Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][C:12]1[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=1.C(N(CC)CC)C>O>[NH2:8][C:7]1[C:2]([NH:10][CH2:11][C:12]2[O:16][C:15]([CH2:17][OH:18])=[CH:14][CH:13]=2)=[N:3][CH:4]=[N:5][C:6]=1[Cl:9]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: NCc1ccc(CO)o1
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1c(Cl)ncnc1NCc1ccc(CO)o1
Reaction time: 10 h
Yield: 76.6 %

Procedure:
A mixture of 16.3 parts of 4,6-dichloro-5-pyrimidinamine, 14 parts of 5-(aminomethyl)-2-furanmethanol, 12 parts of N,N-diethylethanamine and 200 parts of water was stirred for 10 hours at reflux temperature. The reaction mixture was evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH(NH3) 95:5). The eluent of the desired fraction was evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 19.5 parts (76.6%) of 5-[[(5-amino-6-chloro-4-pyrimidinyl)amino]methyl]-2-furanmethanol; mp. 136.7° C. (interm. 17).
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6](=[S:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])C.N1C=CC=CC=1.NOS(=O)(=O)O>C(O)C>[S:12]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:5][CH:4]=[N:2]1
Reactant: CCOC(=O)C(=S)/N=C/N(C)C
Agent: NOS(=O)(=O)O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1ncns1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To ethyl {[(1E)-(dimethylamino)methylidene]amino}(thioxo)acetate (I78) (1.42 g, 7.54 mmol) and pyridine (1.220 mL, 15.09 mmol) dissolved in Ethanol (20 mL) was added (aminooxy)(hydroxy)sulfane dioxide (0.938 g, 8.30 mmol) dissolved in Ethanol (18 ml) and the mixture stirred at 25° C. for 48 hr. The solvents were concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with saturated sodium bicarbonate solution (25 mL), aqueous phase back extracted with ethyl acetate (25 mL) and the organic extracts were combined. The solution was washed with brine (25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil. The crude oil was purified by flash chromatography (Isolera, 50 g, 0-100% ethyl acetate/iso-hexane, 15 column volumes) to afford product in 246 mg.
Reaction SMILES: [NH2:1][N:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:28].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36].C(OCC)(=O)C>O1CCCC1.O>[C:35]([NH:1][N:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:16]2[CH:17]=[C:18]([O:26][CH3:27])[C:19]([O:24][CH3:25])=[C:20]([O:22][CH3:23])[CH:21]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:28])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1N
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NC(C)=O
Yield: 52.3 %

Procedure:
To a solution of the compound obtained in Example 68 (200 mg) and pyridine (120 mg) in tetrahydrofuran (15 ml) is added dropwise a solution of acetyl chloride (61.3 mg) in tetrahydrofuran (5 ml) under ice-cooling, and the mixture is stirred under ice-cooling for one hour, and further stirred at room temperature overnight. To the reaction mixture are added ethyl acetate and water, and the ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue is crystallized from a mixture of hexanediethyl ether to give 2-acetylamino-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (116 mg) as listed in Table 6.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Cu](C#N)[C:13]#[N:14].C(OCC)(=O)C.O>CN1CCCC1=O>[F:11][C:4]1[CH:3]=[C:2]([CH:9]=[C:6]([CH:7]=[O:8])[C:5]=1[F:10])[C:13]#[N:14]
Reactant: N#C[Cu]C#N
Reactant: O=Cc1cc(Br)cc(F)c1F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(F)c(C=O)c1
Temperature: 170 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 10.0 g of 5-bromo-2,3-difluorobenzaldehyde in 40.0 mL of 1-methyl-2-pyrrolidone was added 4.26 g of copper cyanide (I) at room temperature and stirred at 170° C. for 8 hours. Adding ethyl acetate and water, the solution was stirred, and insoluble substances were filtered out through celite. The organic layer of filtrate was washed successively with saturated aqueous ammonium chloride, water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:20), to afford 2.64 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]([CH:3]([CH:9]([CH3:11])[CH3:10])[C:4]([O:6]CC)=O)#[N:2].[CH2:12]([NH:14][C:15]([NH2:17])=[O:16])[CH3:13].[O-]CC.[Na+].Cl>C(O)C.O>[CH2:12]([N:14]1[C:1]([NH2:2])=[C:3]([CH:9]([CH3:10])[CH3:11])[C:4](=[O:6])[NH:17][C:15]1=[O:16])[CH3:13]
Reactant: CCNC(N)=O
Reactant: CCOC(=O)C(C#N)C(C)C
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCn1c(N)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 12.25 h
Yield: 39.3 %

