Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)C.C([NH:13][C:14]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)=[S:15])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:24]1[CH:25]=[C:21]([CH2:20][S:19][CH2:18][CH2:17][NH:16][C:14]([NH2:13])=[S:15])[N:22]=[CH:23]1
Reactant: O=C(NC(=S)NCCSCc1c[nH]cn1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: NC(=S)NCCSCc1c[nH]cn1
Yield: 61.7 %

Procedure:
A solution of 4(5)-[(2-aminoethyl)thiomethyl]imidazole (6.0 g.) and benzoyl isothiocyanate (6.0 g.) in chloroform (150 ml.) was heated under reflux for one hour. Concentration followed by recrystallisation from ethyl acetate-isopropyl acetate afforded N-benzoyl-N'-[2-(4-imidazolylmehylthio)-ethyl]thiourea (7.5 g.). An analytically pure sample (from aqueous isopropyl alcohol) had m.p. 126°-128°. (ii) The benzoyl thiourea (6.0 g.) was added to a solution of potassium carbonate (1.4 g.) in water (80 ml.), at 60°. The solution was maintained at this temperature for one hour, concentrated to low bulk and acidified with hydrochloric acid. Benzoic acid was removed by filtration and the filtrate was basified with potassium carbonate and concentrated under reduced pressure. Following extraction with isopropyl alcohl and concentration, the product was crystallised from isopropyl acetate. Recrystallisation from water gave N-[2-(4-imidazolylmethylthio)ethyl]thiourea (2.5 g.) m.p. 135°-137°. (Found: C, 38.9; H, 5.5; N, 26.1; S, 29.6. C7H12N4S2 requires: C, 38.9; H, 5.6; N; 25.9; S, 29.6).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5])C.[ClH:13]>>[ClH:13].[CH3:12][N:9]1[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)C1CCN(C)CC1
Agent: Cl
Product: CN1CCC(C(=O)O)CC1
Yield: 48 %

Procedure:
A solution of 1-methyl-piperidine-4-carboxylic acid ethyl ester (2.0 g, 11.7 mmol) in conc. hydrochloric acid (20 mL) was heated to 100° C. and maintained for 6 h. The mixture was then concentrated to dryness in vacuo to give a solid, which was washed with acetonitrile-diethyl ether (1:1) and dried in vacuo to afford 1-methyl-piperidine-4-carboxylic acid hydrochloride (1.0 g, 48%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:11]([CH3:12])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(O)[C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=2)[CH2:3]1>Cl>[CH3:1][N:2]1[CH:11]([CH3:12])[CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]2[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COc1ccc2c(c1)CN(C)C(C)C2(O)c1ccccc1
Agent: Cl
Product: COc1ccc2c(c1)CN(C)C(C)C2c1ccccc1
Reaction time: 16 h

Procedure:
Saturated ethanolic hydrogen chloride (800 ml) was added to (7) (21 g) and the solution was refluxed for 2 hr. and left to stand at room temperature for 16 hr. Ethanol was removed under reduced pressure, the residue was taken up in methanol and sodium borohydride (30 g) added portion-wise. Methanol was removed under reduced pressure and the residue taken up in water and ether. The aqueous layer was extracted with ether and the combined ether layers extracted with dilute sulphuric acid(2N). The acid layers were basified and extracted with ether. The combined ether layers were dried (MgSO4). Removal of the solvent under reduced pressure gave the title compound as an oil.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1.C(N(CC)CC)C>C(OCC)(=O)C>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([NH:1][N:2]2[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]2)=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CN1CCN(N)CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(Nc2ccc(Br)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
Heat a mixture of 1-amino-4-methyl piperazine (0.217 mol, 25.0 g), 5-bromo-2-fluoronitrobenzene (0.239 mol, 52.6 g) and triethylamine (0.46 mol, 46 g) in ethyl acetate (900 mL) to reflux for 16 h. Cool the reaction mixture to room temperature, dilute with ethyl acetate, and wash with water and brine. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Purify on a silica gel column using 5% methanol in dichloromethane as eluent to give the title compound (43.2 g, 63%). ES-MS m/z 315 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][CH:17]=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(C2=CCNc3ccnn32)c1
Yield: 24.6 %

Procedure:
To a stirred mixture of 25.0 g of 7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine in 250 ml of glacial acetic acid, at room temperature, under nitrogen was added portionwise 14.92 g of sodium cyanoborohydride. The resultant solution was stirred for 24 hours, and then was evaporated in vacuo to give an oil. The oil was dissolved in chloroform and washed with saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give a semi-solid which was chromatographed on a silica gel column using a mixture of 25% ethyl acetate and 75% hexane as the solvent system. The product fraction was collected and evaporated to give 6.2 g of the desired product as orange crystals, mp 61°-64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH:18][CH3:19]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([N:18]([CH3:19])[CH3:17])=[O:10])[CH2:6]1
Reactant: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Reactant: CNC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1OC1CN(C(=O)N(C)C)C1
Reaction time: 72 h

