Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]=1.[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14]>>[Cl:9][CH2:10][C:11]1[N:1]=[C:2]2[S:3][C:4]([S:7][CH3:8])=[N:5][N:6]2[C:13](=[O:14])[CH:12]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CSc1nnc(N)s1
Product: CSc1nn2c(=O)cc(CCl)nc2s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-amino-5-methylthio-1,3,4-thiadiazole (9.4 g) was reacted with ethyl 4-chloro-acetoacetate (15.8 g) in polyphosphoric acid (50 g) under stirring at 100° C. for 1 hour. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered and washed with water until neutral to give 7-chloromethyl-2-methylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 168°-169° C. (12.4 g), which was reacted with triphenylphosphine (14.4 g) in acetonitrile (250 ml) under stirring at reflux temperature for 24 hours. After cooling the precipitate was filtered and washed with isopropyl ether to give (2-methylthio-5-oxo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-7-yl)-methyl-triphenylphosphonium chloride (24 g), which was suspended in dimethylsulphoxide (100 ml) and treated dropwise with potassium terbutoxide (5 g) dissolved in dimethylsulphoxide (80 ml) at a temperature of about 20° C. The solution of the ylide so obtained was then reacted with benzaldehyde (4.65 g) at room temperature for 60 minutes. After dilution with ice water the precipitate was extracted with ethyl acetate and the organic solution was evaporated in vacuo to dryness: after purification over SiO2 column with CHCl3 -hexane, crystallization from CH2Cl2 -methanol gave 3.8 g of 2-methylthio-7-trans-(2-phenyl-ethenyl)-5H-1,3,4-thiadiazolo[3,2-a]pyrimidine-5-one, m.p. 180°-182° C., N.M.R. (CDCl3) δp.p.m.: 2.82 (s) (3H, --SCH3), 6.35 (s) (1H, C-6 proton), 6.70 (d) (1H, β-ethenyl proton), 7.2-7.7 (m) (5H, phenyl protons), 7.70 (d) (1H, α-ethenyl proton); JHαHβ =16 Hz.
Reaction SMILES: C[O:2][C@H:3]1[C@@H:7]2[O:8]C(C)(C)[O:10][C@@H:6]2[C@@H:5]([C:13](=[N:19][OH:20])[CH2:14][C:15](=O)[CH2:16][CH3:17])[O:4]1>C(O)(=O)C>[CH2:16]([C:15]1[O:20][N:19]=[C:13]([C@H:5]2[O:4][CH:3]([OH:2])[C@H:7]([OH:8])[C@@H:6]2[OH:10])[CH:14]=1)[CH3:17]
Reactant: CCC(=O)CC(=NO)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CC(=O)O
Product: CCc1cc([C@H]2OC(O)[C@H](O)[C@@H]2O)no1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
1-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pentane-1,3-dione 1-oxime (0.5 g) was dissolved in aqueous acetic acid (18 mg) and the mixture heated at 100° C. for 2 h. The solution was cooled and concentrated in vacuo to afford a brown oil which was azeotroped with toluene. Purification by chromatography on silica gel (Varian Bondelut silica gel cartridge), eluting with (i) dichloromethane, (ii) ether, (iii) ethyl acetate, (iv) methanol, gave the title compound (150 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O.[Cu](Br)Br>[S:13]1[CH:14]=[CH:15][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12]1
Reactant: Brc1ccsc1
Reactant: c1ccc2[nH]ccc2c1
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc2c(c1)ccn2-c1ccsc1
Temperature: 180 °C

Procedure:
A mixture of indole (16 g, 0.136 M), 3-bromothiophene (24.75 g, 0.146 M), potassium carbonate (20.1 g, 0.146 M) and copper bromide (0.84 g, 0.003 M) in 160 ml of N-methyl-2-pyrrolidinone was stirred and heated to 180° C. (under nitrogen atmosphere) for 42 hours. After this time, the reaction mixture was poured onto 800 ml of water and extracted with ethyl acetate (2×350 ml). The combined ethyl acetate extracts were washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo leaving a dark brownblack oil. The crude reaction product was chromatographed on a silica gel column with hexane/CH2Cl2 3:1 as eluant. Yield=9.14 g of yellow liquid which was homogeneous by thin layer chromatography. MS: M+ =199.
Reaction SMILES: [Na].C(O[CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:25])[CH:11]2[NH:15][C:16](=[O:24])[CH2:17][C:18]2[S:19][CH2:20][CH2:21][S:22][CH:23]=2)[C:8]=1[C:26]([OH:28])=[O:27])(=O)C.[S-][C:30]#[N:31].[K+].P(=O)(O)(O)O>O.C(C(C)=O)C(C)C.N1C=CC=CC=1>[C:26]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][N+:31]1[CH:30]=[CH:26][CH:8]=[CH:7][CH:6]=1)[CH:11]([NH:15][C:16](=[O:24])[CH2:17][C:18]1[S:19][CH2:20][CH2:21][S:22][CH:23]=1)[C:10]2=[O:25])([O-:28])=[O:27]
Reactant: N#C[S-]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)CC3=CSCCS3)C2SC1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: c1ccncc1
Solvent: CC(=O)CC(C)C
Product: O=C(CC1=CSCCS1)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CSC12
Temperature: 60 °C
Yield: 35.2 %

