Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O[CH2:3][CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([NH2:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[C:4]([CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)#[CH:3]
Reactant: O=C([O-])OCC=Cc1ccccc1
Reactant: Nc1cccc2ccccc12
Product: C#CC(Nc1cccc2ccccc12)c1ccccc1
Reaction time: 16 h
Yield: 83.4 %

Procedure:
The general procedure was followed with cinnamyl carbonate (0.188 g, 0.979 mmol) and 1-napthylamine (0.170 g, 1.18 mmol). The reaction was conducted at room temperature for 16 h. 1H NMR analysis of the crude reaction mixture indicated the ratio of regioisomers to be 98/2. The mixture was purified by flash column chromatography on silica gel (1.5% ethyl acetate in hexanes) to give the title compound (0.210 g, 83%). HPLC analysis indicated the enantiomeric excess of the product was 95% [Diacel CHIRALCEL OD-H (0.46 cm×25 cm); hexane/2-propanol=99/1; flow rate=0.6 mL/min; detection wavelength=254 μm; TR=29.3 (minor), 40.3 (major) min]: [α]DRT=(c, CHCl3). 1H NMR (400.13 MHz, CDCl3) δ 7.68 (dd, J=8.4, 1.6 Hz, 1H), 7.62 (dd, J=7.6, 2.0 Hz, 1H), 7.30-7.03 (m, 9H), 6.39 (dd, J=6.6, 1.8 Hz, 1H), 5.97 (ddd, J=17.2, 10.4, 6.0 Hz, 1H), 5.18 (dt, J=16.8, 1.2 Hz, 1H), 5.10 (dt, J=10.0, 1.2 hz, 1H), 4.95 (d, J=6.0 Hz, 1H), 4.57 (br s, 1H). 13C NMR (100.59 MHz, CDCl3) δ 141.95, 141.57, 138.88, 134.17, 128.74, 128.67, 127.46, 127.08, 126.41, 125.61, 124.69, 123.37, 119.79, 117.59, 116.25, 106.20, 60.86. Anal. Calcd for C19H17N: C, 87.99; H, 6.61; N, 5.40. Found: C, 88.07; H, 6.53; N, 5.49.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH2:21])[CH2:7][CH2:6]1)=[O:4].Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>CC#N>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:21][C:23]2=[O:25])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](CNCCc2ccccc2N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](CN2CCc3ccccc3NC2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of trans-4-{[2-(2-Amino-phenyl)-ethylamino]-methyl}-cyclohexanecarboxylic acid methyl ester (2.99 g, 7.97 mmol) in CH3CN (100 mL) at 0° C. under argon was added portion wise triphosgene (1.53 g, 5.15 mmol) over 30 min. The reaction mixture was stirred at 0° C. for 30 min, warmed to room temperature and stirred additionally for 7 h. Then an excess of TEA was added and a precipitate was formed. Solvent was removed under reduced pressure and the crude product purified by flash chromatography on silica to afford the titled compound (4.3 g, yield 59%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O=[C:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH:17]1[C:22](OC)=[O:23]>>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]3[C:16]4[CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[C:22](=[O:23])[O:13][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1CNCCC1=O
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: Cl
Product: O=c1oc2cc(-c3ccccc3)ccc2c2c1CNCC2
Yield: 54.1 %

Procedure:
Prepared by the method described for Example 1 from 3-phenylphenol (17 g, 0.1 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (19.3 g, 0.1 moles). The crude material is washed with water and dried to give the product (15 g), mp 250°-270° C.
Reaction SMILES: C(OC([N:7]1[C@:11]2([C@@H:16]([F:17])[CH2:15][C@@H:14]3[C@H:12]2[C@H:13]3[C:18]([OH:20])=[O:19])[C:10](=[O:21])[O:9]C1)=O)C=C.[C:22]([O:28][CH2:29]Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[NH2:7][C@@:11]1([C:10]([OH:9])=[O:21])[C@@H:16]([F:17])[CH2:15][C@@H:14]2[C@H:12]1[C@H:13]2[C:18]([O:20][CH2:29][O:28][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19]
Reactant: C=CCOC(=O)N1COC(=O)[C@]12[C@H]1[C@@H](C[C@@H]2F)[C@@H]1C(=O)O
Reactant: CC(C)(C)C(=O)OCCl
Product: CC(C)(C)C(=O)OCOC(=O)[C@H]1[C@@H]2C[C@H](F)[C@@](N)(C(=O)O)[C@@H]21
Yield: 14.8 %

