Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:17]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]1[C:25](=[O:42])[N:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:29]=1)=O.O>O1CCCC1>[CH3:14][CH2:13][O:12][C:10]([CH:9]=[CH:17][C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]1[C:25](=[O:42])[N:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:29]=1)=[O:11]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1sccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1sccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Yield: 33.5 %

Procedure:
To a solution of 7.5 mg of ethyl diethylphosphonoacetate in tetrahydrofuran was added 1.3 mg of sodium hydride in nitrogen atmosphere under ice-cooling, followed by the dropwise addition of a solution of 10 mg of 3-(2-formylthiophen-3-yl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one in tetrahydrofuran. After stirring the mixture at room temperature for 1 hour in nitrogen atmosphere, water was added thereto. Then, it was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 4 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:30]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][CH2:28][NH:29][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: NCCC(c1ccccc1)c1ccccc1
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCC(c4ccccc4)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 5 °C

Procedure:
A solution of 6-chloro-9-β-D-ribofuranosylpurine (2.87 g, 0.010 mol) and 3,3-diphenylpropylamine (5.28 g, 0.025 mol, 250 mol %) in absolute ethanol (75 ml) is heated at reflux for six days, during which time the starting material is mostly consumed according to TLC analysis (5/1 CHCl3 /MeOH). The solution is cooled to 5° C. and the resulting first and second crops of white crystals are combined to give N6 -(3,3-diphenylpropyl)adenosine, mp 103°-118° C. (from absolute ethanol).
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=O)=O.[C:24]([O-])(=[O:26])[CH3:25].[K+]>CN(C)C=O>[C:24]([O:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[CH2:7]1)(=[O:26])[CH3:25]
Reactant: CS(=O)(=O)O[C@@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CCN(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of (3R)-3-methanesulfonyloxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (7.50 g, 21.8 mmol) (obtained as described in Reference Example 52(2)) in dimethylformamide (225 ml) was added potassium acetate (6.41 g, 65.3 mmol), and the mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed successively with 10% aqueous sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford (3S)-3-acetoxy-1-(p-nitrobenzyloxycarbonyl)pyrrolidine (5.51 g, yield 82%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>CN(C)C=O.ClCCl>[CH3:8][C:5]1[S:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]2[C:6]=1[NH:7][C:14](=[O:16])[NH:1]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1sc(C)c(N)c1N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C)c2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 4777.4 %

Procedure:
Methyl 3,4-diamino-5-methylthiophene-2-carboxylate (3.0 g) was dissolved in a mixture of N,N-dimethyl formamide (5 ml) and dichloromethane (15 ml). To the solution was added triphosgene (2.4 g) in portions. The mixture was stirred for two days at room temperature, and precipitates were collected by filtration, washed with dichloromethane and dried. Resultant white powder (2.4 g) was suspended in N,N-dimethylformamide (25 ml). To the suspension was added sodium hydride (60% in oil; 0.55 g), and the mixture was stirred for three days at room temperature. The solvent was evaporated under reduced pressure. To the residue was added 2N-HCl. Resulting precipitates were collected by filtration, washed with water, ether and methanol successively, followed by drying to afford the title compound (82 g, 53%) as pale brown powder.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1>C1COCC1>[Cl:1][CH2:2][C:3]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=C(CCl)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of mL 2-chloroacetyl chloride (1.409 mL, 17.71 mmol) and THF (50 mL) was cooled to 0° C. and pyrrolidine (1.259 g, 17.71 mmol) was slowly added and stirred at ambient temperature for 3 hours. Partitioned between CH2Cl2 and water, and the organic layer was separated, dried, filtered, and concentrated to give the title compound (1.73 g, 66.19% yield) as a clear oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10]([C:12]1[S:16][C:15](Br)=[N:14][CH:13]=1)=[O:11])[CH3:8].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>COCCOC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:15]1[S:16][C:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])=[CH:13][N:14]=1
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2ccccc2F)s1
Temperature: 80 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
Tetrakis(triphenylphosphine)palladium (O) (0.58 g, 0.5 mmol), and a degassed solution of 2.0M Na2CO3 (10 mL) are added to a degassed solution of 2-bromo-1,3-thiazole-5-carboxylic ethyl ester (1.18 g, 5.0 mmol) and 2-fluorophenylboronic acid (0.77 g, 5.5 mmol) in DME (10 mL). The resulting suspension is stirred under argon at 80° C. for 4 hours. The reaction mixture is cooled, diluted with EtOAc, and then washed with two portions of 1.0 M NaOH, then one portion of brine. The combined organic phases are concentrated in vacuo and the resulting oil purified with flash chromatography. Yield 37%. HRMS (FAB) calculated for C12H10FNO2S+H 252.0495, found 252.0496.
Reaction SMILES: C([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)=O.N>O1CCOCC1.Cl.O>[C:11]([C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:8]=1[OH:15])[CH2:4][NH2:3])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(CNC=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(CN)cc(C(C)(C)C)c1O
Temperature: 25 °C
Yield: 96.8 %