Procedure:
A stirred solution of 3.9 g (0.015 mole) of 3-(2-chloro-6-methylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 5.1 mL (0.045 mole) of 40% aqueous dimethylamine. After stirring for 72 h the raction mixture was diluted with 200 mL of water and the oil which separated was extracted into methylene chloride (3×30 mL). The combined extracts were dried by filtering through Whatman PS paper and concentrated in vacuo (3.6 g). The crude oil solidified when cooled in a dry ice/acetone bath and was recrystallized from ethyl ether in a dry ice-acetone bath yielding, after filtering cold, 2.6 g (64.5%) of coarse white crystals, mp 46°-47° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][NH2:16])=[N:13][CH:14]=1>C(Cl)Cl>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][NH:16][C:5](=[O:7])[CH3:6])=[N:13][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: NNc1ccc(Br)cn1
Solvent: ClCCl
Product: CC(=O)NNc1ccc(Br)cn1
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Acetic anhydride (1.13 mL, 12.0 mmol) was added to a solution of 5-bromo-2-hydrazinylpyridine (1.90 g, 10.0 mmol) and TEA (2.09 mL, 15.0 mmol) in DCM (200 mL). After 16 hours, the reaction mixture was concentrated by rotoevaporation and the residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with water and brine, dried with Na2SO4, and the solvent was removed under vacuum. The resulting residue was triturated with DCM to afford the title compound as a white solid (1.86 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25](Cl)=O)[CH3:22]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH:15]4[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]4)[C:22]([CH2:21][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: Nc1cnc2cc(Br)ccc2c1NCC1CCCCC1
Reactant: CCOCC(=O)Cl
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CC1CCCCC1
Temperature: 90 °C

Procedure:
A modification of the method described in Part A of Example 9 was used to treat 7-bromo-N4-(cyclohexylmethyl)quinoline-3,4-diamine (7.3 g, 22 mmol) with ethoxyacetyl chloride (2.75 mL, 24.0 mmol). The reaction was heated overnight at 90° C. and then concentrated under reduced pressure to provide 7-bromo-1-cylcohexylmethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline as a dark brown semi-solid.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[N:3]=1.[Cl-].[NH4+:11]>CO>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([NH2:11])=[NH:9])[N:3]=1
Reactant: [NH4+]
Reactant: N#Cc1cccnn1
Agent: [Cl-]
Agent: [Na]
Solvent: CO
Product: N=C(N)c1cccnn1
Temperature: 35 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 1.60 g (0.068 mol) of sodium in 300 ml of anhydrous methanol was treated with a solution of 53.5 g (0.510 mol) of pyridazine-3-carbonitrile in 100 ml of methanol and the mixture was stirred for 8 hours at 35° C. Then, 29 g of ammonium chloride were added and the mixture was refluxed for approximately 14 hours. The hot mixture was filtered and the solid was discarded. 53.3 g of the title compound were obtained from the cold mother liquor by means of filtration.
Reaction SMILES: N[CH:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=[O:28].Cl>C(N(CC)CC)C>[O:28]=[C:2]1[C:23](=[O:24])[N:4]2[C:5]([C:10]([O:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[O:11])=[C:6]([Cl:9])[CH2:7][S:8][C@H:3]12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Cl)CS[C@@H]2C(=O)C(=O)N12

Procedure:
4-Nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate, trifluoromethanesulfonic anhydride, triethylamine and hydrochloric acid were reacted in the same manners as those of Examples 1-4 to give 4-nitrobenzyl 7-oxo-3-chloro-3-cephem-4-carboxylate (monohydrate). Mp. 105°-106° C. (dec.).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:10]([NH2:9])=[S:11])=[CH:15][C:14]=1[O:20][CH3:21]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NC(N)=S)ccc1Cl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Benzoyl isothiocyanate (8.8 mL, 64 mmol) was added dropwise to a solution of 4-chloro-3-methoxy-benzenamine (10 g, 63 mmol) in 160 mL THF. The mixture was stirred at room temperature for 40 minutes, volatiles were removed and the residue was dissolved in 400 mL methanol. A solution of potassium carbonate (26.3 g, 190 mmol) in 200 mL water was added and the mixture was stirred at room temperature for 90 minutes. The tide product (13.5 g, 98%) precipitated after removal of 450 mL of the solvents.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=O)=[CH:5][CH:4]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]=[C:10]2[NH:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(NCc1ccccc1)=CCC2
Temperature: 25 °C

