Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:11])[CH:9]=[CH2:10]>C1(C)C=CC=CC=1>[CH2:8]([NH:11][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH:9]=[CH2:10]
Reactant: COCC(Cl)C=O
Reactant: C=CCN
Solvent: Cc1ccccc1
Product: C=CCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Allylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-allylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([C:20]#[C:21][Si](C)(C)C)[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:20]([C:18]1[CH:17]=[CH:16][C:3]([NH:4][C:5]2[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=2)=[C:2]([F:1])[CH:19]=1)#[CH:21]
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(N)=O)c(F)c1
Yield: 73 %

Procedure:
4-{2-Fluoro-4-[(trimethylsilyl)ethynyl]anilino}-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with K2CO3 in MeOH/THF as for example 12, step B. The resulting crude product was purified by column chromatography on silica gel (50% acetone/CH2Cl2 as eluant) to give 4-(4-ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow-orange solid (73%), m.p. (CH2Cl2/MeOH) 269-272° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.60 (s, 1H), 8.37 (s, 1H), 7.91 (br s, 1H), 7.51 (t, J=8.4 Hz, 1H), 7.48 (br s, 1H), 7.46 (dd, J=11.4, 1.7 Hz, 1H), 7.33 (dd, J=8.3, 0.9 Hz, 1H), 5.71 (s, 1H), 4.25 (s, 1H), 3.37 (s, 3H). Anal. Calcd for C15H12FN3O2.0.25H2O: C, 62.2; H, 4.4; N, 14.5. Found: C, 62.6; H, 4.1; N, 14.6.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN.O>C(O)C>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCC(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCCCC(c1ccccc1)c1ccccc1

Procedure:
Batch size: 18.5 g (45.0 mmol) 2-(8,8-diphenyl-octyl)-iso-indol-1,3-dione and 8.0 ml (160 mmol) hydrazine.hydrate in ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C@@H:7]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C@@H:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH3:11])=[C:4]([C:30]#[N:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:45]([O:47][C:48](=[O:52])[CH2:49][CH2:50][NH2:51])[CH3:46]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C@@H:7]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C@@H:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:51][CH2:50][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:52])=[O:17])=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH3:11])=[C:4]([C:30]#[N:31])[CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)[C@@H](Oc1ccc(Br)cc1C#N)c1ccc(Cl)cc1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)[C@@H](Oc1ccc(Br)cc1C#N)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
The product from step A was dissolved in THF (10 mL) then CDI (1.018 g, 6.28 mmol) was added. After being stirred for one hour, β-alanine ethyl ester hydrochloride (560 mg, 6.28 mmol) was added, then the mixture was stirred overnight at RT. The mixture was diluted with EtOAc then washed with water then brine. The organic layer was dried over MgSO4, filtered, then concentrated. The resulting residue was purified by silica gel chromatography to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.72 (d, J=2.5 Hz, 1H); 7.67 (d, J=8.5 Hz, 2H); 7.50 (dd, J=9.0, 2.5 Hz, 1H); 7.37 (d, J=8.0 Hz, 2H); 7.24 (d, J=8.0 Hz, 2H); 7.13 (d, J=8.5 Hz, 2H); 6.81 (d, J=9.5 Hz, 1H); 5.63 (d, J=6.0 Hz, 1H); 4.12 (q, J=7.5 Hz, 2H); 3.61 (t, J=7.0 Hz, 2H); 3.19 (m, 1H); 2.62 (t, J=7.0 Hz, 2H); 2.00-1.94 (m, 1H); 1.73-1.67 (m, 1H); 1.22 (t, J=7.5 Hz, 3H); 1.19-1.16 (m, 2H); 0.83 (t, J=7.0 Hz, 3H). LC2 2.38 min. (M+H)+ 597.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:3])[CH3:2].[NH2:14]CC1SC=CC=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH2:14])=[O:9])(=[O:3])[CH3:2]
Reactant: NCc1cccs1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Oc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-acetoxybenzoic acid (8.1 mg, 0.0450 mmol), 5-aminomethylthiophene 18d (22.3 mg, 0.0473 mmol), 1-hydroxybenzotriazole (HOBt, 4.7 mg, 0.0348 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC, 8.5 mg, 0.0443 mmol) was dissolved in DMF (0.6 ml) and stirred overnight at r.t. Work-up (AcOEt/H2O; brine/Na2SO4), concentration, filtration over a silica gel plug (EtOAc) and evaporation gave the intermediate 3-acetoxybenzamide, which was deacetylated by siring in MeOH (2 ml) and Et3N (0.4 ml) for 1 h at 55° C. Evaporation gave 28.5 mg (103%) of the title 3-hydroxy-benzamide as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[Na+].O>CS(C)=O>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
10.4 g of 4-hydroxy-carbazole (57 mmol) were dissolved in 31.1 ml of DMSO. 6.9 ml of epichlorohydrin (88 mmol) were added and next 57 ml of a 1 N sodium hydroxide solution. The mixture was stirred for 8 h at 40° C. It was cooled to 20° C. adn 130 ml of water were added. The product was filtered under suction, and washed with 3×30 ml water. The crude material was recrystallized from isopropanol. The substance was dried at 60° C. for 12 h.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([OH:12])[CH2:8][CH2:9][CH2:10][OH:11].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C.O>CN(C)C=O.CN(C1C=CC=CN=1)C>[CH3:14][C:13]([Si:17]([CH3:19])([CH3:18])[O:11][CH2:10][CH2:9][CH2:8][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[OH:12])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCC(O)c1ccccn1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCC(O)c1ccccn1
Yield: 51.8 %

