Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:21][CH2:22][CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)=[O:25].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:24](=[O:25])[CH2:23][CH2:22][CH2:21][N:11]2[CH2:10][CH2:9][C:8](=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:13][CH2:12]2)=[CH:31][CH:30]=1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CCCN1CCC(=C(c2ccccc2)c2ccccc2)CC1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 99.9 g (0.4 mole) of 4-diphenylmethylenepiperidine, 88 g (0.44 mole) of 4-chloro-4'-fluorobutyrophenone, 64.0 g (0.64 mole) of potassium bicarbonate and a small amount of potassium iodide in 1500 ml of toluene was refluxed for 5 days. The reaction mixture was filtered, and the filtrate was concentrated at reduced pressure leaving a residue which was dissolved in about 800 ml of ethyl acetate. This solution was concentrated to about 500 ml and allowed to stand for one day. The resulting precipitate was recrystallized from methanolethyl acetate, made basic with sodium hydroxide solution, water washed, and the product recrystallized from 75°-90° petroleum ether to give the title compound, M.P. 111°-114° C.
Reaction SMILES: CC(C)([O-])C.[K+].O1CCCC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:29]=[CH:30][CH:31]=1)[C:16]([C:18]1[C:19]([N:24]([CH3:28])[C:25](=[O:27])[CH3:26])=[N:20][CH:21]=[CH:22][CH:23]=1)=O>O>[Cl:12][C:13]1[CH:14]=[C:15]([C:16]2[C:18]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:24]([CH3:28])[C:25](=[O:27])[CH:26]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)N(C)c1ncccc1C(=O)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
Under ice-cooling, potassium tert-butoxide (623 mg, 5 mmol) was added to tetrahydrofuran (10 ml) solution of N-[3-(3-chlorobenzoyl)-2-pyridyl]-N-methylacetamide (1.40 g, 5 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was mixed with water and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (benzene-ethyl acetate) to give 4-(3-chlorophenyl)-1-methyl-1,8-naphthyridin-2(1H)-one (709 mg, 54%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[CH:15]=[C:14]2[C:8]([CH2:9][N:10]=[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:12]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:13]=32)=[N:7]1)C.[NH3:28]>>[Cl:20][C:18]1[CH:17]=[CH:16][C:13]2[C:14]3[C:8](=[N:7][N:6]([CH2:5][C:4]([NH2:28])=[O:3])[CH:15]=3)[CH2:9][N:10]=[C:11]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:12]=2[CH:19]=1
Reactant: CCOC(=O)Cn1cc2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: N
Product: NC(=O)Cn1cc2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2

Procedure:
Heating a mixture of 0.8 g (2.1 mmol) of 8-chloro-6-phenyl-2H,4H-pyrazolo[3,4-d][2]benzazepine-2-acetic acid ethyl ester and 20 ml of methanolic ammonia (ca. 20%, v/v) in an autoclave on the steam bath for 20 hr gave after crystallization from ethyl acetate/ether colorless crystals with mp 236°-238°. The analytical sample was recrystallized from ethyl acetate/methylene chloride/ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Br:8].[Li]CCCC.[CH3:14][CH:15]([CH3:34])[CH2:16][CH:17]([N:27]=[CH:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[C:18]12[O:25][CH2:24][C:21]([CH3:26])([CH2:22][O:23]1)[CH2:20][O:19]2>CCOCC>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([CH:28]([NH:27][CH:17]([C:18]23[O:25][CH2:24][C:21]([CH3:26])([CH2:22][O:23]2)[CH2:20][O:19]3)[CH2:16][CH:15]([CH3:34])[CH3:14])[C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[CH:7][CH:2]=1
Reactant: Brc1ccccc1Br
Reactant: CC(C)CC(N=Cc1nccs1)C12OCC(C)(CO1)CO2
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)CC(NC(c1ccc(Br)cc1)c1nccs1)C12OCC(C)(CO1)CO2

