Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([O:27]C)=[O:26])[CH:16]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>CO.C1COCC1.O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]3[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=3)[C:25]([OH:27])=[O:26])[CH:16]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a stirred solution of methyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoate (0.3 g, 0.72 mmol) in methanol/THF (2/2, 4 mL) was added LiOH (0.122 g, 2.9 mmol) in H2O (4 mL) and the reaction mixture was stirred at rt for 2 h. It was concentrated under reduced pressure. the residue was diluted with water (2 mL) and was extracted with dichloromethane (5 mL). The aqueous layer was separated and was acidified with 1.5 N HCl (pH ˜5-6) to get a white precipitate, which was collected by filtration and dried under vacuum to give 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoic acid (0.2 g 69%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][NH:18]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:25]1([S:31]([Cl:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>CN(C)C=O.O>[ClH:34].[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][N:18]3[S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1ccc(CN2CCN(c3cccc4[nH]ncc34)CC2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: O=S(=O)(c1ccccc1)n1ncc2c(N3CCN(Cc4ccccc4)CC3)cccc21
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
A solution of 4-(4-benzylpiperazin-1-yl)-1H-indazole (2.34 g, 8.00 mmol) in dry dimethyl formamide is treated with 0.48 g unwashed 60% NaH in mineral oil (12.0 mmol of NaH). After stirring under nitrogen for 15 min, the reaction is treated with benzenesulfonylchloride (1.53 mL, 12.0 mmol), stirred for 24 hr at ambient temperature, treated with saturated aqueous NaHCO3 and water and extracted with ether. The organic layer is washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a residue. The residue is purified by flash chromatography on silica gel using 1:1 ethyl acetate:hexanes as eluant to afford the free amine of the title compound as an oil (3.14 g, 91%). A portion of this oil (432 mg, 1.0 mmol) is dissolved in ether and treated with 1.0M HCl in ether (1.1 mL, 1.1 mmol). The resulting solid is filtered, washed with ether, and dried under vacuum to provide the title compound as a light tan solid, mp 208-209° C., identified by HNMR and mass spectral analyses.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[OH-].[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O.CO>[C:1]([O-:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:8]([N+:15]([CH3:18])([CH3:17])[CH3:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: O=C([O-])C(=O)O

Procedure:
Oxalic acid in an amount of 21.56 g (0.239 mol) was dissolved in acetone, making a total of 100 g. The resultant solution was mixed with 100 g of 40% by weight solution of benzyltrimethylammonium hydroxide (0.261 mol) in methanol (produced by Tokyo Kasei Kogyo Co., Ltd.), and then 1500 g of acetone was added to the resultant mixture to form white precipitate. Subsequently, the precipitate was collected by means of suction filtration method, dispersed in 500 g of acetone and filtered to collect cake. The resultant cake was subjected to drying treatment under vacuum at 80° C. for 24 hours to form 46.80 g (0.208 mol) of mono(benzyltrimethylammonium) oxalate at a yield of 87.0% based on the fed oxalic acid. The resultant mono(benzyltrimethylammonium) oxalate, which had a melting point of about 130° C. in a stream of nitrogen, was thermally decomposed in a stream of nitrogen at about 230° C. with a latent heat of fusion of about 123 J/g.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18](O)=[O:19])[N:14]3[CH3:17])=[C:10]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)[CH3:2].[C:31]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([N:35]1[CH2:40][CH2:39][N:38]([C:18]([C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)=[O:19])[CH2:37][CH2:36]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)O)n(C)c2n1
Reactant: CC(C)(C)N1CCNCC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)N3CCN(C(C)(C)C)CC3)n(C)c2n1