Procedure:
A flask was charged with ethyl 2-cyano-3-methylbutanoate (3b, 10.0 g, 64.4 mmol), ethyl urea (3a, 5.96 g, 67.6 mmol) and EtOH (129 mL). To the slurry at room temperature was added sodium ethoxide in ethanol (21% w/w soln, 28.8 mL), mild exotherm detected. The heterogeneous reaction mixture was then heated to reflux. The reaction was refluxed for 4 to 12 h. Upon reaction completion, as determined by TLC analysis, the reaction mixture was concentrated and solvent exchanged to acetonitrile (ACN) through 3×20 mL co-evaporations leaving a basic 1-2 vol. solution in ACN. To the reaction mixture was added 1-2 vol. of water followed by a pH adjustment with 2N HCl (aq.). As the pH approached 10 white to off-with solids began forming and as the pH was further reduced to 9 (by pH paper) white slurry resulted. This slurry was aged for 0.5-24 h and then filtered. The resulting solids were washed with 1 vol. of water and 2×2 vol. MTBE. The white to off-white solids were then dried in a vacuum oven at 40-50° C. giving 4.99 g (39%) of 1-ethyl-5-isopropyl-6-amino uracil 2:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[Cl:13][C:14]1[C:23]([Cl:24])=[C:22]2[C:17]([C:18](=[O:25])[CH2:19][CH2:20][S:21]2)=[CH:16][CH:15]=1.Cl>CCOCC>[Cl:13][C:14]1[C:23]([Cl:24])=[C:22]2[C:17]([C:18](=[O:25])[CH:19]([C:3](=[O:5])[C:2]([F:1])([F:8])[F:9])[CH2:20][S:21]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: O=C1CCSc2c1ccc(Cl)c2Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Product: O=C1c2ccc(Cl)c(Cl)c2SCC1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 19.4 h

Procedure:
Ethyl trifluoroacetate (0.29 g, 2.0 mmol) was placed in a round bottom flask, and dissolved in ether (12 mL). To the stirred solution was added sodium methoxide (25%) (0.84 g, 3.9 mmol), followed by 7,8-dichlorothiochroman-4-one from Step 2 (0.42 g, 1.8 mmol). The reaction was stirred at room temperature overnight (19.4 hours) and treated with 3N hydrochloric acid. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo to give a brown oily solid which was used without purification in the next step.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[CH3:59][C:60]1[CH:65]=[CH:64][C:63]([S:66]([N-:69][Cl:70])(=[O:68])=[O:67])=[CH:62][CH:61]=1.O.O.O.[Na+].S([O-])([O-])=O.[Na+].[Na+].CC1C=CC(S(N)(=O)=O)=CC=1>C(#N)C.O>[CH3:59][C:60]1[CH:65]=[CH:64][C:63]([S:66]([NH:69][Cl:70])(=[O:68])=[O:67])=[CH:62][CH:61]=1
Reactant: Cc1ccc(S(=O)(=O)[N-]Cl)cc1
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: Cc1ccc(S(N)(=O)=O)cc1
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCl)cc1