Procedure:
9.81 g (37.3 mmol) N-formyl-3,5-di-tert.butyl-4-hydroxybenzyl-amine was dissolved in 24 mL dioxane and 7.2 mL concentrated hydrochloric acid. The mixture was heated to reflux for one hour. The mixture was allowed to cool down to room temperature and diluted with 50 mL water. The mixture was made alkaline, using a 10% ammonia solution. 3,5-di-tert.butyl-4-hydroxybenzyl amine precipitated from the medium, was isolated by filtration and dried. 8.5 g (97%) of 3,5-di-tert.butyl-4-hydroxybenzyl amine was isolated (m.p.: 159-9° C.). 3,5-di-tert.butyl-4-hydroxybenzyl amine has a tendency to lose ammonia upon heating, forming the corresponding di- and tribenzyl derivatives.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1.O>CN(C)C=O>[C:14]([Si:18]([CH3:20])([CH3:19])[O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102 %

Procedure:
To a solution of ethyl 3-hydroxyphenylacetate (6 g) and tertbutyldimethylsilyl chloride (6 g) in 80 ml of anhydrous dimethylformamide are added 5.66 g of imidazole and the mixture is stirred at room temperature for 1 hour 30 minutes. The reaction mixture is then poured into water and extracted twice with ethyl acetate. The pooled organic extracts are dried over sodium sulfate and concentrated to dryness to give 10 g of the product as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.O>[Cl:1][CH2:2][C:3]([N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: C1CCNCC1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CCl)N1CCCCC1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
Add chloroacetyl chloride (1.242 g, 11.0 mmol) to a mixture of potassium carbonate (2.073 g, 15 mmol) and piperidine (852 mg, 10 mmol) in THF (50 mL) at 0° C. Stir the reaction for 12 h and gradually raise to room temperature. Dilute with water, extract with EtOAc three times. Combine the organic extracts and wash sequentially with saturated aqueous NaHCO3, 0.1N aqueous HCl and brine. Dry over Na2SO4, filter and concentrate to give the title compound (1.65 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH2:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: N#Cc1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazine-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carbonitrile (100) and 2-bromoacetophenone according to General Procedure B. Yield 117 mg (23%), MP 316° C.; 1H-NMR (DMSO-d6): δ 3.81 (m, 4H), 3.94 (m, 4H), 5.86 (s, 2H), 7.17 (dd, J=3.6, 5.2 Hz, 1H), 7.51 (dd, J=1.2, 3.6 Hz, 1H), 7.61 (m, 2H), 7.73 (m, 1H), 7.81 (dd, J=1.2, 5.2 Hz, 1H), 8.12 (m, 2H), 8.36 (dd, J=2.4 Hz, 1H), 8.67 (d, J=2.4 Hz, 1H); EIMS: 518 (M+1). Anal. (C26H20ClN5O3S) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cccc(-c2cccc([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc(N)c2)c1
Reaction time: 1 h
Yield: 82.1 %