Procedure:
To a solution of dibromobenzene (760 mg, 3.2 mmol) in dry ether was added 2.5 M solution of nBuLi in hexanes (1.3 mL, 3.2 mmol) at −30° C. After stirring forl h, a solution of [3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-thiazol-2-ylmethylene-amine (500 mg, 1.6 mmol) in 5 mL of dry ether was added slowly. The reaction mixture was allowed to stir at the same temperature for 2 h and then the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dried over MgSO4. The solvent was evaporated in vacuo. The crude was flash column chromatographed using 2:1 hexanes:EtOAc as an eluant to get [(4-bromo-phenyl)-thiazol-2-yl-methyl]-[3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-amine as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7].[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)([O-:23])=[O:22].[H-].[Na+]>CN(C)C=O>[CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][N:5]([CH3:19])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:30][C:27]2[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)(=[O:8])=[O:7]
Reactant: CN(C)CCN(C)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN(C)S(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)c([N+](=O)[O-])c1
Reaction time: 20 h

Procedure:
To a solution of N-(2- dimethylaminoethyl)-N-methyl-4- chloro-3-nitrobenzenesulfonamide (2.2 g, 6.84 mmol) and 4- nitrophenol (0.97 g, 7.0 mmol) in dimethylformamide (30 mL) was added 60% sodium hydride-mineral oil suspension (0.28 g, 7.0 mmol). The resulting solution was stirred at 60° for 20 hours under N2. After concentrating under reduced pressure at 50° , the residue was partitioned between ethyl acetate and water. The ethyl acetate extract was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was flash chromatographed over silica gel and 2.8 g of the nitrophenyl ether eluted with 3% methanol-97% chloroform.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][CH:12]3[CH2:14][CH2:13]3)=[N:9][N:10]=[C:4]2[C:3]=1[C:15]#[N:16].[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:12]1([CH2:11][C:8]2[N:5]3[CH:6]=[CH:7][C:2]([N:26]4[CH2:27][CH2:28][CH:23]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:24][CH2:25]4)=[C:3]([C:15]#[N:16])[C:4]3=[N:10][N:9]=2)[CH2:14][CH2:13]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1c(Cl)ccn2c(CC3CC3)nnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(CC3CC3)nnc12
Temperature: 150 °C
Yield: 48.8 %

Procedure:
A mixture of compound D5 (0.2 g, 0.86 mmol), 4-phenylpiperidine (0.166 g, 1.031 mmol), K2CO3 (0.148 g, 1.074 mmol) in CH3CN (5 ml) was heated in a sealed tube at 150° C. under microwave irradiation for 5 min. The mixture was then cooled to r.t. and the solvents evaporated in vacuo. The residue thus obtained was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 3% as eluent). The desired fractions were collected and concentrated in vacuo to yield compound E13 as yellow solid (0.150 g, 49%).
Reaction SMILES: CN([CH2:4][N:5]([CH3:7])[CH3:6])C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[O:27][CH:28]=[CH:29][CH:30]=2)=[CH:20][N:19]=1>C(O)(=O)C>[CH3:4][N:5]([CH2:7][C:12]1[O:8][C:9]([CH2:13][S:14][CH2:15][CH2:16][NH:17][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[O:27][C:28]([CH2:7][N:5]([CH3:4])[CH3:6])=[CH:29][CH:30]=3)=[CH:20][N:19]=2)=[CH:10][CH:11]=1)[CH3:6]
Reactant: CN(C)CN(C)C
Reactant: O=c1[nH]c(NCCSCc2ccco2)ncc1Cc1ccco1
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(CSCCNc2ncc(Cc3ccc(CN(C)C)o3)c(=O)[nH]2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Bis-dimethylaminomethane (1.23 g,) was added whilst stirring 2-[2-(2-furanylmethylthio)ethylamino]-5-(2-furanylmethyl)-4-pyrimidone (0.8 g) was suspended in glacial acetic acid (8 ml). The mixture was then stirred at room temperature for 3 hr and allowed to stand for ca 16 hr. The acid was evaporated at reduced pressure azeotropically with water. The residual oil was dissolved in water, filtered and the filtrate taken to pH 9 using aqueous sodium carbonate solution. The basic solution was extracted using ethyl acetate, the extracts dried (MgSO4) and evaporated to give 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-furanylmethyl)-4-pyrimidone as an oily residue (1.01 g). The oily residue was dissolved in a minimum volume of ethanol and then acidified with ethanolic hydrochloric acid. The acidic solution was then evaporated to dryness and the residual oil was crystallised from isopropanol/ethanol to give the white solid trihydrochloride salt (1.33 g) m.p. 177°-9° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]I)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:30])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22]>C(OCC)C>[CH3:10][O:11][C:12](=[O:30])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH2:19][CH2:20][C:21]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[OH:22]
Reactant: Clc1ccc([Mg]I)cc1
Reactant: COC(=O)C1CCCCN1CCC(=O)c1ccc(F)cc1
Solvent: CCOCC
Product: COC(=O)C1CCCCN1CCC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 4.5 %