Procedure:
To a stirred solution of (DHQ)2-PHAL (0.11 g, 0.14 mmol, 5 mol %) in 20 mL of acetonitrile and 20 mL of water, in any convenient-sized glass vessel or vial, was added desired olefin (all commercially available from Aldrich, 2.8 mmol), Chloramine-T trihydrate (2.42 g, 8.4 mmol, 3 eq) and K2OsO2(OH)4 (41.6 mg, 0.112 mmol, 4 mol %). As the reaction proceeded to completion over the course of about one and half hours at room temperature, the color of the solution changed from yellow to pale green, then deep green and finally back to yellow (for entry 3 in Table 1, the yellow color remains throughout). After addition of aqueous sodium sulfite (1.0 g in 15 mL H2O), the phases were separated, and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with brine, dried over MgSO4 and the solvent concentrated to give the crude product, which also contains the p-toluenesulfonamide by-product produced upon the reduction of the excess Chloramine-T. In the case of the ethyl crotonate derivative, product 5, flash chromatography (6:4:1 hexane/CHCl3/MeOH) of this material provided 0.44 g (52% yield, 74% ee) of (2R,3S)-ethyl-N-(p-toluenesulfonyl)-2-hydroxy-3-amino-butanoate (5) as a clear oil eluting before the p-toluenesulfonamide impurity (52% yield, 74% ee). Similar purification provides compounds 2, 6, 7, 8 and 9. with the indicated yields and conditions shown in FIG. 4. NOTE: Replacement of the 3 eq of Chloramine-T with 1.5 eq of Chloramine-T and 1.5 eq of Et4NOAc gives comparable results and reduces the amount of p-toluenesulfonamide by-product formed. This can greatly simplify product isolation, especially in cases where the product and the toluenesulfonamide have similar chromatographic mobilities.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([CH2:14][C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[CH:17][C:16]=2[Cl:22])=[N:4][N:3]=1.[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Cl:21])[C:15]=1[CH2:14][C:5]1[C:6]2[C:11](=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=2)[C:2]([NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[N:3][N:4]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: Nc1nccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Nc3nccs3)c2c1
Yield: 40.7 %

Procedure:
At 100° C. a solution of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (0.5 g, 1.41 mmoles), prepared as described in example 45, 2-aminothiazole (0.424 g, 4.23 mmoles), triethylamine (0.59 ml, 4.23 mmoles), palladium acetate (16 mg, 0.07 mmoles) and triphenylphosphine (56 mg, 0.21 mmoles) was stirred under N2. After 20 hours the mixture was poured into water/ice and extracted more times with CH2Cl2. The organic phase was washed with water, anhydrified and concentrated to give a solid which was flash chromatographed (eluent: hexane/ethyl acetate 7:3) yielding 0.24 g of the title compound (yield: 50%). m.p.: 218-220° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26]([N:34]=[C:35]=[S:36])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC(C)=O>[C:26]([NH:34][C:35](=[S:36])[NH:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Solvent: O
Solvent: CC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(=S)NC(=O)c3ccccc3)nc21
Temperature: 0 °C
Yield: 88.4 %