Procedure:
Following General Procedure K, 2-(2-Ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purine-8-carboxylic acid was coupled with 1-tert-butylpiperazine according to General Procedure K to give 567. LCMS m/z: 266.7 (2M+H+)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([OH:13])=[O:12].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[S:25][C:24]([CH:26]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:29])=[O:28])=[CH:23][C:22]=2[CH:33]=1.[CH2:34]([C:41]1[N:46]=[C:45]([CH2:47]O)[CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([CH:14]([CH3:16])[CH3:15])[C:11]([O:13][CH2:47][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:46]=1)=[O:12].[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[S:25][C:24]([CH:26]([CH:30]([CH3:31])[CH3:32])[C:27]([O:29][CH2:47][C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:46]=3)=[O:28])=[CH:23][C:22]=2[CH:33]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: OCc1cccc(Cc2ccccc2)n1
Reactant: CC(C)C(C(=O)O)c1cc2ccccc2s1
Product: CC(C)C(C(=O)OCc1cccc(Cc2ccccc2)n1)c1cc2cc(Cl)ccc2s1
Product: CC(C)C(C(=O)OCc1cccc(Cc2ccccc2)n1)c1cc2ccccc2s1

Procedure:
Following the procedure of Example 12, the acid chloride of each of 2-(2-benzothienyl)-3-methylbutanoic acid and 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid is reacted with (6-benzyl-2-pyridyl)methanol to yield (6-benzyl-2-pyridyl)methyl 2-(2-benzothienyl)-3-methylbutanoate and (6-benzyl-2-pyridyl)methyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:4].[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14].C(N(C(C)C)CC)(C)C>C(#N)C>[CH2:13]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:4])[CH3:14]
Reactant: CCNc1ccccc1
Reactant: O=C(CCl)Nc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN(CC(=O)Nc1ccc(O)cc1)c1ccccc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 40.7 %

Procedure:
To a solution of compound 17a (250 mg, 1.35 mmol) and N-ethylaniline (0.326 mg, 2.69 mmol) in acetonitrile (6.0 mL) was added diisopropylethylamine (0.55 mL, 4.04 mmol) dropwise. After the addition was complete, the reaction was stirred at 60° C. for 12 hours. The reaction mixture was concentrated and purified by column chromatography to isolate the compound 17 as a colorless oil (150 mg, 0.55 mmol 41% yield). MS (ESI, positive) m/z calcd. for C16H19N2O2 [M+H]+: 271.14, found: 270.95. 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 7.27-7.31 (m, 4H), 6.88 (t, J=7.2 Hz, 1H), 6.80 (t, J=8.4 Hz, 4H), 3.96 (s, 2H), 3.53 (q, J1=J2=7.2, 2H), 2.20 (s, 1H), 1.24 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:32])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1>CC(CC)=O>[ClH:1].[CH3:32][N:8]([CH3:7])[C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:10][CH2:11][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[O:17])[CH2:13][CH2:14]1
Reactant: C[Si](C)(C)Cl
Agent: Cc1ccc(NC(=O)CC2CCC(c3ccccc3)(N(C)C)CC2)cc1
Solvent: O
Solvent: CCC(C)=O
Product: Cl

Procedure:
Chlorotrimethylsilane (0.477 ml) and water (34 μl) were added to a solution of the more polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-p-tolyl-acetamide (1.2 g, 3.4 mmol) in ethyl methyl ketone (10 ml). The hydrochloride was extracted as an oil with hexane and isolated in a yield of 78% (1.04 g; 2.7 mmol) (Example 60).
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][C:5]1[CH2:10][CH2:9][C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[CH:6]=1.Cl>CCOCC.[Cu]I>[CH3:11][C:8]1([CH3:12])[CH2:9][CH2:10][C:5]([CH3:2])([CH3:4])[CH2:6][C:7]1=[O:13]
Reactant: CC1=CC(=O)C(C)(C)CC1
Reactant: CI
Agent: [Cu]I
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)C(=O)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
5.3 g of magnesium shavings are covered with 100 ml of ether and 30.8 g of methyl iodide are added dropwise in such a manner that the mixture boils slightly. After the addition of 100 ml of ether, the mixture is held at reflux temperature for a further 3 hours, cooled by means of an ice-bath and treated with 20.7 g of copper (I) iodide. After stirring for 15 minutes at 0° C., a solution of 10 g of 3,6,6-trimethyl-2-cyclohexenone in 40 ml of ether is added and the mixture is stirred at 0° C. for a further 3 hours. The green suspension is subsequently poured on to ice, acidified with 2N hydrochloric acid and extracted with ether. The insoluble constituents of the organic phase are filtered off, the filtrate is washed with dilute sodium thiosulphate solution, dried and evaporated. After distillation of the crude product, there are obtained 8.5 g of 2,2,5,5-tetramethylcyclohexanone as a colourless liquid of boiling point 60°-67° C./13 mm Hg.
Reaction SMILES: C(O[C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)C.O1CCCC1.[NH2-].[Na+].[CH2:29]([N:31]=[C:32]=[O:33])[CH3:30]>O>[N+:18]([C:14]1[CH:13]=[C:12]([N:11]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:5]=3[C:4](=[O:21])[N:31]([CH2:29][CH3:30])[C:32]2=[O:33])[CH:17]=[CH:16][CH:15]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)c1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: CCN=C=O
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c(=O)c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 1 h
Yield: 54.9 %

