: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)Nc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Temperature: 50 °C

Procedure:
460 mg (1.1 mmol) of 1-[4′-(2,4-dioxo-thiazolidin-5-ylidenemethyl)biphenyl-3-yl]-3-phenylurea in 20 ml of a methanol/dioxane mixture (1/1) are placed in a reactor. The reaction medium is degassed and 560 mg (1.2 equivalents by mass) of 10% palladium-on-charcoal are then added. The system is placed under 3 bar of hydrogen and heated at 50° C. for hours. The reaction medium is filtered through Celite and evaporated, and the residue obtained is purified by chromatography on a column of silica with a gradual increase in the polarity of a 9/1 mixture of heptane and ethyl acetate to a 4/6 mixture of heptane and ethylacetate. After evaporation of the solvents, 150 mg (33%) of 1-[4′-(2,4-dioxothiazolidin-5-ylmethyl)-biphenyl-3-yl]-3-phenylurea are obtained in the form of a white solid with a melting point of 185° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH2:17].C(=O)([O-])O.[Na+].CN(C)C(=O)C>O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:17][CH2:16][C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)([O-:10])=[O:9]
Reactant: NCc1ccco1
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=[N+]([O-])c1ccccc1NCc1ccco1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 15.7 parts of 1-chloro-2-nitrobenzene, 9.7 parts of 2-furanmethanamine, 8.4 parts of sodium hydrogen carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at about 120° C. The reaction mixture was cooled, water was added and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue was triturated in petroleumether. The product was filtered off and dried, yielding 15 parts of N-(2-nitrophenyl)-2-furanmethanamine; mp. 85.6° C. (intermediate 1).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=1)[C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1
Reactant: NCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1ccc(C(CNc2nc3ccccc3[nH]2)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2,2-bis(4-fluorophenyl)ethylamine (prepared by Procedure B from 2,2-bis(4-fluoro-phenyl)acetaldehyde) by Procedure A (20 min at 170° C.). The product was isolated by preparative LCMS to give the title compound as the free base (white solid, mp 155-157° C.). MS(ES+) m/z 350 ([M+1]+, 100) 1NMR (DMSO-d6) δ 3.90 (m, 2H), 4.46 (t, 1H), 6.50 (m, 1H), 6.80-6.90 (m, 2H), 7.07-7.18 (m, 6H), 7.35-7.42 (m, 4H), 10.5 (s, 1H).