Procedure:
A solution of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 234 mg, 0.69 mmol) and benzoyl isothiocyanate (0.1 ml, 0.83 mmol) in acetone (3 ml) was stirred at room temperature for 3 h. The reaction mixture was cooled to 0° C. and water was added. The resulting brown solid was collected by filtration and air-dried to give 4-(3-benzoylthioureido)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (306 mg, 88% yield)
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([NH2:24])[CH2:19]2)=[O:10])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.C(N(CC)CC)C.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:11][C:9]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([Br:8])[N:4]=2)=[O:10])[CH2:19]1)(=[O:34])[CH3:33]
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cnccc1N1CCCC(N)C1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCCN(c2ccncc2NC(=O)c2nc(Br)cnc2N)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To solution of 3-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-6-bromopyrazine-2-carboxamide in CH2Cl2 at a concentration of 0.5 M at room temperature was added triethylamine (3 eq) followed by acetic anhydride (1.2 eq). The reaction was stirred at room temperature for 30 minutes, concentrated, purified by reverse phase HPLC and lyophilized to provide N-(4-(3-acetamidopiperidin-1-yl)pyridin-3-yl)-3-amino-6-bromopyrazine-2-carboxamide, as the TFA salt. LCMS (m/z): 434.1 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:18])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[S:11][C:12]=1[CH3:13])=[CH2:2]>CO.[Pd]>[CH2:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:18])[C:7]=1[C:8]1[CH:9]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[S:11][C:12]=1[CH3:13])[CH3:2]
Reactant: C=Cc1cnn(C)c1-c1cc(C(=O)OC)sc1C
Agent: [Pd]
Solvent: CO
Product: CCc1cnn(C)c1-c1cc(C(=O)OC)sc1C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a solution of methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (135 mg, 0.52 mmol) in methanol (2.6 ml) was added Pd—C (21.9 mg, 0.21 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N2, filtered through Celite and concentrated affording methyl 4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (145 mg, 0.51 mmol, 99% yield) as a yellow oil which was used without further purification: LCMS (ES) m/e 265 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=O)[O:15]C3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[CH:4][N:3]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([F:36])([F:35])[CH:32]([F:34])[F:33])=[CH:25][CH:24]=1.C(O)C.O.[NH2:41][NH2:42]>O1CCCC1>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:15])[NH:41][NH2:42])=[CH:11][CH:12]=2)[N:5]=[CH:4][N:3]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]([F:35])([F:36])[CH:32]([F:34])[F:33])=[CH:25][CH:24]=1
Reactant: O=C(Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1)Oc1ccccc1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: NNC(=O)Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Yield: 97.8 %

Procedure:
Phenyl 4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-1H,4H-1,2,4-triazol-1-yl]phenylcarbamate (5.6 g) was added to a mixture of ethanol (100 ml) and tetrahydrofuran (100 ml). To the resulting mixture was added hydrazine hydrate (3 g) with stirring. The resultant was stirred at 80° C. for 2 hours and concentrated under reduce pressure to about 20 ml. After water (100 ml) was added, the precipitated crystals were collected by filtration, washed with ethanol and dried under reduced pressure to give 4-[4-[5-oxo-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1H,4H-1,2,4-triazol-1-yl]phenyl]semicarbazide (4.8 g, 98%) as colorless prisms.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][CH2:6][O:5]1.[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1>[O:5]1[CH2:6][CH2:7][CH2:8][O:9][CH:4]1[CH2:3][CH2:2][CH:17]([CH:11]1[CH2:12][CH:13]2[CH2:16][CH:10]1[CH:15]=[CH:14]2)[OH:18]
Reactant: BrCCC1OCCCO1
Reactant: O=CC1CC2C=CC1C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(CCC1OCCCO1)C1CC2C=CC1C2
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
A Grignard reagent was customarily prepared from 36.2 g of 2-(2-bromoethyl)-1,3-dioxane in 200 ml of dry tetrahydrofuran. Then 19.5 g of 5-norbornene-2-carbaldehyde was added dropwise over 30 minutes to the Grignard reagent at 20° C. Stirring was continued for 30 minutes whereupon the reaction solution was added to a saturated aqueous solution of ammonium chloride to stop reaction. After diethyl ether extraction, the organic layer was successively washed with water, saturated sodium bicarbonate water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 36.2 g of 3-(1,3-dioxan-2-yl)-1-(5-norbornen-2-yl)-1-propanol (boiling point 125° C./27 Pa, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.CN(C)CCN(C)C.C([Li])CCC.[CH:31]([CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)=[O:32].[NH4+].[Cl-]>CCCCCC.C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:31]([OH:32])[CH:33]3[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])[CH2:35][CH2:34]3)[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1c(C(O)C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: -40 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (750 mg, 3.0 mmol) and N,N,N′,N′-Tetramethylethylenediamine (0.9816 mL, 6.504 mmol) in tetrahydrofuran (38 mL, 460 mmol) was added 1.6 M of n-butyllithium in hexane (4.065 mL) at −78° C. The resulting orange cloudy mixture was stirred at −78° C. for 45 minutes and at −40° C. for 5 minutes. Tert-butyl 4-formylpiperidine-1-carboxylate (1.261 g, 5.913 mmol) in 2 mL of THF was then added. The resulting yellow mixture was stirred at −78° C. for 1 hour. The reaction was then allowed to warm to room temperature. The reaction was then stirred at room temperature for 20 minutes. The reaction was then poured onto sat. NH4Cl. the product was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by FCC (0-10% MeOH in DCM) to give the title compound as a white foam. LCMS m/z 467.3 (MH+).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>[C:15]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3][C@@H:2]1[CH3:1])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-tert-butyl 3-methylpiperazine-1-carboxylate (6.00 g, 30.0 mmol) was dissolved in dry DMF (40 mL) and N,N-diisopropylethylamine (DIEA) (6.00 mL). Benzoyl chloride (3.65 mL, 31.5 mmol) was added drop-wise and the reaction was stirred at rt for 16 hours. The reaction was taken up in ethyl acetate (200 mL) and washed with aqueous K2CO3 (10%), water, and saturated sodium chloride. The organic phase was dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/0-50% ethyl acetate gave an off-white solid.
Reaction SMILES: [C:1]1(/[C:7](/[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26]Br)=[CH:20][CH:19]=2)=[C:8](/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)\[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][NH2:29]>C(O)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:29][CH3:28])=[CH:20][CH:19]=2)=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC/C(=C(\c1ccccc1)c1ccc(OCCBr)cc1)c1ccccc1
Reactant: CN
Solvent: CCO
Product: CNCCOc1ccc(C(=C(CCO)c2ccccc2)c2ccccc2)cc1
Yield: 73 %