Procedure:
A mixture containing 7-methoxytetralone (25.0 g), benzylamine (15.8 mL), toluene and 4 Å molecular sieves (42.0 g) was heated at reflux for 3.5 h. The mixture was cooled to room temperature, filtered through a layer of Florisil® and concentrated under reduced pressure to yield 42.1 g of crude title compound of Step A.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([OH:33])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].O[C:35]1[CH:36]=[CH:37][C:38]2[CH2:44][CH2:43][CH2:42][C:41]([C:45]([O:47][CH3:48])=[O:46])=[CH:40][C:39]=2[CH:49]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([O:33][C:35]2[CH:36]=[CH:37][C:38]3[CH2:44][CH2:43][CH2:42][C:41]([C:45]([O:47][CH3:48])=[O:46])=[CH:40][C:39]=3[CH:49]=2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(OC3CCN(C(=O)OC(C)(C)C)CC3)ccc2CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.4 %

Procedure:
To triphenylphosphine (2361 mg, 9.00 mmol), 1-tert-butoxycarbonyl-4-hydroxypiperidine (1812 mg, 9.00 mmol) and methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (655 mg, 3.00 mmol) dissolved in THF (15 ml) was added at 0° C. a solution of diisopropyl azodicarboxylate (1.772 ml, 9.00 mmol) in THF (2 ml), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography (silica gel: 70 g, ethyl acetate/hexane=1/9→1/7). The objective fractions were concentrated under reduced pressure to obtain methyl 2-[(1-tert-butoxycarbonylpiperidin-4-yl)oxy]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1270 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)=[O:10])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]([Si](C)(C)C)([F:28])[F:27].[F-].C[N+](C)(C)C>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:23])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:19][CH2:18][C:17](=[O:20])[N:16]([CH3:21])[C:15]=3[CH:22]=2)([OH:10])[C:26]([F:28])([F:27])[F:25])=[C:4]([Cl:24])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C(=O)c1ccc2c(c1)N(C)C(=O)CO2)c1ccc(Br)cc1Cl
Agent: C[N+](C)(C)C
Agent: [F-]
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 1, step 3, 6-[2-(4-bromo-2-chloro-phenyl)-propionyl]-4-methyl-4H-benzo[1,4]oxazin-3-one was reacted with (trifluoromethyl)trimethylsilane and tetramethylammonium fluoride to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=475.9 [M−H+].
Reaction SMILES: [NH2:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].[N:23]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][CH2:35][C@@H:24]1[C:25](ON1C(=O)CCC1=O)=[O:26]>>[N:23]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][CH2:35][C@@H:24]1[C:25]([NH:1][C@H:2]([C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)ON1C(=O)CCC1=O
Reactant: N=C(NCCC[C@H](N)C(=O)OCc1ccccc1)N[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared as an oily product from 9 g of H-Arg(NO2)-OBzl and 9 g of Boc-D-Pro-OSu in the same manner as in Example 7-(1).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3].[CH:28]1(Br)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.Cl>CN(C=O)C>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:23]([CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:24]([O:26][CH3:27])=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: BrC1CCCCC1
Reactant: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc(OCc2ccc3ccccc3n2)c(CC(C)C)c1)C1CCCCC1
Temperature: 0 °C

Procedure:
12 g (0.003 mol) of methyl 2-[3-isobutyl-4-(quinolin-2-yl-methoxy)phenyl]acetate and 6.52 g (0.04 mol)=4.9 ml of cyclohexyl bromide are dissolved in 36 ml of DMF under an argon atmosphere and the solution is cooled to 0° C. 4.88 g (0.04 mol) of potassium tertiary butylate, dissolved in 80 ml of DMF, are added dropwise thereto with stirring. After a reaction time of about 2 hours the temperature is allowed to rise to RT and the mixture is acidified with 2N hydrochloric acid and evaporated to dryness in vacuo. The remaining residue is extracted with 100 ml of dichloromethane and 50 ml of water, the organic phase is separated off, dried with Na2SO4, evaporated to a small volume in vacuo and the remaining residue is separated by column chromatography (silica gel 60, mobile solvent: dichloromethane/ethyl acetate=100/2).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.Cl.CN.[CH:22]([N:25](CC)C(C)C)(C)C>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH:25][CH3:22])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)COC2
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CO
Product: CNc1nc(Cl)nc2c1COCC2c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Preparation I) (194 mg, 0.690 mmol) in MeOH (6901 μL) was added methanamine hydrochloride (69.9 mg, 1.035 mmol) and N,N-Diisopropylethylamine (301 μL, 1.725 mmol). The resulting mixture was stirred at RT for 2 h. The reaction mixture was then concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave 2-chloro-N-methyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (126 mg, 0.457 mmol, 66.2% yield). LC-MS (M+H)+=276.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.28 (2H, t, J=7.32 Hz), 7.20-7.25 (1H, m), 7.14-7.20 (2H, m), 4.47-4.62 (2H, m), 4.47 (1H, s), 4.00-4.11 (2H, m), 3.95 (1H, d, J=3.36 Hz), 3.08 (3H, d, J=4.88 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:11])([CH3:10])[CH2:8][OH:9].[C:12]([O-])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C[O-].C[N+](C)(C)CC1C=CC=CC=1>[C:12]([CH:8]([OH:9])[C:7]([OH:11])([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:10])(=[O:34])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CC(O)(CO)C1CCCCO1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)C(O)C(C)(O)C1CCCCO1
Temperature: 70 °C
Yield: 44.1 %