Procedure:
(1S,2S,3S,5R,6S)-3′-((Allyloxy)carbonyl)-3-fluoro-5′-oxospiro[bicyclo[3.1.0]hexan-2,4′-oxazolidine]-6-carboxylic acid (A-1-2, 400 mg) and chloromethyl pivalate (193 mg) were treated in the same manner as in Example A-1 (3) and (4) to give the title compound (A-7, 60 mg) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][CH:7]([CH3:9])[CH3:8])=[CH:4][CH:3]=1.C(O)(=O)C.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>O>[CH:7]([N:6]([C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:9])[CH3:8]
Reactant: CC(C)Nc1ccc(Cl)cc1
Reactant: C=C1CC(=O)O1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)CC(=O)N(c1ccc(Cl)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 500 ml reaction flask fitted with a condenser, drying tube, magnetic stirrer and therometer was charged with 89.5 g (0.528 mole) of 4-chloro-N-isopropylaniline, 200 ml of glacial acetic acid and 18.5 g (0.58 mole) of mercuric acetate. To the stirred solution there was added dropwise 48.8 g (0.58 mole) of diketene while the reaction temperature was maintained at 30°-5°. The reaction solution was allowed to stir overnight at ambient temperature. The solution was mixed with two liters of water and twice extracted with ether. The organic phase was washed with water and dried over sodium sulfate. After removing the solvent, the liquid residue weighed 134 g (100%). N.M.R. (CDCl3) ∂1.0 and 1.2 (isopropyl, doublet), 1.8 (CH3, enol), 2.1 (CH3, keto), 3.2 (CH2), 4.7-5.2 (CH, isopropyl), 7.1-7.5 (aromatic).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH2:20]([Mg]Br)[CH3:21]>CCOCC>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)([OH:7])[CH2:20][CH3:21])[N:3]=[CH:2]1
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Reactant: CC[Mg]Br
Solvent: CCOCC
Product: CCC(O)(c1ccc2cc(OC)ccc2c1)c1c[nH]cn1

Procedure:
In a similar manner to that described in Example 1-(iv), the reaction of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.60 g) with a solution of ethyl magnesium bromide in ether (3.0 M, 2.4 ml) was carried out to give the titled compound (0.28 g) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:30]1[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(F)cc2nc1OC
Reactant: Cc1ccccc1N1CCNCC1
Product: COc1nc2cc(F)ccc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 77 %

Procedure:
Ethyl N-(6-fluoro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 85 to obtain the titled compound (yield, 77%). 1H NMR (200 MHz, CDCl3): δ 2.95 (s, 3H), 2.99-3.02 (m, 4H), 3.74-3.77 (m, 4H), 4.15 (s, 3H), 7.01-7.05 (m, 2H), 7.17-7.42 (m, 5H), 7.81-7.84 (m, 1H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[CH:9]=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[C:8]([CH3:14])[C:9]([Br:15])=[C:10]([CH3:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(C)cc(C)cc21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(=O)N1CCc2c1cc(C)c(Br)c2C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Acetyl-4,6-dimethylindoline (5.5 g) was dissolved in acetic acid (150 ml), and bromine (2.2 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour, and poured into ice water. The precipitated solid was collected by filtration, and recrystallized from methanol to give 6.5 g of the title compound (1).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.C([Sn](CCCC)(CCCC)C1[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=1)CCC>C1COCC1>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:5]([C:3]4[N:33]=[CH:34][N:35]([CH3:37])[CH:36]=4)[NH:6][C:7]([CH:8]=1)=[C:12]23)([CH3:25])([CH3:24])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Solvent: C1CCOC1
Product: Cn1cnc(-c2[nH]c3cc(NC(=O)OC(C)(C)C)cc4c3c2C=NNC4=O)c1
Temperature: 130 °C
Yield: 57.8 %

Procedure:
A mixture of intermediate 147(d) obtained from example 147 (184 mg, 0.5 mmol), 4-(tributylstannyl)-1-methyl-1H-imidazole (223 mg, 0.6 mmol) and Pd(PPh3)Cl2 (35 mg, 0.05 mmol) in THF (3 mL) was heated in a microwave oven (Personal Chemistry) for 2 hours at 130° C. The mixture was concentrated and the residue was purified by silica gel chromatography (5% MeOH/EtOAc) to give the title compound (110 mg, 0.289 mmol) in 59% yield as an orange powder.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O>C(Cl)Cl>[N:10]1([CH2:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: ClCc1ccncc1
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: c1cc(CN2CCOCC2)ccn1
Reaction time: 50 h
Yield: 84.4 %