Procedure:
A solution of the product from step (a) (0.67 g), tert-butylchlorodimethylsilane (0.6 g), triethylamine (0.56 ml) and dimethylaminopyridine (0.01 g) in dimethylformamide (5 ml) was stirred for 2hat 0° C. and at 20° C. for 16 h. Water was added and the mixture was extracted with ethyl acetate (three times). The combined organic extracts were washed with water, dried (sodium sulphate), evaporated and purified by chromatography on silica eluting with petrol-acetone to give the sub-title compound as a colourless oil (0.58 g).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[F:13][C:14]1([C:33](O)=[O:34])[C:23]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=2[F:32])=[CH:22][C:17]2=[N:18][CH2:19][N:20]([CH3:21])[C:16]2=[CH:15]1.C1(N=C=NC2CCCCC2)CCCCC1.CCOC(C)=O>C1COCC1>[F:1][C:2]1[C:7]([O:8][C:33]([C:14]2([F:13])[C:23]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][C:26]=3[F:32])=[CH:22][C:17]3=[N:18][CH2:19][N:20]([CH3:21])[C:16]3=[CH:15]2)=[O:34])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(=O)O)C=C21
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1CN=C2C=C(Nc3ccc(I)cc3F)C(F)(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)C=C21

Procedure:
A solution of pentafluorophenol (21.6 g, 0.113 mol) DMF (100 ml) at room temperature was slowly added to a suspension of 5-fluoro-6-(2-fluoro-4-iodo-phenylamino)-3-methyl-3H-benzoimidazole-5-carboxylic acid (40.0 g , 0.093 mol) in 165 ml of THF, followed by dicyclohexylcarbodiimide (24.14 g, 0.118 mol). The mixture was stirred overnight at room temperature (TLC-EtOAc), evaporated under vacuum and is added 200 g of crushed ice to the residual DMF solution. The light yellow compound separated was filtered and vacuum dried to give the title compound (crude), which is directly proceeded to next step without purification. Yield: 55 g (99%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].N1C=CC=CC=1.[C:15](Cl)(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])O.[Na+]>C(OCC)C>[C:15]([O:3][C:2](=[CH2:4])[C:1]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)C(C)=O
Reactant: CCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=C(OC(=O)CCCCCCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.7 %

