Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:11])([CH3:10])[O:6][CH2:7][C:8]#[CH:9])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:17](Br)([Br:20])([F:19])[F:18]>C1COCC1>[Br:20][C:17]([F:19])([F:18])[C:9]#[C:8][CH2:7][O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:10])[CH3:11]
Reactant: C#CCO[Si](C)(C)C(C)(C)C
Reactant: FC(F)(Br)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC#CC(F)(F)Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 759.1 %

Procedure:
To a solution of tert-butyl-dimethyl-prop-2-ynyloxy-silane (11.6 g, 6.78 mmol) in dry THF (190 mL) was added nBuLi (46.6 mL, 1.6 M solution in hexanes) dropwise (via an addition funnel) over 30 min at 0° C. under N2. The reaction mixture was stirred at rt for 1.5 h before being cooled to −78° C. Then, CF2Br2 (18.8 mL, 20.3 mmol) was added dropwise over 30 min. After stirring for 2.5 h at −78° C., the reaction mixture was quenched with a saturated solution of NH4Cl and was extracted with ether. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. Vacuum distillation (0.35-0.7 Torr) provided (4-bromo-4,4-difluoro-but-2-ynyloxy)-tert-butyl-dimethyl-silane (15.4 g, 76% yield) as a yellow liquid (55-70° C.): 1H NMR (400 MHz, CDCl3) δ0.15 (s, 6H), 0.93 (s, 9H), 4.46 (t, J=4.08 Hz, 2H); 19F NMR (376.19 MHz, CDCl3) δ −33.01 (t, J=4.1 Hz, 2F).
Reaction SMILES: C(OCC)(=O)CC(OCC)=O.[H-].[Na+].C1(CBr)CC1.[CH2:19]([O:21][C:22](=[O:33])[CH:23]([CH2:29][CH2:30][CH:31]=[CH2:32])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22](=[O:33])[CH:23]([CH2:29][CH:30]1[CH2:32][CH2:31]1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:20]
Reactant: C=CCCC(C(=O)OCC)C(=O)OCC
Agent: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(CC1CC1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of diethyl malonate (3.0 g, 18.7 mmol) in THF (30 mL) was added, portionwise over 15 min, sodium hydride (0.824 g, 60% in oil, 20.6 mmol). The mixture was stirred at RT for 30 min, and then cooled in an ice bath. Cyclopropylmethyl bromide (2.36 mL, 24.3 mmol) was added and the reaction mixture stirred at RT for 1 h and then refluxed for 6 h. The cooled mixture was concentrated in vacuo, the residue was partitioned between diethyl ether and dilute aqueous NH4Cl; and the aqueous phase was extracted with diethyl ether. The combined organic phases were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% EtOAc in cyclohexane) affording a mixture of the title compound and 2-but-3-enylmalonic acid diethyl ester (3.24 g, 10:1 ratio respectively). This mixture was dissolved in DCM (150 mL) and a solution of mCPBA (0.77 g, 4.46 mmol) in DCM (5 mL) added. The reaction mixture was stirred at RT for 16 h, and then washed with a saturated solution of NaHCO3, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-8% EtOAc in cyclohexane) affording the title compound as a colourless oil (2.68 g, 67%). 1H NMR (CDCl3, 300 MHz): δ 4.20 (4H, q, J=7.1 Hz), 3.44 (1H, t, J=7.5 Hz), 1.81 (2H, t, J=7.3 Hz), 1.27 (6H, t, J=7.1 Hz), 0.80-0.67 (1H, m), 0.48-0.42 (2H, m), 0.12-0.07 (2H, m).
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[Cl:29])[N:20]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[Cl:29])[N:20]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Nc1ccc2c(Cl)cccc2n1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc2c(Cl)cccc2n1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.5 %