Procedure:
A suspension of 4-picolyl chloride hydrochloride (10.0 g, 60.98 mmol) in 100 ml of methylene chloride at room temperature is treated with morpholine (26.52 g, 304.9 mmol, 5.0 equiv.) at once. After stirring for 50 h, the reaction mixture is poured into 250 ml of water, extracted six times with ethylacetate, three times with ethylacetate-methanol (9:1) and the combined organic extracts are dried over Na2SO4. The concentrated filtrate is chromatographed with 350 g of silica gel, packed and eluted with acetone-methylene chloride (1:2), to give 9.17 g (84%) of 4-(4-morpholinyl)methylpyridine as a yellow liquid.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]=[O:11]>>[OH:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: NC(=O)c1ccccc1
Product: O=C(NCO)c1ccccc1
Yield: 84 %

Procedure:
The compound N-(hydroxymethyl)benzamide is prepared in 84% yield from benzamide and formaldehyde using the procedure described by Monti, Gazz. Chim., 50: 39 (1930).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8](OC2C=CC=CC=2)=[N:9][C:10]#[N:11])=[CH:3][CH:2]=1.[NH2:19][NH2:20]>CO>[NH2:11][C:10]1[N:9]=[C:8]([O:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[NH:20][N:19]=1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Reactant: NN
Solvent: CO
Product: Nc1n[nH]c(Oc2ccccc2)n1
Reaction time: 2 h

Procedure:
Diphenylcyanocarbonimidate (9.53 g) and methanol (150 ml) were cooled to 0° C. and hydrazine (1.5 ml) was gradually added dropwise thereto. The mixture was stirred at 0° C.-room temperature for 2 hours. Methanol was distilled away under reduced pressure and the residue was subjected to silica gel column chromatography (chloroform-methanol) to quantitatively give white crystals.
Reaction SMILES: [CH3:1]N(C=O)C.[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:16])[CH:8]=1.C(=O)([O-])O.[K+].IC>O>[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:1])=[O:12])=[C:9]([OH:16])[CH:8]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(F)cc1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(F)cc1O
Reaction time: 0.17 h

Procedure:
1.1 50 ml of DMF are added under argon to 6.0 g of 4-fluoro-2-hydroxybenzoic acid and 4.52 g of potassium hydrogencarbonate, and the mixture is stirred for 10 minutes. 3.05 ml of iodomethane are added dropwise, and the mixture is stirred at 40° for 3 hours. The mixture is poured into 150 ml of water and subjected to conventional work-up, giving 6.48 g of methyl 4-fluoro-2-hydroxybenzoate (“1a”).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])[CH:5]=[C:6]([S:8]CC[Si](C)(C)C)[CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])[CH:5]=[C:6]([SH:8])[CH:7]=1
Reactant: C[Si](C)(C)CCSc1cc(F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: OC(c1cc(F)cc(S)c1)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Yield: 44.2 %

Procedure:
To a solution of 5-fluoro-3-(hexafluoro-2-hydroxyprop-2-yl)-1-(2-trimethylsilylethylthio)benzene (1 g, 2.54 mmol Step 2) in dry DMF (20 mL) was added tetrabutylammonium fluoride (1M in THF) (Aldrich) (6.4 mL, 6.4 mmol) and the reaction mixture was heated at 60° C. for 30 min.. The reaction mixture was then added to H2O and extracted with EtOAc. The combined organic phase were washed with brine, dried and evaporated to give a residue which was chromatographed on silica gel eluting with 8:2 mixture of hexane:EtOAc to afford the title compound (330 mg, 44%).
Reaction SMILES: [O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[O:1]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:13]=[CH:12][C:9](/[CH:10]=[CH:22]/[CH:23]=[O:24])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(-c2nnco2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1ccc(-c2nnco2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(1,3,4-oxadiazol-2-yl)benzaldehyde (prepared as described in Reference Example 77) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 201 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][CH:23]([CH2:26][OH:27])[CH2:24][OH:25]>>[OH:25][CH2:24][CH:23]([NH:22][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21])[CH2:26][OH:27]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: NC(CO)CO
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NC(CO)CO)cc2c1=O
Temperature: 150 °C
Yield: 28.6 %