Procedure:
While ethyl pyruvate (174 g, 1.5 mol) was being stirred at 0° C., pyridine (120 g, 1.5 mol) was dropped into the ethyl pyruvate. After it was stirred at 0° C. for 10 minutes, octanoyl chloride (243 g, 1.5 mol) was slowly dropped into this mixture. After the temperature of the reaction solution reached room temperature, the reaction solution was stirred for 48 hours. An aqueous solution of saturated sodium hydrogencarbonate and diethyl ether were added to the reaction solution, and an organic layer was separated by use of a separating funnel. Diethyl ether was again added to an aqueous layer and an organic compound was extracted. The obtained organic layer was then mixed with the organic compound, and sodium sulfate was added for dehydration. Thereafter, the sodium sulfate was removed by filtration and the solvent was removed by use of an evaporator under a reduced pressure. The concentrate was distilled under a reduced pressure (1 mmHg, 95 to 100° C.) to give ethyl α-octanoyloxyacrylate (126 g, yield: 34%).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:21]3[C:26]([N:27]=[C:28]4[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=1)=[O:10])C1C=CC=CC=1.[BrH:44]>C(O)(=O)C>[BrH:44].[C:9]([C:11]1[CH:12]=[CH:13][C:14]([N:17]([S:34]([C:37]2[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=2)(=[O:35])=[O:36])[C:18]([C:20]2[C:33]3[C:28]([N:27]=[C:26]4[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]4)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:19])=[CH:15][CH:16]=1)([OH:10])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)O)cc2)cc1
Temperature: 60 °C

Procedure:
1.17 g (2 mmol) of N-(4-benzyloxycarbonylphenyl)-N-(4-toluenesulfonyl)acridine-9-carboxamide are stirred with 10 ml of 33% strength solution of hydrogen bromide in glacial acetic acid while heating at 60° C. for 4 hours. After cooling, the precipitate is filtered off with suction and dried in vacuo. Yield: 1.00 g (87% of theory)
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11]C(O)=O>CCOCC.C1COCC1>[Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:11])=[O:5]
Reactant: O=C(O)c1cccnc1Br
Reactant: CC(=O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccnc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of CH2N2 (4 eq.) in Et2O (1 M) was added dropwise to a solution of 2-bromonicotinic acid in THF (0.5 M) at RT. The reaction mixture was stirred at room temperature overnight, then quenched by dropwise addition of AcOH (4 eq.). The organic phase was washed with water and brine and dried (MgSO4). Evaporation of the solvent yielded (75%) the title compound which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3, 300K) δ 8.47 (1H, dd, J=4.8 Hz, 2.1 Hz), 8.07 (1H, dd, J=7.8 Hz, 2.1 Hz), 7.35 (1H, dd, J=7.5 Hz, 4.5 Hz), 3.93 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
A mixture of 3,6-dichloropyridazine (20.1 g, 135 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (25.46 g, 122 mmol) and potassium carbonate (50.7 g, 367 mmol) in 1,4-dioxane (500 mL) and water (200 mL) under nitrogen was degassed by bubbling in nitrogen for 15 min. Dichlorobis(triphenylphosphine)palladium (II) (1.2%, 1 g, 1.4 mmol) was than added and nitrogen was bubbled in the mixture for another 10 min. The reaction mixture was stirred at 90° C. for 3 h, then cooled to room temperature and concentrated in vacuo to remove the majority of the 1,4-dioxane. The residue was partitioned between 1 N aqueous potassium carbonate (400 mL) and ethyl acetate (400 mL) and the phases separated. The aqueous layer was extracted with ethyl acetate (2×300 mL) and dichloromethane (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in-vacuo. The residue was stirred in diethyl ether (150 mL) and the orange precipitate was filtered and dried to return the title compound (12.76 g, 65.6 mmol, 54% yield). The filtrate was concentrated onto silica gel and purified by flash chromatography on silica gel using a gradient of 0-50% ethyl acetate/hexane to return starting 3,6-dichloropyridazine as a white solid (9.9 g, 66.4 mmol, 49% yield).
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[CH:17]=[CH:16][CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:3]1[O:4][C:5]2[C:10]([C:11](=[S:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: S=c1c(Br)coc2ccccc12
Reactant: c1cc[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: S=c1cc(-c2ccc[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 50.4 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, pyrrole (134 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography and the purified product was recrystallized from benzene/hexane to give the titled compound (57.5 mg; yield=54.0%) as ocher crystals. Melting point: 135°-136 ° C. 1H-NMR(CDCl3, δ ppm): 7.02 (s, H3), 8.51 (dd, H5), 7.56 (t, H6), 7.61-7.68 (m, H7), 7.61-7.68 (m, H8), 7.22 (hr. t, H2'), 6.44 (br. t, H3'), 6.44 (br. t, H4'), 7.22 (br. t, H5').
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:30]([O:34][CH3:35])(=[O:33])[CH:31]=[CH2:32]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:16])[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:32][CH2:31][C:30]([O:34][CH3:35])=[O:33])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cc1ccccc1)c1cccc(OCc2ccccc2)c1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCC(C(=O)c1cccc(OCc2ccccc2)c1)c1ccccc1
Reaction time: 0.67 h
Yield: 90.3 %