Procedure:
7 ml (2 mmol) of 0.28 M solution of 4-chlorophenylmagnesium iodide in diethyl ether [prepared from 1-chloro-4-iodobenzene (Aldrich) and magnesium] was added dropwise to an ice-cooled solution of 0.605 g (2 mmol) N-[3-(4-fluorophenyl)-3-oxopropyl]pipecolic acid methyl ester (from Step 1) in 12 ml anhydrous diethyl ether with stirring under nitrogen. The mixture was stirred at room temperature for 16 hours, poured onto crushed ice and extracted with dichloromethane. The combined organic extracts were washed with brine, concentrated and the residue purified by preparative silica gel TLC with 25% ethyl acetate in hexanes to give 0.037 g (yield 4.5%) N-[3-(4-chlorophenyl)-3-(4-fluorophenyl)3-hydroxypropyl]pipecolic acid methyl ester (Compound B30).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3C(OC(C)(C)C)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[CH:13][CH:12]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)[N:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2C[C@H]1CCCN1
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of tert-butyl (2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidine-1-carboxylate (270 mg, 0.54 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of trifluoroacetic acid (10 mL) dropwise with stirring over 10 min. The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum to give 0.216 g (crude) of 3-[4-(3-fluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a brown oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][Br:13])=[CH:10][C:5]=2[S:4][C:3]1=[O:15].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][Br:13])=[CH:10][C:5]=2[S:4][C:3]1=[O:15]
Reactant: Cn1c(=O)sc2cc(C(=O)CBr)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)sc2cc(CCBr)ccc21
Temperature: 25 °C

Procedure:
0.15 mol of 3-methyl-6-bromoacetylbenzothiazolin-2-one (42.9 g) is dissolved in 1 mol of trifluoroacetic acid (77 cm3) in a 250 cm3 ground-neck flask. 0.33 mol of triethylsilane (52.70 cm3) is introduced dropwise using a dropping funnel, with magnetic stirring. A calcium chloride drying tube is fitted and stirring is maintained for the required time at room temperature. The reaction mixture is poured into 500 cm3 of ice-cold water. The precipitate obtained is filtered off, washed with water until the wash liquors are neutral, dried and then recrystallized.
Reaction SMILES: [F:1][CH2:2][S:3](Cl)(=[O:5])=[O:4].S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25]Cl)=[N:23][CH:24]=1>O.C(O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][S:3]([CH2:2][F:1])(=[O:5])=[O:4])=[N:23][CH:24]=1
Reactant: O=S(=O)(Cl)CF
Reactant: ClCc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(CF)Cc1ccc(Br)cn1
Temperature: 100 °C
Yield: 15.2 %