Procedure:
A mixture of 100 mg (0.314 mmol) of N-(6-fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide and 142 mg (1.55 mmol) of 2-amino-1,3-propanediol in a closed vial is heated in a microwave reactor at 150° C. for 20 minutes. After cooling, the reaction mixture is concentrated to dryness and the product purified by HPLC-chromatography on a RP-C18 column using a gradient of water/acetonitril/0.1% TFA as eluent. 35 mg of the title compound are obtained as a red powder, m.p. 126-145° C. (decomp.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[N:3]=1.[CH2:13](Br)[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.CN(C)C=O>O>[C:16]1([C:14]2[N:1]=[C:2]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[NH:5][C:4](=[O:12])[N:3]3[CH:13]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Nc1nc(=O)[nH]c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2c2nc(-c3ccccc3)cn12
Temperature: 120 °C

Procedure:
1.61 g (0.01 mol) of 4-amino-2-quinazolinone and then 2.2 g (0.011 mol) of phenacyl bromide are added to 25 ml of dimethylformamide. The mixture is heated at 120° C. (external heating) for 3 hours, then left to cool and water is added. The brown precipitate formed is filtered out (1.34 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[CH:9][C:8]2=[O:22])([O:3]C)=[O:2].[O:23]1[CH:25]([CH2:26][CH3:27])[CH2:24]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:24][CH:25]([OH:23])[CH2:26][CH3:27])=[CH:9][C:8]2=[O:22])([OH:3])=[O:2]
Reactant: CCC1CO1
Reactant: COC(=O)c1ccc2oc(-c3ccccc3O)cc(=O)c2c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(O)COc1ccccc1-c1cc(=O)c2cc(C(=O)O)ccc2o1
Yield: 39.3 %

Procedure:
A mixture consisting of 6-carbomethoxy-2'-hydroxy-flavone (10 g), obtained according to the method described in Example 2, and 1,2-epoxy-butane (6 g) and benzyl-trimethylammonium hydroxide (0.5 ml) in dioxane (40 ml) was kept at reflux temperature for 48 hours. After cooling, dilution with water, and extraction with ethylacetate, the organic phase was washed with potassium carbonate 5% and water. The solution was evaporated to dryness, and the resulting product was treated with the stoichiometric quantity of a solution of potassium hydroxide 1% in ethanol 95% at reflux temperature for an hour. After acidification with acetic acid, concentration under vacuum, dilution with water, filtration and double crystallisation from ethanol, 6-carboxy-2'-(2-hydroxy-butoxy)-flavone (4.7 g) was obtained.
Reaction SMILES: [C:1]([NH:5][N:6]=[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20]Cl>CCCCC>[C:1]([N:5]=[N:6][C:7]1([Cl:20])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NN=C1CCCCC1
Reactant: ClCl
Solvent: CCN(CC)CC
Solvent: CCCCC
Product: CC(C)(C)N=NC1(Cl)CCCCC1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 252 grams (1.5 moles) of cyclohexanone t-butylhydrazone and 160 grams (1.5 moles) of triethylamine in 1200 ml pentane in a 3 liter 4 neck flask equipped with a mechanical stirrer, thermometer and gas inlet tube, was added 107 grams (1.5 moles) of chlorine gas, holding the temperature at -10° to 0° C. After the chlorine addition was complete, the reaction mixture was stirred an additional 15 minutes and the insoluble triethylamine hydrochloride filtered off. The filter cake was washed with an additional 300 ml pentane and the filtrate stripped of pentane under reduced pressure. The yield of 1-t-butylazo-1-chlorocyclohexane was 266 grams (87.5% crude yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4]([NH2:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21].C[O-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:4](=[N:11][C:20]([NH2:21])=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[Cl:12])[N:9]=2)[N:3]=1
Reactant: N#CCc1ccccc1Cl
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(N)c2nc(-c3ccccc3Cl)c(N)nc2n1