Procedure:
A stirred solution of benzyl (3-benzyloxyphenyl) ketone (10 g) in tetrahydrofuran (100 mL) cooled at 0° C. is treated with potassium tert-butoxide (370 mg). After 40 minutes at 0° C., the mixture is treated with methyl acrylate (2.9 g) and stirring is continued at ambient temperature. The reaction is then concentrated under reduced pressure, partitioned between water and ethyl acetate and the organic layer is dried over magnesium sulphate. Concentration gives methyl (RS)-5-(3-benzyloxyphenyl)-5-oxo-4-phenylpentanoate (11.6 g), in the form of a colourless oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:12]1[C:16]([CH2:17]O)=[C:15]([Cl:19])[N:14]=[C:13]1[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH2:5]([N:12]1[C:16]([CH2:17][Cl:3])=[C:15]([Cl:19])[N:14]=[C:13]1[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)c(CO)n2Cc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2nc(Cl)c(CCl)n2Cc2ccccc2)cc1
Reaction time: 2.5 h

Procedure:
Thionyl chloride (0.90 ml, 1.48 g, 12.4 mmol) was added dropwise to a stirred suspension of 1-benzyl-4-chloro-5-(hydroxymethyl)-2(4-nitrophenyl)imidazole (18.5 g, 5.4 mmole) in chloroform (15 ml) at room temperature. The brown solution was stirred for 2.5 hours then evaporated to dryness. Toluene (12 ml) was added to the residue and evaporated to dryness. The residue was dissolved in chloroform (20 ml) and used in the next step for introduction of the cyano functional group.
Reaction SMILES: N1C(N)=NC(N)=NC=1N.[C:10]1(=[O:20])[O:15][C:13](=[O:14])[CH:12]2[CH2:16][CH2:17][CH:18]=[CH:19][CH:11]12.[OH2:21]>>[C:10]([OH:15])(=[O:20])[CH:11]1[CH:19]=[CH:18][CH2:17][CH2:16][CH:12]1[C:13]([OH:21])=[O:14]
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: O
Agent: Nc1nc(N)nc(N)n1
Product: O=C(O)C1C=CCCC1C(=O)O