Procedure:
Water (47 cc.) and pyridine (16.1 cc.) are added to the sodium salt of 3-acetoxymethyl-2-carboxy-7-[(5,6-dihydro-1,4-dithiin-2-yl )acetamido]-8-oxo-5-thia-1-aza- bicyclo[4,2,0]oct-2-ene (45.2 g.) and potassium thiocyanate (194 g.). After stirring, a homogeneous syrupy mixture is obtained, the pH of which is adjusted to 6.5 by addition of concentrated phosphoric acid. The mixture is heated at 60° C. for 5 hours. After cooling, the reaction mixture is diluted with distilled water (1 liter) and is washed three times with chloroform (total 800 cc.). The last traces of chloroform in the aqueous phase are removed by distillation under reduced pressure (20 mm.Hg) and the resulting solution is then treated with decolourizing charcoal, filtered through "Supercel" and cooled by means of an ice-water bath. The solution is then acidified to pH 2 by addition of 4 N hydrochloric acid whilst keeping the temperature below 5° C.; a product precipitates. The mixture is stirred for one hour whilst continuing to cool it with a mixture of ice and water, and is then washed twice by decantation with ice-water (1 liter). The precipitate is filtered off and is washed three times with ice-water (total 2 liters). The solid obtained is suspended in water (120 cc.) and a 25% solution of "Amberlite LA 2" in methyl isobutyl ketone (120 cc.) is added. The mixture is stirred until the solid has dissolved completely, and then the organic phase is decanted and discarded. The aqueous phase is extracted twice with a 25% solution of "Amberlite LA 2" in methyl isobutyl ketone (total 240 cc.), then with ethyl acetate (300 cc.) and finally three times with diethyl ether (total 300 cc.). The water is evaporated under reduced pressure (20 mm.Hg) at 40° C. An oil is obtained which is triturated in acetone (800 cc.). The resulting solid is filtered off, washed three times with acetone (total 300 cc.) and then dried under reduced pressure (0.5 mm.Hg). 2-Carboxylato-7-[(5,6-dihydro-1,4-dithiin-2-yl )acetamido]-8-oxo-3- (1-pyridinio-methyl)-5-thia-1-aza-bicyclo[4,2,0]- oct-2-ene (8.3 g.) is thus obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:7][CH2:6][NH:5]1.[N:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=[O:37])=[CH:31][CH:30]=3)=[O:27])=[CH:25][C:20]=2[NH:19][CH:18]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:17]1[C:21]2[CH:22]=[CH:23][C:24]([C:26]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36]([N:5]4[CH2:6][CH2:7][N:8]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=5[CH3:16])[CH2:9][CH:4]4[CH2:3][CH2:2][OH:1])=[O:37])=[CH:31][CH:30]=3)=[O:27])=[CH:25][C:20]=2[NH:19][CH:18]=1
Reactant: O=C(O)Cc1ccc(NC(=O)c2ccc3nc[nH]c3c2)cc1
Reactant: Cc1ccccc1N1CCNC(CCO)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(NC(=O)c3ccc4nc[nH]c4c3)cc2)C(CCO)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(2-hydroxyethyl)-4-(2-methylphenyl)piperazine from Step 2 of Example 20 (0.20 g; 0.91 mmol), 4-(5-benzimidazolylcarbonylamino)phenylacetic acid (0.299 g; 1.00 mmol), HOBT (0.14 g; 1.0 mmol), and EDC (0.210 g; 1.09 mmol) in DMF (30 mL) was added DIEA (0.23 mL; 1.3 mmol). The reaction was stirred at ambient temperature for 18 h and the solvent was evaporated under reduced pressure. The residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The organic phase was separated and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 95:5:0.5 CH2Cl2 : MeOH:NH4OH as eluant. Trituration in EtOAc gave the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([S:9][CH2:10]Cl)([CH3:8])[CH3:7])=[CH:4][CH:3]=1.[P:14]([S-:22])(=[S:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17].[K+]>CC(C)=O>[P:14]([S:22][CH2:10][S:9][C:6]([CH3:8])([CH3:7])[C:5]1[CH:12]=[CH:13][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[S:21])([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]
Reactant: CC(C)(SCCl)c1ccc(Cl)cc1
Reactant: CCOP(=S)([S-])OCC
Agent: [K+]
Solvent: CC(C)=O
Product: CCOP(=S)(OCC)SCSC(C)(C)c1ccc(Cl)cc1