Procedure:
Pyridine (1 ml) and 4-chlorobenzenesulfonyl chloride (255 mg) were added to 2-amino-5-chloroquinoline (119 mg, Preparation Example 2) at room temperature. After stirring at room temperature for 3 days, water was added thereto and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated. Then, the resulting solid was washed with methanol, to give the title compound (20 mg).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O)[CH2:2][CH3:3].[F:13][C:14]1[CH:25]=[C:24]2[C:17]([NH:18][CH:19]=[C:20]2[CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.COCCOCCOC>[F:13][C:14]1[CH:25]=[C:24]2[C:17](=[CH:16][CH:15]=1)[NH:18][CH:19]=[C:20]2[CH2:21][CH2:22][NH:23][CH2:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=1
Reactant: NCCc1c[nH]c2ccc(F)cc12
Reactant: CCCOc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CO
Product: CCCOc1cccc(CNCCc2c[nH]c3ccc(F)cc23)c1

Procedure:
Combine 3-propoxybenzaldehyde (29.6 mg; 0.18 mmol) and 5-fluorotryptamine (14.2 mg; 0.080 mmol) in methanol (2 mL). Add a solution of sodium borohydride in diglyme (1 ml of a 0.5 M solution; 0.50 mmol) and agitate. After 63 h at room temperature concentrate in a stream of nitrogen. Dissolve the residue in methanol and add to a 1 gm SCX column previously rinsed pith 5% acetic acid in methanol. Elute the product from the SCX column with 1 M ammonia in methanol to give the title compound: MS (ES+): m/e (M+1); HPLC (10-90% water/acetonitrile over 10 min, Tr=4.08 min.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH:3]=1.[CH3:16][CH:17]1[NH:21][C:20](=O)[CH2:19][CH2:18]1.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([C:20]3[CH2:19][CH2:18][CH:17]([CH3:16])[N:21]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)Nc1ccccc1O2
Reactant: CC1CCC(=O)N1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3Oc3ccc(Cl)cc32)=N1

Procedure:
Reaction of 2-chlorophenoxazine, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 2-CHLORO-10-(5-METHYL-1-PYRROLIN-2-YL)-PHENOXAZINE as a distillable oil, b.p. 150-170° C. at 0.1 mm Hg. Conversion of the free base to the hydrochloride salt affords 2-CHLORO-10-(5-METHYL-1-PYRROLIN-2-YL)PHENOXAZINE HYDROCHLORIDE, m.p. 213.5-215.5° C., as a crystalline solid in a 34% overall yield by refluxing with benzene.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)([O-])=O>C1COCC1>[N:4]1([CH2:3][CH2:2][O:1][C:17]2[CH:18]=[CH:19][C:14]([NH2:11])=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-hydroxyethyl)pyrrolidine in THF was added dropwise to a slurry of NaH in THF under N2 at 25° C. over a 5 min period. The mixture was stirred at 25° C. for 30 min, during which time it turned to a dark amber solution. A solution of 4-nitrofluorobenzene in THF was added dropwise and the resultant mixture was stirred at 25° C. for 48 h. The dark brown solution was carefully quenched by the addition of saturated aqueous NaHCO3 and was diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with saturated aqueous NaHCO3, brine (2×) and were dried over MgSO4 and concentrated in vacuo to give a pale amber oil that was used without further purification. A solution of 1-[2-(4-nitrophenoxy)ethyl]pyrrolidine in EtOH under N2 was treated with 10% Pd/C and placed under an atmosphere of H2 via Parr apparatus. The mixture was agitated for 3 h at ˜45 psi of hydrogen and was then purged with N2, and filtered through a plug of Celite (EtOAc/EtOH wash) under N2 to give a dark brown oil. Purification of the oil by flash chromatography (12 g pre-packed silica gel ISCO column, 0-15% CH3OH/CH2Cl2) afforded 4-(2-pyrrolidin-1-ylethoxy)aniline as a brown oil. A solution of Methyl 5-(4-chlorophenyl)-3-{[(E)-(dimethylamino)methylidene]amino}2-thiophenecarboxylate (Example J13) and aniline in EtOH under N2 was stirred and heated at reflux for 48 h. The mixture was filtered and the white solid was washed with EtOH and dried in vacuo. Purification by reverse phase chromatography (Gilson, 10-95% acetonitrile/water) and concentration via lyophilization afforded the desired product as a TFA salt. 1H NMR (DMSOd6) δ 9.80 (br s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 4.36 (m, 2H), 3.61 (m, 4H), 3.14 (m, 2H), 2.03 (m, 2H), 1.88 (m, 2H). LCMS m/z=452 (M++H).
Reaction SMILES: [CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24][C:25]([CH3:31])([CH3:30])[O:26][C:27](=[O:29])[CH:28]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C3(C#N)CC3)=C(F)C=2)CCCC1>>[CH:1]1([C:6]([OH:32])([CH2:22][C:23]2[O:24][C:25]([CH3:30])([CH3:31])[O:26][C:27](=[O:29])[CH:28]=2)[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:19]#[N:20])[CH2:16][CH2:17][CH2:18]3)=[C:11]([F:21])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Product: CC1(C)OC(=O)C=C(CC(O)(CCc2ccc(C3(C#N)CCC3)c(F)c2)C2CCCC2)O1