Procedure:
Commercially available fluoromethanesulfonyl chloride (975 mg, 7.36 mmol) is added dropwise to a solution of sodium sulfite (1.85 g, 14.7 mmol) and sodium bicarbonate (1.24 g, 14.7 mmol) in water (2 mL). The reaction mixture is heated in a microwave reactor to 100° C. for 20 minutes. After cooling to room temperature commercially available 5-bromo-2-(chloromethyl)pyridine (894 mg, 3.68 mmol) in ethanol (2 mL) is added. The mixture is heated in a microwave reactor to 100° C. for 20 minutes. The reaction mixture is cooled to 0° C. and the solid filtered off and discarded. The filtrates are diluted with saturated sodium carbonate (10 mL), extracted with tertiarybutyl methyl ether (50 mL). The organic layer is separated, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give the title compound (150 mg): m/z 268.9 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>>[CH2:32]([NH:34][C:35]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:36])[CH3:33]
Reactant: CCN=C=O
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 25 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and ethyl isocyanate (Aldrich), to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethylamide. HRMS, observed: 399.2143; Calcd for (M+H)+: 399.2139.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1.[C:22]([C:28]([O:30][CH3:31])=[O:29])#[C:23][C:24]([O:26][CH3:27])=[O:25]>CO>[CH3:27][O:26][C:24](/[C:23](/[NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][CH2:20][CH3:21])=[C:6]([C:8]2[N:16]=[C:15]3[C:11](=[N:12][N:13]=[N:14]3)[C:10](=[O:17])[N:9]=2)[CH:7]=1)=[CH:22]/[C:28]([O:30][CH3:31])=[O:29])=[O:25]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CCCOc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Solvent: CO
Product: CCCOc1ccc(N/C(=C\C(=O)OC)C(=O)OC)cc1C1=NC(=O)C2=NN=NC2=N1
Yield: 46.6 %

Procedure:
2-(5-Amino-2-propoxyphenyl)-8-azapurin-6-one (1.43 g), dimethyl acetylenedicarboxylate (0.85 g) and dry methanol (20 ml) were stirred and heated together at reflux for 5 hours. The resulting mixture was then cooled in an ice-bath for 30 minutes and the resulting yellow crystalline precipitate was filtered off and recrystallised from ethanol to give (Z)-2-[5-{1,2-bis(methoxycarbonyl)vinylamino}-2-propoxyphenyl]-8-azapurin-6-one (1.0 g), m.p. 199°-200° C. (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[C:19]([F:27])[CH:18]=1)[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:30][C@H:31]1[C:39]2[C:38]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)=[N:37][CH:36]=[N:35][C:34]=2[C@H:33]([OH:46])[CH2:32]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:27][C:19]1[CH:18]=[C:17]([C@@H:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:14]([N:43]2[CH2:42][CH2:41][N:40]([C:38]3[C:39]4[C@H:31]([CH3:30])[CH2:32][C@@H:33]([OH:46])[C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:45][CH2:44]2)=[O:15])[CH:22]=[CH:21][C:20]=1[C:23]([F:26])([F:24])[F:25]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(C(F)(F)F)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(C(F)(F)F)c(F)c4)[C@@H]4CCCN4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
(S)-2-((S)-1-(tert-Butoxycarbonyl)pyrrolidin-2-yl)-2-(3-fluoro-4-(trifluoromethyl)phenyl)acetic acid (0.036 g, 0.092 mmol) and (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol di-hydrochloride (0.028 g, 0.092 mmol) were slurried in dichloromethane (5 mL) and then treated with diisopropylethylamine (0.06 mL, 0.34 mmol). This was followed by treatment with HBTU (0.036 g, 0.095 mmol). The mixture was stirred at ambient temperature for 1 hour. The reaction was concentrated in vacuo and purified by column chromatography, eluting with ethyl acetate. (0.040 g, 72% yield). MS (APCI+) [M+H] 608.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=[O:9].Br[CH:13]([CH2:16][CH3:17])[CH:14]=O>C1(C)C(C)=CC=CC=1>[CH2:16]([C:13]1[N:1]2[C:2]([CH:3]=[CH:4][CH:5]=[CH:6]2)=[C:7]([C:8]([OH:10])=[O:9])[CH:14]=1)[CH3:17]
Reactant: CCC(Br)C=O
Reactant: COC(=O)Cc1ccccn1
Solvent: Cc1ccccc1C
Product: CCc1cc(C(=O)O)c2ccccn12