Procedure:
To 32.5 g. of chloromethyl p-chloro-α,α-dimethyl- benzyl sulfide (prepared from p-chloro-α,α-dimethyl α -toluenethiol obtained as in Example 1 from p-chloro-α,α-dimethylbenzyl alcohol) in 250 ml. of acetone is added 23.4 g. of potassium O,O-diethyl phosphorodithioate. After stirring the mixture for several hours at room temperature the bulk of the acetone is removed under vacuum and the residue is mixed with methylene chloride. The methylene chloride mixture is washed with water and then dried over magnesium sulfate. Removal of solvent under vacuum leaves 38.2 g. of crude product which is purified by the dry-column technique on a 1.5 inch diameter column of silica gel using 25% methylene chloride in hexane as the developing solvent and ultraviolet light for detection. A major band, cut from the column and eluted with ethyl acetate, affords 12.8 g. colorless product on concentration. It is homogeneous by thin layer chromatography and the structure is consistent with both the infrared and proton magnetic resonance spectra.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH:22]3[CH2:24][CH2:23]3)[NH:19][N:18]=2)[N:3]=1.[C:25](B1OC(C)(C)C(C)(C)O1)([CH3:27])=[CH2:26]>>[CH:22]1([C:20]2[NH:19][N:18]=[C:17]([NH:16][C:4]3[N:3]=[C:2]([C:25]([CH3:27])=[CH2:26])[C:11]4[C:6]([CH:5]=3)=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[CH:21]=2)[CH2:24][CH2:23]1
Reactant: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(Cl)c2cc1OC
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Product: C=C(C)c1nc(Nc2cc(C3CC3)[nH]n2)cc2cc(OC)c(OC)cc12

Procedure:
Similar procedure as described in example 131 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-cyclopropyl-1H-pyrazol-3-yl)-amine and isopropenylboronic acid pinacol ester to give (5-Cyclopropyl-1H-pyrazol-3-yl)-(1-isopropenyl-6,7-dimethoxy-isoquinolin-3-yl)-amine. LC-MS m/e 351(MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][NH:25]2.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]([C@@H:9]([NH:11][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: Cc1ccc2c(c1)nc([C@H](C)N)n2-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1ccc2c(c1)nc([C@H](C)Nc1ncnc3[nH]cnc13)n2-c1ccccc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(5-methyl-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 14 (100 mg, 0.398 mmol), 6-chloro-9H-purine (74 mg, 0.478 mmol) and DIPEA (0.347 mL, 1.99 mmol) in n-butanol (2 mL) was stirred in a sealed vial for 20 h at 120° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-20% MeOH in EtOAc) and then triturated with acetonitrile affording 117 as an off-white solid (54 mg, 37%). LCMS: RT 3.11 min [M+H]+ 370.1. 1H NMR (DMSO, 400 MHz): δ 12.90 (1H, bs), 8.20-8.00 (2H, m), 7.84 (1H, s), 7.69-7.39 (6H, m), 7.07-6.89 (2H, m), 5.49 (1H, bs), 2.39 (3H, s), 1.53 (3H, d, J=6.79 Hz)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1.O>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: OCc1ccccn1
Reactant: N#Cc1c(Cl)nc(N)nc1OCc1ccccn1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1OCc1ccccn1
Reaction time: 1 h
Yield: 47.9 %