Procedure:
The desired product was prepared analogously to Example A(86) step 6, substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclobutanecarbonitrile (1.200 g, 2.7 mmol) from step 2 above in place of 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile. Yield: 1.00 g, 84%. MS (ESI): 440 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([Cl:16])(=[O:15])=[O:14])=[CH:9][C:8]=1[CH3:17])[CH3:2].C(OC(=O)CO[C:25]1[C:34]2CCCCC=2C=C[CH:26]=1)C>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[C:8]2[CH2:17][CH2:34][CH2:25][CH2:26][C:9]=2[C:10]([S:13]([Cl:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)COc1cccc2c1CCCC2
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Product: CCOC(=O)COc1ccc(S(=O)(=O)Cl)c2c1CCCC2

Procedure:
The title compound was prepared according to the method described for preparing compound 10.2, using compound 22.1 as the starting material. 1H NMR (400 MHz) (CDCl3) δ 7.93 (1H, d, J=8.9 Hz); 6.62 (1H, d, J=9.0 Hz); 4.73 (2H, s); 4.29 (2H, q, J=7.1 Hz); 3.27-3.24 (2H, m); 2.81-2.78 (2H, m); 1.85-1.82 (4H, m); 1.32 (3H, t, J=7.2 Hz).
Reaction SMILES: [OH:1][C:2]1C=C(O)C=CC=1CC1C=C(Cl)C=C(CC2C=CC(O)=CC=2O)C=1O.[CH2:27]=[O:28].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1.[OH-].[Na+]>O>[OH:1][CH2:2][C:34]1[CH:35]=[C:30]([Cl:29])[CH:31]=[C:32]([CH2:27][OH:28])[C:33]=1[OH:36]
Reactant: C=O
Reactant: Oc1ccc(Cc2cc(Cl)cc(Cc3ccc(O)cc3O)c2O)c(O)c1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCc1cc(Cl)cc(CO)c1O