Procedure:
2-tetrahydropyranyl propylene glycol (16.0 grams, 0.1 mole) is inter esterified with 39 grams behenate using 4 ml. of 40% trimethyl benzyl ammonium methoxide as a catalyst. The reactants are stirred in a 250 ml. flask heated at 60-80° C. under a reduced pressure of 200 mm. Hg for 6 hours. The reactants are poured into 600 ml. of hexane and the hexane solution washed with 400 ml. of 1% potassium bicarbonate solution. The washed hexane layer is diluted with 200 ml. ethanol and 75 grams urea are added to the sample. Adduct formation with urea is accomplished by stirring the sample initially at 40° C. and allowing the mixture to cool at 25° C. during a two-hour interval. The urea adduct is removed by filtration and discarded. The adduction with urea is repeated using 60 grams urea. The filtrate from the second urea adduction is water-washed three times and the hexane layer is evaporated to dryness. The residue is dissolved in 300 ml. hexane and the solution is crystallized at -18° C. Filtration at -18° C. yields 21.3 grams of 1-behenoyl-2-tetrahydropyranyl propylene glycol. 1-behenoyl-2-tetrahydropyranyl propylene glycol (8 grams, 0.0165 mole) is cleaved by reaction with 11 ml. of 1.6 molar boric acid in trimethyl borate. The reactants are heated in a boiling water bath with application of vacuum. Heating is continued for 15 minutes with a vacuum of 2-5 mm. Hg pressure during the final 10 minutes. The residue is cooled to room temperature and dissolved in 200 ml. ethyl ether and water-washed three times. The ether phase is dried with sodium sulfate, and evaporated to dryness on an evaporator without warming above 30° C. The residue is dissolved in 100 ml. petroleum ether and crystallized at 70° F. The crystals recovered at 70° F. are recrystallized from 200 ml. petroleum ether at 50° F. to yield ca. 5 grams of 1-propylene glycol monobehenate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH2:7])[CH3:2].C[O:12][C:13]([C:15]1[N:16]=[CH:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]=2)=O>CCO>[CH2:1]([O:3][C:4](=[O:10])[C:5]([CH3:9])([CH3:8])[CH2:6][NH:7][C:13]([C:15]1[N:16]=[CH:17][C:18]2[C:23]([C:24]=1[OH:25])=[CH:22][CH:21]=[C:20]([O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:19]=2)=[O:12])[CH3:2]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CCOC(=O)C(C)(C)CN
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 26.7 %

Procedure:
To a solution of the 3-amino-2,2-dimethyl-propionic acid ethyl ester (598 mg, 4.12 mmol) in EtOH (9.1 mL) at r.t. were added 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (811 mg, 2.75 mmol) to give suspension solution, the reaction mixture was allowed to reflux for 18 h. After cooled to rt, the solvent was evaporated in vacuo, the crude was purified by silica gel chromatography to give 300 mg of title compound as a yellow oil: MS (m/z) 409.0 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH3:14])[CH:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)#[N:2].[NH:22]1[C:30]2[C:25](=[C:26]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:14][CH2:13][CH2:12][N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[C:6]([CH:15]2[CH2:20][CH2:19][CH:18]([N:34]3[CH2:35][CH2:36][N:31]([C:26]4[C:25]5[CH:24]=[CH:23][NH:22][C:30]=5[CH:29]=[CH:28][CH:27]=4)[CH2:32][CH2:33]3)[CH2:17][CH2:16]2)=[CH:7]1
Reactant: CCCn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCn1cc(C2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
A solution of 4-(5-cyano-1-n-propyl-indol-3-yl)-cyclohexanone (1.68 g, 6 mmol), 1-(indol-4-yl)piperazine (1.27 g, 6.3 mmol), sodium triacetoxyborohydride (1.84 g, 8.9 mmol) and acetic acid (0.94 ml, 16 mmol) in 1,2-dichloroethane (80 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (20 ml), extracted with methylene chloride (3×100 ml) and washed with brine (3×100 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.42 g(15%) of product as a white powder.