Procedure:
To a stirred suspension of 130 mg (0.50 mmol) 2-amino-4-chloro-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile in 10 ml DME were added 0.17 ml (1.74 mmol) 2-(hydroxymethyl)pyridine and 0.11 ml (0.75 mmol) DBU and stirring continued for 1 hour at room temperature. 50 ml water was then added and the resulting crystals collected by filtration and washed with ether to afford 80 mg (48%) 2-amino-4,6-bis-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 357 (M+Na+, 40), 335 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[N+:18]([O-])=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[H][H]>C(O)C.[Pt]>[CH2:1]([O:3][P:4]([CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1[NH2:18])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(CNc1ccc(Cl)cc1[N+](=O)[O-])OCC
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CCOP(=O)(CNc1ccc(Cl)cc1N)OCC

Procedure:
A solution of [(4-Chloro-2-nitro-phenylamino)-methyl]-phosphonic acid diethyl ester (45g, 0.139 moles) in ethanol (500 mL) was treated under nitrogen at once with 5% Platinum on carbon (1.125 g) and then hydrogenated at 30° C. until the hydrogen uptake ceased. After purging the reaction vessel with nitrogen the reaction mixture was filtered through solka floc. The filter cake was washed with ethanol (100 mL) and the filtrate was used as such for next step without purification.
Reaction SMILES: [F:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1.[H][H]>FC(F)(F)C(O)=O.[Pd]>[F:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c(=O)c2cc(F)c(F)cc2n2ccccc12
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)CCCC2
Yield: 88.8 %

Procedure:
A mixture of 0.5 g of ethyl 8,9-difluoro-6-oxo-6H-benzo[c]quinolizine-5-carboxylate and 0.5 g of 10% palladium-on-carbon in 50 ml of trifluoroacetic acid was shaken under 40 lb. of hydrogen in a Parr apparatus for 2 hours. The mixture was filtered and the solvent evaporated. The concentrate was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic layer was dried followed by adding hexanes to give 0.45 g of the desired product, mp 166°-168° C.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:27]=[C:26]([CH3:28])[O:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:27]=[C:26]([CH3:28])[O:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Reactant: Cc1cc(N)no1
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cc(C)on2)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 37.2 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al., J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-amino-5-methylisoxazol (96 mg, 0.978 mmol) was added. The resulting mixture was stirred, at room temperature for four days and the final product was collected by filtration and washed with diethylether to yield the title compound (35 mg, 37.2% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2(S(C3C=CC=CC=3)(=O)=O)[CH2:11][CH2:10]2)=[CH:4][N:3]=1.P([O-])([O-])[O-].[Na+].[Na+].[Na+].C(=O)([O-])O.[Na+]>CO.[Na].[Hg]>[CH:9]1([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[N:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(OC2(S(=O)(=O)c3ccccc3)CC2)cn1
Agent: O=C([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(OC2CC2)cn1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
2-Methyl-5-[1-(phenylsulfonyl)cyclopropoxy]pyridine (540 mg, 1.87 mmol) was dissolved in methanol (5.5 mL), added sodium phosphite (671 mg, 5.598 mmol), and sodium amalgam (3.58 g, 7.47 mmol) under ice-cold conditions, stirred at the same temperature for 30 minutes, and then stirred at room temperature for 3 hours. The reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, and extracted with diethylether. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by distillation, and the title compound (240 mg (yield 86%)) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].O=[CH:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:10][CH2:11][C:12]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:13]1
Reactant: CCOC(=O)C1(CC=O)CCCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccncc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCOC(=O)C1(CCNc2cnccc2C)CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 24 h

Procedure:
4-Methylpyridin-3-amine (36.0 mg, 0.000333 mol) was added to a solution of 1-tert-butyl 3-ethyl 3-(2-oxoethyl)piperidine-1,3-dicarboxylate (0.095 g, 0.00032 mol) in 1,2-dichloroethane (1.9 mL, 0.025 mol) and followed by sodium triacetoxyborohydride (0.20 g, 0.00095 mol) and the mixture was stirred for 24 h. The mixture was poured into pre-cooled water, extracted with ethyl acetate. The organic layer was separated, dried and concentrated. The product was purified by CombiFlash using CH2Cl2EtOAc (max EtOAc 50%). LC-MS: 392.3 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]3[NH:17][C@H:16]([C:18]([F:21])([F:20])[F:19])[CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=1>CN(C)C=O>[F:36][C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([F:37])[CH:33]=1)[CH2:29][N:17]1[C:9]2=[N:8][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:12][C:11](=[O:13])[N:10]2[CH2:14][CH2:15][C@H:16]1[C:18]([F:20])([F:21])[F:19]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc2n1CC[C@@H](C(F)(F)F)N2Cc1cc(F)cc(F)c1