Procedure:
A stirred solution of 1.5 grams (0.010 mole) of 2,4,6-triamino-5-nitrosopyrimidine in 80 mL of N,N-dimethylformamide was heated to reflux, and 2.0 grams (0.01 3 mole) of 2-chlorophenylacetonitrile was added in one portion. Upon completion of addition, the reaction mixture was cooled, and 0.7 gram (0.013 mole) of sodium methoxide was added in one portion. The reaction mixture was again heated at reflux for 15 minutes. The reaction mixture was cooled in an ice-bath and then was filtered to collect a solid. The solid was slurried in diethyl ether and then was again collected by filtration, yielding, when dried, 2.5 grams of 2,4,7-triamino-6-(2-chlorophenyl)pteridine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=2[CH:21]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([SH:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([S:32][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH2:19][CH3:20])([CH2:17][CH3:18])[C:11]=3[CH:21]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: CCC1(CC)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: COc1ccc(S)cc1OC
Product: CCC1(CC)OC(=O)Nc2ccc(OCCCCSc3ccc(OC)c(OC)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-diethyl-4H-3,1-benzoxazin-2-one and 3,4-dimethoxy-thiophenol.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[S:23][CH:24]=[CH:25][C:18]=12>CN(C)C=O>[S:23]1[C:19]2=[N:20][CH:21]=[CH:22][C:17]([O:13][CH:10]3[CH2:9][CH2:8][CH:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH2:12][CH2:11]3)=[C:18]2[CH:25]=[CH:24]1
Reactant: OC1CCC(N2CCOCC2)CC1
Reactant: Clc1ccnc2sccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OC2CCC(N3CCOCC3)CC2)c2ccsc2n1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-(morpholin-4-yl)cyclohexan-1-ol (164 mg, 0.89 mmol, 1.50 equiv) in N,N-dimethylformamide (15 mL), sodium hydride (47 mg, 1.96 mmol, 2.00 equiv). The resulting mixture was stirred at 80° C. for 30 minutes. Then 4-chlorothieno[2,3-b]pyridine (100 mg, 0.59 mmol, 1.00 equiv) was added to the mixture. The resulting solution was stirred for 4 h at 120° C. in an oil bath. The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×15 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The crude product (120 mg) was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, CH3CN and water with 0.05% HCOOH (10.0% water with 0.05% HCOOH up to 50.0% in 10 min, up to 100.0% in 2 min, down to 10.0% in 2 min); Detector, uv 254/220 nm. This resulted in 72.2 mg (32%) of 4-(4-[thieno[2,3-b]pyridin-4-yloxy]cyclohexyl)morpholine as a white semi-solid. MS: (ES, m/z): 319.10 [M+H]+ 1H NMR (400 MHz, D2O, ppm): δ1.53-1.71 (m, 4H), 2.19-2.33 (dd, J1=29.7 Hz, J2=9.3 Hz, 4H), 3.24-3.30 (m, 3H), 3.51 (m, 2H), 4.07 (s, 2H), 4.60 (m, 1H), 6.98 (d, J=4.5 Hz, 1H), 7.37 (d, J=4.5 Hz, 1H), 7.52 (d, J=4.5 Hz, 1H), 8.33 (d, J=4.5 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([C:20]#N)[CH:9]1[CH2:22][CH2:23][CH:24]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[H-].C([Al+]CC(C)C)C(C)C.C(O)(=[O:49])C>C(OCC)C.C1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH:12]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[CH2:11][CH:10]([CH:20]=[O:49])[CH:9]1[CH2:22][CH2:23][CH:24]([O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(=O)O
Reactant: CCCCCC(CCC1C(C#N)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCCCCC(CCC1C(C=O)CC(OC2CCCCO2)C1OC1CCCCO1)OC1CCCCO1
Reaction time: 0.25 h

Procedure:
To a vigorously stirred solution of crude 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)-octyl]cyclopentane carbonitrile (7.9 g.) [prepared as described in (1) above] in dry diethyl ether (50 ml.) was added a solution of di-isobutylaluminium hydride (4.6 g.) in dry benzene (20 ml.) at 3°-7° C. The mixture was stirredat room temperature for 15 minutes and then added with stirring to aqueous 2N acetic acid solution (75 ml.) at below 15° C. The organic phase was separated, and the aqueous layer extracted with diethyl ether. The combined organic phases were washed with aqueous sodium bicarbonate and with water, dried over magnesium sulphate, and the solvents removed in vacuo to give crude 3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentane carbaldehyde (7.7 g.), which was used as starting material in the following preparation (n) of ethyl 7-{3,4-di(2-tetrahydropyranyloxy)-2-[3-(2-tetrahydropyranyloxy)octyl]cyclopentyl}hepta-2,4,6-trienoate without further purification.