Procedure:
The heat reactable 2,6-bis(2,4-dihydroxy phenyl methyl)-4-chlorophenol composition used in the dip of the present invention is made by the process of first reacting about 2 mols of formaldehyde with 1 mol of parachlorophenol in water containing sodium hydroxide. The precipitated sodium salt is filtered off, washed, dissolved in hot water acidified with acetic acid, cooled, filtered and washed until free of acid. The resulting intermediate product can then be recrystallized from alcohol to obtain the 2,6-bis hydroxy methyl -4-chlorophenol which then is reacted with about 2 mols of resorcinol to give the heat reactable bis (dihydroxy phenyl methyl)chlorophenol composition. The final product may be treated to remove unused starting materials and by-products. However, it or the intermediate product should be washed or treated as much as practical to remove all or essentially all of the alkali metal ions or salts. The product as produced is substantially heat reactable 2,6-bis(2,4-dihydroxy phenyl methyl)-4-chlorophenol composition having an average molecular weight of up to about 800 and a melting point of up to about 240°C. It is added to or mixed with the latex of the rubbery vinyl pyridine copolymer in the form of a solution 5 to 30% solids in water containing NH3 sufficient to render the solution alkaline, usually about 0.5 to 7.5%. More information on how to prepare the heat reactable 2,6-bis(2,4-dihydroxy phenyl methyl)-4-chlorophenol composition is shown by Mather, "Development of a Polyester-Rubber Adhesive," British Polymer Journal, Volume 3, March, 1971, pages 58 to 62 and U.S. Pat. No. 3,660,202. The chlorophenolic composition is heat reactable so that it can react with itself, the rubber and possibly also the cord.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][N:19]=[C:20]([C:22]2[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[CH3:21])=[CH:14][CH:13]=1.N1C=C(C=[N+](C)C)[CH:32]=N1>O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:32]=[C:21]([CH:8]=[O:9])[C:20]([C:22]3[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)=[N:19]2)=[CH:16][CH:17]=1
Reactant: C[N+](C)=Cc1cn[nH]c1
Reactant: CN(C)C=O
Reactant: CC(=NNc1ccc(Cl)cc1)c1ccc([N+](=O)[O-])o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cn(-c2ccc(Cl)cc2)nc1-c1ccc([N+](=O)[O-])o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Add 37 g of phosphorus oxychloride dropwise to 153 ml of dimethylformamide at from 10° to 20° C. Stir the thus-obtained admixture for 30 minutes at room temperature before adding 18.3 g of 5-nitro-2-acetylfuran-p-chlorophenylhydrazone in portions, thus causing the temperature to rise to 40° C. Stir for 4 additional hours at 40° C and then pour the solution containing the 4-pyrazolylmethylenedimethylammonium salt onto 1 kg of ice and water. Heat the so-cooled solution for 1 hour at 40° C, and then (vacuum) filter it at room temperature. Wash filter residue with water to obtain a 92% yield of 1-(p-chlorophenyl)-3-(5-nitro-2-furyl)pyrazole-4-carboxaldehyde [m.p. 192° to 193° C (from toluene)].
Reaction SMILES: [F:1][C:2]([O:10][C:11]([F:14])([F:13])[F:12])([C:6](F)([F:8])[F:7])C(F)=O.[F:15][C:16]([O:24][C:25]([F:31])([F:30])[C:26]([F:29])([F:28])[F:27])([C:20](F)([F:22])[F:21])C(F)=O>>[F:1][C:2]([O:10][C:11]([F:14])([F:13])[F:12])=[C:6]([F:8])[F:7].[F:15][C:16]([O:24][C:25]([F:30])([F:31])[C:26]([F:27])([F:28])[F:29])=[C:20]([F:22])[F:21]
Reactant: O=C(F)C(F)(OC(F)(F)F)C(F)(F)F
Reactant: O=C(F)C(F)(OC(F)(F)C(F)(F)F)C(F)(F)F
Product: FC(F)=C(F)OC(F)(F)C(F)(F)F
Product: FC(F)=C(F)OC(F)(F)F

Procedure:
dehalocarbonylating an intermediate mixture comprising 2,3,3,3-tetrafluoro-2-(trifluoromethoxy)propionic acid fluoride (PMPF) and 2,3,3,3-tetrafluoro-2-(pentafluoroethoxy)propionic acid fluoride (PEPF) formed in step (a) to form a product mixture comprising perfluoromethyl perfluorovinyl ether (PMVE) and perfluoroethyl perfluorovinyl ether (PEVE).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]#[N:28])[CH2:23][CH2:22]4)([CH3:20])[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH:29][NH:30][C:31](=N)[C:32]([CH3:35])([CH3:34])[CH3:33]>>[C:32]([C:31]1[N:28]=[C:27]([N:24]2[CH2:23][CH2:22][CH:21]([C@@:18]3([CH3:20])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:26][CH2:25]2)[O:29][N:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: C[C@@]1(C2CCN(C#N)CC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Reactant: CC(C)(C)C(=N)NO
Product: CC(C)(C)c1noc(N2CCC([C@]3(C)Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)n1

Procedure:
The title compound is prepared from (S)-4-[5-(4-methanesulfonyl-phenyl)-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl]-piperidine-1-carbonitrile (Intermediate 33; the configuration of the stereocenter is arbitrarily assigned) and N-hydroxy-2,2-dimethyl-propionamidine following a procedure analogous to that described in Example 2. LC (method 4): tR=0.93 min; Mass spectrum (ESI+): m/z=497 [M+H]+.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[C:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH:24]=[CH:25][C:26](=[O:28])[CH3:27])[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])[CH3:14].[OH-].[Na+]>C(O)C.O>[C:13]([C:16]1[C:17]([CH3:29])=[C:18]([CH:24]2[CH2:25][C:26](=[O:28])[CH:27]=[C:3]([OH:4])[CH2:2]2)[C:19]([CH3:23])=[CH:20][C:21]=1[CH3:22])(=[O:15])[CH3:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C=Cc1c(C)cc(C)c(C(C)=O)c1C
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)c1c(C)cc(C)c(C2CC(=O)C=C(O)C2)c1C
Yield: 79 %