Procedure:
A solution of methyl 2-pyridylacetate (6 ml) 2,6-lutidine (6 ml) and 2-bromobutyraldehyde (5.5 g) (P. Duhamel, L. Duhamel, J-Y. Valnot, Bull. Soc. Chim. Fr. 1973(4) 1465) in xylene (200 ml) was heated under reflux overnight, removing water by means of a Dean and Stark apparatus. The reaction mixture was cooled, washed with dilute citric acid solution and the organic phase dried (Na2SO4) and concentrated. Column chromatography (SiO2, CH2Cl2) of the residue afforded the methyl ester of the title compound (4.6 g). A solution of the ester (4.6 g) in EtOH (100 ml) and 1N NaOH (50 mL) was heated under reflux for 3h. The reaction mixture was cooled, the EtOH evaporated and the aqueous residue washed with Et2O (50 mL). Acidification of the aqueous layer afforded the title compound (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15](=O)/[CH:16]=[CH:17]/[N:18](C)C)=[N:9]2)=[CH:4][CH:3]=1.[C:22]1([NH:32]N)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[C:10]([C:15]3[N:32]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[N:18]=[CH:17][CH:16]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: NNc1cccc2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(Cl)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(Cl)cc2)nc1-c1ccnn1-c1cccc2ccccc12

Procedure:
The product was obtained starting from 1-(4-Chloro-phenyl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-24) and naphthalen-1-yl-hydrazine according to the method described for example 1. MS: M=399.1 (M+H)+
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[C:10]2=[N:11][CH:12]=1.[NH3:39]>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]4[C:23]([CH3:29])([CH3:28])[C:24](=[O:26])[NH:39][C:20]=4[N:21]=3)=[N:14][N:13]([CH2:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:34])([F:36])[F:35])[C:10]2=[N:11][CH:12]=1
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(CCC(F)(F)C(F)(F)F)c3ncc(F)cc23)nc1O
Reactant: N
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncc(F)cc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.172 ml of phosphoryl chloride were added to 290 mg (0.606 mmol) of the compound from Example 17A, and the mixture was stirred at RT overnight. The reaction mixture was dissolved in 40 ml of acetonitrile and, with ice-cooling, stirred into 27 ml of concentrated aqueous ammonia solution (33% strength). The mixture was stirred at room temperature for 2 days. The mixture was then concentrated. The residue was taken up in water and ethanol and treated in an ultrasonic bath. A precipitate was formed, which was filtered off with suction and washed with water, ethanol and then with diethyl ether. DMF was added to this residue, acetonitrile and water were added and the mixture was then once more filtered off with suction. The precipitate was washed with acetonitrile and water and then dried under high vacuum. This gave 149 mg of the title compound (52% of theory, purity 94%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:7][CH:6]=1.C([Li])CCC.[C:37](Cl)(=[O:41])[O:38][CH2:39][CH3:40].[Cl-].[Na+]>O1CCCC1.CCCCCC>[CH2:39]([O:38][C:37]([N:15]([CH2:14][CH2:13][CH:12]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][CH:9]=1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:17])=[O:18])=[O:41])[CH3:40]
Reactant: COCOc1ccc(CC(CCNS(=O)(=O)c2ccc(Cl)cc2)c2cccnc2)cc1
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N(CCC(Cc1ccc(OCOC)cc1)c1cccnc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
In argon atmosphere, 329 mg of N-[4-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)butyl]-4-chlorobenzene sulfonamide was dissolved in 12 ml of dry tetrahydrofuran, and cooled to 0° C., followed by addition of 0.67 ml of the solution of 1.55M n-butyl lithium in hexane, which was then stirred for 30 minutes. At the same temperature, 116 mg of ethyl chlorocarbonate dissolved in 3 ml of dry tetrahydrofuran was added dropwise and stirred at room temperature for 24 hours. To the reaction mixture was added saturated aqueous sodium chloride, and the organic phase was separated which was then extracted with ethyl acetate. The organic phases combined were washed in saturated aqueous sodium chloride and dried over magnesium sulfate, so the solvent was distilled off under reduced pressure. The obtained residue was subjected to preparative silica gel TLC which was then developed with methanol-methylene chloride (4:96 v/v) to obtain 204 mg of N-ethoxycarbonyl-N-[4-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)butyl]-4-chlorobenzene sulfonamide from a band of 0.36 to 0.53.