Procedure:
42,3 g of (Z)-1,2-diphenyl-1-[4-(2-bromoethoxy)phenyl]-1-buten-4-ol is stirred kith 500 ml of 33% methylamine in ethanol for 10 h at 100° C. in autoclave. The solvent is evaporated and the evaporation residue is dissolved in ethyl acetate in the presence of 2M sodium carbonate solution. After washing the ethyl acetate layer kith water and drying kithsodium sulfate the solvent is evaporated. Recrystallization from toluene gives 27,2 g (73%) of the product having m.p. 135°-9° C.
Reaction SMILES: [OH:1][C:2]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([CH3:26])[C:3]=1[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=O.[H][H]>C(O)(=O)C.[Pd]>[OH:1][C:2]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[CH:19]=[C:18]([CH3:26])[C:3]=1[CH2:4][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: [H][H]
Reactant: COC(=O)CCCCCCCCC(=O)c1c(C)cc(OC)c(OC)c1O
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)CCCCCCCCCc1c(C)cc(OC)c(OC)c1O

Procedure:
A solution of methyl 9-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)nonanoate (formula II-1 wherein R=H3CO, X=H, Y=OH, n=8, in the form of methyl ester) (0.12 part) in acetic acid (17 volume parts) was shaken with 5% palladium-on-carbon in a current of hydrogen gas at 50°-60° C. The catalyst was removed by filtration and the acetic acid was distilled off under reduced pressure. The residue was subjected to column chromatography on silicic acid (6 parts) and elution was carried out with chloroform. The procedure provided methyl 10-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)decanoate (formula II-2 wherein R=H3CO, X=H, Y=OH, n=8, in the form of methyl ester) (0.09 part) as a colorless oil.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CC1CCCN1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCC3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 2-methylpyrrolidine (74.8 mg, 0.88 mmol, 2.00 equiv), potassium carbonate (181.6 mg, 1.32 mmol, 3.00 equiv), and N,N-dimethylformamide (4 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was t quenched by the addition of water and the resulting solution was extracted with 5×20 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:100). This resulted in 110.3 mg (72%) of methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.