Procedure:
To a solution of 5.7 g of 2-(m-nitroanilino)nicotinic acid ethyl ester and 50 ml of dry tetrahydrofuran was added 1.1 g of sodium amide and the solution was stirred for one hour. To this was added dropwise under cooling 2.9 g of ethyl isocyanate and this mixture was reacted at 60°C for 10 hours. After the reaction was complete, the solvent was distilled off from the mixture, and to the residue obtained was added water to precipitate a crude product. This product was collected by filtration and recrystallized from methanol to give 3.4 g of 1-(m-nitrophenyl)-3-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as colorless needles, melting at 210°-211°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[N+:31]([C:33]([CH3:36])([CH3:35])[CH3:34])#[C-:32]>CO>[Br:1][C:2]1[C:3]2[N:4]([C:32]([NH:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[C:14]([C:13]3[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=3)[N:9]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1ncc(Cl)cc1Br
Reactant: O=Cc1cccc(Cl)c1
Reactant: [C-]#[N+]C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(C)(C)Nc1c(-c2cccc(Cl)c2)nc2c(Br)cc(Cl)cn12
Reaction time: 0.08 h
Yield: 12.1 %

Procedure:
3-bromo-5-chloropyridin-2-amine (200 mg, 964 μmol, Eq: 1.00), 3-chlorobenzaldehyde (142 mg, 115 μl, 1.01 mmol, Eq: 1.05) and p-toluenesulfonic acid monohydrate (55.0 mg, 289 μmol, Eq: 0.3) were dissolved in MeOH (1.5 mL) and the intensive yellow solution was stirred for 5 min. To this yellow solution was added dropwise 2-isocyano-2-methylpropane (80.1 mg, 110 μL, 964 μmol, Eq: 1.00) and the corresponding yellow solution was stirred for 3 h. The solvent was removed and the oily residue was treated with dichloromethane and filtered over a cartridge. Two fractions were taken. From fraction 1 the product crystallized after treatment with DMSO-d6. The crystals were filtered off, washed with water and dried under high vacuum to yield the product (48 mg, 12.1%). LC/MS (acid polar): 413.0 [M]+; 1H-NMR (CDCl3): δ 8.62 (s, 1H), 8.26 (s, 1H), 8.17 (d, 1H), 7.65 (s, 1H), 7.43 (t, 1H), 7.34 (d, 1H), 4.91 (s, 1H), 1.03 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9](O)=[O:10])([O-:3])=[O:2].C(OCC)(=O)C.S(Cl)([Cl:23])=O.Cl>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([Cl:23])=[O:10])([O-:3])=[O:2]
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1cccc([N+](=O)[O-])c1
Yield: 96.9 %