Procedure:
The product is prepared according to the procedure described in Example 22, using 100 mg of (8S)-2-morpholin-4-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Example 1e), 214 mg of caesium carbonate and 75 mg of 1-(bromomethyl)-3,5-difluorobenzene in 2 ml of dimethylformamide. After purification by preparative HPLC/MS (Method C), 85 mg of (8S)-9-(3,5-difluorobenzyl)-2-(morpholin-4-yl)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained in the form of an oil, the characteristics of which are the following:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:5][CH:4]=1.Cl.N1CC[CH:24]([C:27]([C:29]2[CH:38]=[CH:37][C:36]3[C:31](=CC=CC=3)[CH:30]=2)=[O:28])[CH2:23][CH2:22]1>>[ClH:2].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:22][CH2:23][CH2:24][C:27]([C:29]3[CH:38]=[CH:37][CH:36]=[CH:31][CH:30]=3)=[O:28])[CH2:18][CH2:19]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(CC2CCNCC2)c2ccccc12
Reactant: O=C(c1ccc2ccccc2c1)C1CCNCC1
Agent: Cl
Product: O=C(CCCN1CCC(Cc2ccc(Cl)c3ccccc23)CC1)c1ccccc1

Procedure:
When in the procedure of Example 19, 4-[(4-chloro-1-naphthyl)methyl]piperidine hydrochloride is substituted for 2-naphthyl 4-piperidyl ketone hydrochloride, 4-[4-((4-chloro-1-naphthyl)methyl)-1-piperidyl]-1-phenyl-1-butanone hydrochloride is produced.
Reaction SMILES: [NH2-].[Na+].N.[CH:4]([N:7]([CH:19]([CH3:21])[CH3:20])[CH2:8][CH2:9][CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)[C:11]#[N:12])([CH3:6])[CH3:5].[CH3:22][C:23]([CH3:27])=[CH:24][C:25]#[N:26]>CCOCC.O>[CH:19]([N:7]([CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)([C:23]([CH3:27])([CH3:22])[CH2:24][C:25]#[N:26])[C:11]#[N:12])([CH3:21])[CH3:20]
Reactant: CC(C)N(CCC(C#N)c1ccccn1)C(C)C
Reactant: CC(C)=CC#N
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CCC(C#N)(c1ccccn1)C(C)(C)CC#N)C(C)C
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
The mixture of 4.7 g of sodium amide and 400 ml of liquid ammonia is cooled to -40° C., then the solution of 24.5 g of 4-diisopropylamino 2-(2-pyridyl) butane nitrile (Example 1a) in 30 ml of anhydrous ether is added, the temperature being maintained between -40° C. and -33° C. The mixture is stirred for 15 mins. at this temperature then the solution of 9 g of 3,3-dimethyl acrylonitrile in 40 ml of ether is added, still at the same temperature. The temperature is allowed to rise slowly up to ambient temperature (duration: about 5 hrs.). 200 ml of ether are added then water is added drop by drop. The ethereal phase is separated and the aqueous phase is re-extracted with ether. The ethereal extracts are collected and dried over sodium sulfate. The solvent is evaporated to dryness and the residue is chromatographed over a column of alumina with the eluting ethyl acetate-pentane (2.5-100) vol/vol mixture.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C@H:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C@H:16]3[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[C:33]([C@@:41]([C:56]([OH:58])=[O:57])([OH:55])[C@@:42]([C:47](=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([OH:46])[C:43]([OH:45])=[O:44])(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(OCC)(=O)C.C(OC(C)C)(C)C>[C:47]([C@:42]([C:43]([OH:45])=[O:44])([OH:46])[C@:41]([C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([OH:55])[C:56]([OH:58])=[O:57])(=[O:54])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C@H:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C@H:16]3[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Agent: CCOC(=O)C[C@@H]1CN(CC(=O)OCC)CC[C@@H]1N1CCN(c2ccc(C#N)cc2)CC1
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1

Procedure:
6.3 g of (+/-)-cis-diethyl 4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidinediacetate and 5.4 g of (-)-dibenzoyl-L-tartaric acid were dissolved in 180 ml of a mixed solvent of ethyl acetate/diisopropyl ether (1/1) and subjected to resolving crystallization. The crystals obtained were recrystallized several times from a mixed solvent of ethyl acetate/diisopropyl ether (1/1), whereby was obtained 640 mg of (-)-cis-diethyl 4-[4-(4-cyanophenyl)-1-piperazinyl]-1,3-piperidinediacetate (-)-dibenzoyl-D-tartrate (98.4% e.e.).