Procedure:
Diethyl malonate (10.16 g; 69 mmole) was added to a solution of sodium metal (1.46 g; 63 mmole) in anhydrous absolute ethanol (50 ml) and the mixture was heated to reflux temperature. A mixture of 1-(3-acetyl-2,4,6-trimethylphenyl)but-1-en-3-one (14.60 g; 63 mmole) in anhydrous absolute ethanol (50 ml) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. A 30% aqueous solution of sodium hydroxide (100 ml) was added and the mixture was heated under reflux for a further 41/2 hours. The solution was poured into water (200 ml) and the aqueous mixture was washed with diethyl ether (2×100 ml). The aqueous phase was acidified with concentrated hydrochloric acid and warmed gently until the evolution of carbon dioxide ceased. The aqueous mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The product, 5-(3-acetyl-2,4,6-trimethylphenyl)-3-hydroxycyclohex-2-en-1-one (13.55 g; 84.0%), was obtained as a glassy solid. Proton magnetic resonance spectrum (D6 -dimethylsulfoxide; δ in ppm): 2.20 (3H, s); 2.24 (3H, s); 2.38 (3H, s); 2.45 (3H, s); 2.45-3.40 (4H, m); 3.90 (1H, m); 5.25 (1H, s); 6.85 (1H, s); 11.0 (1H, br. s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[N:10]=[C:9]([OH:19])[CH:8]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][N:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl>[NH2:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[N:12]=[C:11]([N:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[N:10]=[C:9]([OH:19])[CH:8]=3)[CH2:3][CH2:2]2)=[CH:23][N:22]=1
Reactant: Oc1cc(C2CCNCC2)nc(N2CCCCC2)n1
Reactant: Nc1ncc(C=O)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Nc1ncc(CN2CCC(c3cc(O)nc(N4CCCCC4)n3)CC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 6-piperidin-4-yl-2-piperidin-1-yl-pyrimidin-4-ol (2.0 mmol), 2-amino-pyrimidine-5-carbaldehyde (2.6 mmol), triethylamine (4.0 mmol) and 3 drops of acetic acid in dry dichloromethane (20 mL) was stirred at room temperature for 3 hours. Then sodium triacetoxyborohydride (6.0 mmol) was added in portions and stirring was continued for 48 hours (monitored by TLC). The mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL), and the product was extracted with dichloromethane (2×10 mL). The extracts were washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to give a crude product. Purification via column chromatography (silica gel, ethyl acetate/hexane) afforded 6-[1-(2-Amino-pyrimidin-5-ylmethyl)-piperidin-4-yl]-2-piperidin-1-yl-pyrimidin-4-ol (606 mg, 82%)
Reaction SMILES: [CH2:1]([O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][CH:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[N+:45]([O-])=O)[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][CH:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[N+:23]([O-])=O.O.O.Cl[Sn]Cl.C(Cl)(Cl)Cl.CO>CO>[CH2:3]([O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]([N:15]2[CH2:19][C:18](=[CH2:20])[CH2:17][CH:16]2[CH2:21][OH:22])=[O:14])=[CH:7][C:6]=1[NH2:23])[CH2:2][CH2:1][O:26][C:27]1[CH:32]=[C:31]([O:33][CH3:34])[C:30]([C:35]([N:37]2[CH2:41][C:40](=[CH2:42])[CH2:39][CH:38]2[CH2:43][OH:44])=[O:36])=[CH:29][C:28]=1[NH2:45]
Reactant: C=C1CC(CO)N(C(=O)c2cc([N+](=O)[O-])c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)CC4CO)cc3[N+](=O)[O-])cc2OC)C1
Agent: Cl[Sn]Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: C=C1CC(CO)N(C(=O)c2cc(N)c(OCCCOc3cc(OC)c(C(=O)N4CC(=C)CC4CO)cc3N)cc2OC)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60.7 %