Procedure:
193.2 g (1 mole) of 3-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and poured into hexane. The precipitate was separated by filtration and dried. 205 g of 3-nitrocinnamoyl chloride was yielded.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[N:25][CH:26]=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.[CH2:50]([N:57]1[CH2:61][CH:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)[CH:59]([CH:70](O)[CH3:71])[CH2:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C1COCC1>[CH2:50]([N:57]1[CH2:61][CH:60]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[C:64]([Cl:69])[CH:63]=2)[CH:59]([CH:70]([O:27][C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][N:25]=2)[CH3:71])[CH2:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(O)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(Cl)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a suspension of PPh3 (PPh3 polymer bound, 3 mmol PPh3/g resin) (3.14 g, 9.4 mmol) in THF (70 mL) at 0° C. were added 5-chloro-pyridin-2-ol (0.832 g, 6.42 mmol) and then DBAD (1.578 g, 6.85 mmol). After 5 minutes was added (SR)-1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanol (X-B-1) (1.50 g, 4.28 mmol). The reaction mixture was stirred over night at RT, filtered on celite and concentrated under vacuo. Extraction with EtOAc/aq.NaOH 1M, followed by column chromatography (SiO2, EtOAc/H, 1:6) yielded 1.71 g (87%) of the title compound as a colorless oil. ES-MS m/e: 461.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13]1[C:14](=O)[C:15](=[O:20])[C:16]=1[O:17]CC)[CH3:11]>C(O)C>[O:17]=[C:16]1[C:15](=[O:20])[C:14]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[C:13]1[O:12][CH2:10][CH3:11]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccc(C#N)cc2)c(=O)c1=O

Procedure:
4-Aminobenzonitrile (17.58 g, 149 mmol) was added to a solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (25.31 g, 149 mmol) in absolute ethanol (450 mL). The mixture was heated at reflux overnight and the resulting suspension filtered hot to remove a small amount of a dirty yellow solid (discarded). The filtrate was gradually concentrated to afford several crops of 4-(3,4-dioxo-2-ethoxy-cyclobut-1-enylamino)benzonitrile, as a bright yellow solid, which were collected by filtration and combined. Yield: 29.11 g (81%): 1H NMR (DMSO-d6): δ11.07 (s, 1H), 7.81 (d, 2H), 7.56 (d, 2H), 4.79 (q, 2H), 1.46 (t, 3H).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[CH2:15]([N:22]1[CH2:27]CC(=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N>CO>[CH2:15]([N:22]1[CH2:23][CH2:24][C:3]2[N:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: O=[N+]([O-])c1cnc2c(c1)CN(Cc1ccccc1)CC2
Yield: 49.7 %

Procedure:
A mixture of 1-methyl-3,5-dinitro-2-pyridone (1.2 g, 6.0 mmol), 1-benzyl-4-piperidone (1.12 g, 5.9 mmol) and ammonia solution in methanol (2.0M, 60 mL) was refluxed for 3 h. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The soluble portion was flash chromatographed over silica gel (eluent: 90:1 v/v ethyl acetate-hexane) to give a yellow solid (0.79 g, 49.7% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH:14]=[N:13][C:12]=3[CH:16]=2)[CH2:7][CH2:6]1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].O>CCS>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]3([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]3)=[CH:16][C:12]=2[N:13]=[CH:14]1
Reactant: COC(=O)C1(c2ccc3ocnc3c2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: O
Product: O=C(O)C1(c2ccc3ocnc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
To a solution of crude 1-benzooxazol-5-yl-cyclopropanecarboxylic acid methyl ester (2.9 g) in EtSH (30 mL) was added AlCl3 (5.3 g, 40.1 mmol) in portions at 0° C. The reaction mixture was stirred for 18 hours at room temperature. Water (20 mL) was added dropwise at 0° C. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/EtOAc 1:2) to give 1-(benzo[d]oxazol-5-yl)cyclopropanecarboxylic acid (280 mg, two steps: 11%). NMR (DMSO, 400 MHz) δ 12.25 (brs, 1H), 8.71 (s, 1H), 7.70-7.64 (m, 2H), 7.40 (dd, J=1.6, 8.4 Hz, 1H), 1.49-1.46 (m, 2H), 1.21-1.18 (m, 2H). MS (ESI) m/e (M+H+) 204.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=2)[CH:10]=[C:9]1[C:25]1[CH:30]=[C:29](Cl)[N:28]=[N:27][C:26]=1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[C:37]([CH3:50])[C:36]=1[OH:51].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:15]=2)[CH:10]=[C:9]1[C:25]1[CH:30]=[C:29]([C:39]2[CH:38]=[C:37]([CH3:50])[C:36]([OH:51])=[C:35]([CH3:34])[CH:40]=2)[N:28]=[N:27][C:26]=1[O:32][CH3:33])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1O
Reactant: COc1nnc(Cl)cc1-c1cc2ccc(CN3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CN3CCN(C)CC3)cc2n1C(=O)OC(C)(C)C
Yield: 90.7 %