Procedure:
10% Palladium on carbon (0.4 g) was added to a solution of methyl 3-(3-nitrophenyl)benzoate (2.0 g) in methanol (30 ml) and the mixture was subjected to catalytic hydrogenation at ambient temperature under atmospheric pressure. After one hour, the catalyst was removed by filtration and the filtrate was evaporated in vacuo. The residue was crystallized from diethyl ether to afford methyl 3-(3-aminophenyl)benzoate (1.45 g).
Reaction SMILES: [Mg].Br[C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[CH2:12]1[O:15][C@H:13]1[CH3:14]>O1CCCC1.CCOCC.[Cu]I>[CH3:12][C@H:13]([OH:15])[CH2:14][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1
Reactant: C[C@H]1CO1
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@H](O)Cc1ccc2c(c1)OCO2
Temperature: -50 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a suspension of magnesium turnings (17 g) in 50 mL tetrahydrofuran was added dropwise a solution of 5-bromo-1,3-benzodioxole (93.6 g). After complete addition, the mixture was diluted with 250 mL tetrahydrofuran and the resulting mixture was stirred overnight. 13 mL of the solution (0.78 M) was transferred to a round bottom flask containing copper(I) iodide (0.12 g). The resulting mixture was cooled to −50 ° C. and a solution of (S)-(−)-propylene oxide in 3 mL tetrahydrofuran was slowly added then stirred 10 min. The mixture was diluted with ether. The isolated organic phase was washed with water and brine. The aqueous wash was extracted with ether (2×) and the combined organic solutions were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (50% ether in pentane) to give 1.66 g of the desired product (91%). Chiral HPLC analysis indicated that the optical purity of the material was 98.3%.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH:16]=[C:15]([Cl:18])[CH:14]=[CH:13][C:12]=2[C:11](=[O:19])[C:10]2=[CH:20][CH:21]=[CH:22][N:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:41]N1C(=O)CCC1=O.[Al]>C1COCC1>[CH2:1]([N:8]1[C:17]2[CH:16]=[C:15]([Cl:18])[CH:14]=[CH:13][C:12]=2[C:11](=[O:19])[C:10]2=[CH:20][CH:21]=[C:22]([Cl:41])[N:9]12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2cccc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al]
Solvent: C1CCOC1
Product: O=c1c2ccc(Cl)cc2n(Cc2ccccc2)n2c(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
5-Benzyl-7-chloropyrrolo[1,2-b]cinnolin-10(5H)-one (4.5 g) was taken up in 50 ml of THF and a catalytic amount of dibenzoyl peroxide was added. N-chlorosuccinimide (1.95 g) was added portionwise over a period of 10 min. The flask was covered with aluminum foil and the mixture stirred at room temperature overnight under N2. The reaction mixture was concentrated and the residue taken up in chloroform and extracted with H2O and brine. The organic layer was then dried (MgSO4), charcoaled, filtered and concentrated to a green semisolid. This was purified by HPLC (silica, dichloromethane) to give a light green powder which was recrystallized from ethanol to yield 2.3 g of green crystals, mp 134°-136°.
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](Cl)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: N#Cc1cc(I)c(N)cc1Cl
Reactant: C1COCCN1
Product: N#Cc1cc(I)c(N)cc1N1CCOCC1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
4-Amino-2-chloro-5-iodobenzonitrile (0.60 g, 2.1 mmol) and morpholine (2.0 mL, 23 mmol) were added to a microwave vial and heated in the microwave to 200° C. After 60 minutes, the residue was concd then purified on silica gel (0-40% EtOAc in hexanes) to yield a white solid as 4-amino-5-iodo-2-morpholinobenzonitrile. Mass Spectrum (pos.) m/e: 330.0 (M+H)+. 4-amino-2-morpholinobenzonitrile was also isolated. 1H NMR (500 MHz, CDCl3) δ ppm 7.35 (1H, d, J=8.3 Hz), 6.28 (1H, dd, J=8.4, 2.1 Hz), 6.20 (1H, d, J=2.0 Hz), 4.14 (2H, br. s.), 3.95 (4H, m), 3.24 (4H, m). Mass Spectrum (pos.) m/e: 204.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:30][N:31]1[C:39]2[C:34](=[C:35]([NH2:40])[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:40][C:35]3[CH:36]=[CH:37][CH:38]=[C:39]4[C:34]=3[CH:33]=[CH:32][N:31]4[CH3:30])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cn1ccc2c(N)cccc21
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc4c3ccn4C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 89.8 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.36 mmol) obtained in Example 19, step 4 and 1-methyl-4-aminoindole (0.076 g, 0.52 mmol), the title compound (0.169 g, 90%) was obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[C:22]([OH:31])[CH:21]=2)[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].O>CN(C)C=O>[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[N:29][CH:28]=[N:27]3)=[C:22]([O:31][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:21]=2)[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2ccc(-n3cncn3)c(O)c2)CC1
Reactant: CN(C)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCOc1cc(C(=O)N2CCC(N(C)CCc3ccccc3)CC2)ccc1-n1cncn1
Reaction time: 1 h
Yield: 42.5 %