Procedure:
In a beaker having an inner volume of 2 liters, 800 ml of deionized water was charged and, with stirring pieces immersed therein, was stirred and boiled on a stirrer provided with a hot plate. In this hot water, 12.6 g of melamine was thoroughly dissolved. Separately, in a beaker having an inner volume of one liter, 500 ml of deionized water was charged and, with stirring pieces immersed therein, was stirred and boiled on a stirrer provided with a hot plate. In this hot water, 15.2 g of tetrahydrophthalic anhydride was added and the resultant mixture was stirred for one hour with heating to give an aqueous solution of tetrahydrophthalic acid. This aqueous solution was added to the aqueous melamine solution mentioned above and the resultant mixture was stirred. The resultant mixed solution, when cooled with ice water, precipitates crystals. The crystals were separated by filtration and then dried in a vacuum drier. By the thermal analysis (DSC), the infrared absorption analysis and the titration with KOH performed in the same manner as in Synthesis Example 1, the crystals were confirmed to have formed a salt of melamine and tetrahydrophthalic acid at a molar ratio of 1:1. This salt will be referred to hereinafter as "melamine-THPA salt".
Reaction SMILES: NCC(O)=O.[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[F:20][C:21]1[CH:22]=[CH:23][C:24](I)=[C:25]([C:27](=[O:29])[CH3:28])[CH:26]=1>[Cu]I>[C:27]([C:25]1[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=1[N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])(=[O:29])[CH3:28]
Reactant: O=C1CCCN1
Reactant: CC(=O)c1cc(F)ccc1I
Agent: [Cu]I
Agent: NCC(=O)O
Agent: O=P([O-])([O-])[O-]
Product: CC(=O)c1cc(F)ccc1N1CCCC1=O
Temperature: 25 °C
Yield: 48.2 %

Procedure:
1,4-Dioxane (50 mL) was degassed by heating briefly to reflux and bubbling nitrogen gas through the solvent for 10 minutes, whilst it cooled to room temperature. CuI (180 mg, 5 mol %), glycine (284 mg, 20 mol %), 2-pyrrolidinone (1.73 mL, 22.73 mmol), K3PO4 (10.05 g, 47.35 mmol) and 1-(5-fluoro-2-iodo-phenyl)-ethanone (5.0 g, 18.94 mmol) were added sequentially to the solvent and the reaction mixture was heated at 100° C. under N2 for 10 hours. The reaction mixture was filtered through a celite plug, eluting with EtOAc and the filtrate was concentrated. The crude product was purified by flash chromatography (5% MeOH in DCM) to give the title compound (2.02 g, 48% yield) as a yellow oil
Reaction SMILES: O[C:2]1[C:3]([C:11]2([CH2:26][OH:27])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[CH2:20]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2([C:3]3=[CH:4][C:5]4[O:9][CH2:8][O:7][C:6]=4[CH:10]=[C:2]3[O:27][CH2:26]2)[C:12]1=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in Example 1, and making non-critical variations using 3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-pentyl-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (80%) as a white solid: mp 85-87° C.; 1H NMR (300 MHz, CDCl3)δ 7.28 (t, 1H), 7.15(d, 1H), 7.02 (t, 1H), 6.89 (d, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.84 (dd, 2H),4.77(ABq, 2H),3.85-3.62 (m, 2H), 1.76-1.66 (m, 2H), 1.40-1.33 (m, 4H), 0.89 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 177.3, 155.9, 148.8, 142.4, 142.3, 132.5, 128.9, 123.9, 119.6, 108.6, 103.0, 101.5, 93.6, 80.5, 58.2, 40.4, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 352 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][C:26]([CH3:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(CC)CC)C>CN(C)C=O>[CH3:38][C:26]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([CH2:25][CH2:24][CH2:23][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccccc1
Reactant: COC(=O)CC(C)(CCCBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccccc2)CC1)c1ccccc1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A solution of 0.634 g (0.002 mol) of biphenyl-2-carboxylic acid-piperidin-4-ylamide, 0.5 g (1.75 mmol) of methyl 5-bromo-2-methyl-2-phenyl-pentanecarboxylate and 1 ml (0.007 mol) of triethylamine are dissolved in 3 ml dimethylformamide. The mixture is stirred for 14 hours at 80° C. Then the reaction mixture is poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate. After column chromatography on silica gel (eluant: dichloromethane/methanol=10:1) colourless crystals remain.