Procedure:
500 mg 2-(6-Chloro-3-methoxy-pyridazin-4-yl)-6-(4-methyl-piperazin-1-ylmethyl)-indole-1-carboxylic acid tert-butyl ester, 233 mg 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 180 mg sodium carbonate, and 98 mg tetrakis(triphenylphosphine)palladium(0) are dissolved in a mixture of 6.7 mL dimethoxyethane and 0.85 mL water. Argon is bubbled through the solution for 5 minutes. The mixture is heated to reflux for 5 hours. After diluting with EtOAc, the organic phase is washed with water and brine, dried with MgSO4 and concentrated in vacuo. 475 mg crude product are obtained.
Reaction SMILES: C(O)(=[O:10])C=CC1C=CC=CC=1.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.NCCC[Si](OC)(OC)OC>>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:10])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CO[Si](CCCN)(OC)OC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
40 g of cinnamic acid and 50 g of dicyclohexylcarbodiimide were added to a 1 L round 3-necked flask equipped with a dropping funnel and a cooler, and also 600 mL of toluene newly distilled from sodium ketyl was added thereto, and the resultant mixture was refluxed to yield a homogeneous solution. After about 30 minutes, 48 g of 3-aminopropyltrimethoxysilane was dropped over 30 minutes through the dropping funnel. The resultant reaction mixture was refluxed for 4 hours, and then toluene was removed by vacuum distillation without contacting with moisture. Dicyclohexyl urea formed in a remaining solution was removed by filtration to yield a product. The resultant product was determined using FT-IR and thin layer chromatography. Yield of the resultant product is about 30 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>ClCCl.O>[Cl:16][CH2:17][CH2:18][C:19]([NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([F:1])[CH:3]=1)=[O:20]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc(F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCl)Nc1cccc(F)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-fluoroaniline (20 g, 0.180 mol) in dichloromethane (100 mL) was added triethylamine (21.816 g, 0.216 mol) and 3-chloropropanoyl chloride (17.18 mL, 0.180 mol) under cooling condition (0° C.) with constant stirring. Reaction mass was allowed to stir at room temperature for 12 h. The reaction mixture was diluted with water (300 mL) and extracted with dichloromethane (4×100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. 1H NMR (400 MHz, CDCl3) δ 7.51-7.48 (d, J=10.4 Hz, 1H), 7.42 (bs, 1H), 7.29-7.24 (dd, J=14.8 Hz, 8.0 Hz, 1H), 7.15-7.13 (d, J=8.0 Hz, 1H), 6.84-6.81 (t, J=6.8 Hz, 1H), 3.89-3.86 (t, J=6.4 Hz, 2H), 2.83-2.80 (t, J=6.4 Hz, 2H). MS (M+1): 201.9.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([CH2:14][C:15]([NH2:17])=[O:16])#[N:13]>N1CCCCC1.Cl.C(O)C>[C:12]([C:14](=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)[C:15]([NH2:17])=[O:16])#[N:13]
Reactant: COc1cc(C=O)ccc1O
Reactant: N#CCC(N)=O
Agent: Cl
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=C(C#N)C(N)=O)ccc1O
Temperature: 25 °C

Procedure:
A reaction mixture of vanillin (1.52 g, 0.01 mol), α-cyanoacetamide (0.84 g, 0.01 mol), ethanol (25 mL) and piperidine (6 drops) is heated at reflux for 1 hour and then allowed to cool to room temperature. The reaction mixture is acidified to pH of about 3-4 by addition of a few drops of concentrated HCl. The product which is collected by filtration, washed with ethanol and dried in air has the following structure supported by mass spectrometry: ##STR23## The yield of product is 1.5 g (68.8%). In methylene chloride the product has an absorption maximum of 352 nm.