Procedure:
A mixture of the diol 35 (0.98 g, 1.49 mmol) and SnCl2.2H2O (3.36 g, 14.9 mmol) in MeOH (35 mL) was heated at reflux and the progress of the reaction monitored by TLC (90% CHCl3/MeOH). After 45 minutes, the MeOH was evaporated in vacuo and the resulting residue was cooled (ice), and treated carefully with saturated NaHCO3 (120 mL). The mixture was diluted with EtOAc (120 mL), and after 16 hours stirring at room temperature the inorganic precipitate was removed by filtration through celite. The organic layer was separated, washed with brine (100 mL), dried (MgSO4), filtered and evaporated in vacuo to give a brown solid. Flash chromatography (95% CHCl3/MeOH) afforded the pure bis-amine 36 as an orange solid (0.54 g, 61%): [α]19D=−31.8° (c=0.30, CHCl3); 1H NMR (270 MHz, CDCl3) δ 6.74 (s, 2Harom), 6.32 (s, 2Harom), 5.00 (br s, 2H, NCH2C═CH2), 4.93 (br s, 2H, NCH2C═CH2), 4.54 (br s, 2H, NCHCH2OH), 4.24-4.14 (m, 4H, OCH2CH2CH2O), 3.98-3.50 (m, 14H, NCHCH2OH, NCH2C═CH2 and OCH3), 2.76 (dd, 2H, J=8.61, 15.91 Hz, NCH2C═CH2CH2), 2.46-2.41 (m, 2H, NCH2C═CH2CH2), 2.33-2.28 (m, 2H, OCH2CH2CH2O); 13C NMR (67.8 MHz CDCl3) δ 171.0 (NC═O), 151.0 (Cquat), 143.5 (Cquat), 141.3 (Cquat), 140.6 (Cquat), 112.4 (C—Harom), 111.9 (Cquat), 107.8 (NCH2C═CH2), 102.4 (C—Harom), 65.2 (OCH2CH2CH2O), 65.0 (NCHCH2OH), 59.8 (NCHCH2OH), 57.1 (OCH3), 53.3 (NCH2C═CH2), 34.4 (NCH2C═CH2CH2), 29.0 (OCH2CH2CH2O); MS (FAB) (Relative Intensity) 596 (M+, 13), 484 (M-NCH2CCH2CH2CHCH2OH, 14), 389 (10), 371 (29), 345 (5), 224 (8), 206 (44), 166 (100), 149 (24), 112 (39), 96 (34), 81 (28); IR (NUJOL7) 3600-3000 (br, OH), 3349 (NH2), 2922, 2852, 2363, 1615, 1591 (NH2), 1514, 1464, 1401, 1359, 1263, 1216, 1187, 1169, 1114, 1043, 891, 832, 761 cm−1.
Reaction SMILES: Cl.Cl.[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][NH:12][CH2:13][C@@H:8]2[CH2:7][CH2:6]1.Cl[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CC(C)C>[OH:3][CH2:4][C@H:5]1[CH2:14][N:9]2[CH2:10][CH2:11][N:12]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)[CH2:13][C@@H:8]2[CH2:7][CH2:6]1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Reactant: Clc1ccc(Cl)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC[C@@H]1CC[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Yield: 65.1 %

Procedure:
A mixture of 1.35 g (5.56 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine dihyrochloride (Preparation 1), 4.11 g (27.8 mmol) of 2,5-dichloropyridine, 2.94 g (27.8 mmol) of sodium carbonate and 60 mL of isoamyl alcohol was heated at reflux for 48 h. The mixture was cooled and the solvent removed in vacuo. Purification by flash silica gel chromatography with 95:5 chloroform: methanol gave 1.02 g (65%) of the title compound. mp (base) 139.0-140.5° C. 13C NMR (CDCl3): δ26.8, 29.1, 39.1, 45.3, 50.8, 54.6, 58.6, 60.6, 66.2, 107.7, 120.1, 137.1,146.2, 157.6.