Procedure:
120 mg of sodium hydride was added, under ice-cooling, to a solution of 1.0 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-hydroxy-4-(1,2,4-triazol-1-yl)benzoyl]piperidine in 10 ml of dimethylformamide. The mixture was stirred for 1 hour. Thereto was dropwise added 320 mg of (2-chloroethyl)dimethylamine. The mixture was stirred at room temperature for 2 hours and then at 50° C. for 2 hours. The reaction mixture was poured into 50 ml of water. The mixture was extracted with three 50-ml portions of ethyl acetate. The extract was washed with 50 ml of a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and subjected to distillation to remove the solvent. The residue was purified by a silica gel column chromatography (eluant: dichloromethane/methanol=10/1 to dichloromethane/methanol/ammonia water=100/10/1). The product was recrystallized from ethyl acetate-n-hexane to obtain 500 mg of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-(2-dimethylaminoethoxy)-4-(1,2,4-triazol-1-yl)benzoyl]piperidine as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17])(=[O:20])[CH3:19]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Reactant: CC(=O)Cl
Product: CC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Yield: 3175.8 %

Procedure:
5-Amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (2.9 g) in acetylchloride (15 mg) was heated at reflux for 2 hours. The reaction mixture was then filtered and the solid residue was triturated with acetyl chloride (10 ml), to give 5-acetamido-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (2.0 g), m.p. 220°-223° C., in the form of a colourless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][CH:29]=3)[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:37]=[O:38]>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([N:27]=[CH:28][C:29]=3[CH:37]=[O:38])[C:20]=2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc(-c3cnc4ccnn4c3C3CCCCC3)cc2)cc1
Reactant: CN(C)C=O
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnn2c(C3CCCCC3)c(-c3ccc(OCc4ccccc4)cc3)cnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice cold solution of 300 mg (0.78 mmol) of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine in 2 mL of dimethylformamide (DMF) and 1 mL of dichloromethane (DCM) was added 0.085 mL (0.9 mmol) of phosphorus oxychloride (POCl3) and the resulting mixture was allowed to warm up to rt and stirred at rt for 4 h when analysis by thin layer chromatography (TLC) indicated complete conversion of starting material to product. The reaction mixture poured into ice-water, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated to give 335 mg of 6-(4-benzyloxy-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (436) as a beige solid as indicated by 1H NMR; LC-MS—calcd for C26H25N3O2 [M++H]+: 412.19, found: 412.1.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)=[O:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(O)C>[CH2:33]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[C:15](=[O:22])[NH:14][C:13]3[CH:23]=[CH:24][CH:25]=[N:26][C:12]2=3)=[O:10])[CH2:2][CH2:3]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2cccnc2N(C(=O)CCN2CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCN(Cc3ccccc3)CC2)c2ccccc21
Yield: 42 %

Procedure:
A mixture of 3.51 g of 5,11-dihydro-11-[3-(1-piperazinyl)-propionyl]-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one and 1.6 g of sodium carbonate were added to the mixture of 2.14 g of benzylbromide in 100 ml of absolute ethanol and the mixture was refluxed for 6 hours. Then, the hot mixture was vacuum filtered and the filtrate was evaporated to dryness in vacuo and purified by a silica gel column. The residue of the eluent was then crystallized from xylene to obtain a 42% yield of 11-[3-(4-benzyl-1-piperazinyl)-propionyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one melting at 205°-207° C.