Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH3:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=1.[Cl:14][C:15]([Cl:25])([Cl:24])[CH2:16][O:17][S:18]([N:21]=[C:22]=[O:23])(=[O:20])=[O:19]>C(Cl)Cl>[CH3:13][O:12][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][N:8]=2)[N:3]=[C:2]([NH:1][C:22]([NH:21][S:18]([O:17][CH2:16][C:15]([Cl:25])([Cl:24])[Cl:14])(=[O:19])=[O:20])=[O:23])[N:11]=1
Reactant: COc1nc(N)nc2nccnc12
Reactant: O=C=NS(=O)(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1nc(NC(=O)NS(=O)(=O)OCC(Cl)(Cl)Cl)nc2nccnc12
Reaction time: 0.17 h
Yield: 95 %

Procedure:
To a suspension of 0.88 g (0.005 mol) of 2-amino-4-methoxypteridine in 40 ml of absolute methylene chloride were added with stirring to 1.35 g (0.053 mol) of 2,2,2-trichloroethoxysulfonyl isocyanate. After about 10 minutes, a clear solution had formed and it was heated to reflux. After 10 minutes, the mixture was evaporated to dryness and the residue was treated with diisopropyl ether and a little acetone. The mixture was vacuum filtered and the product was dried to obtain 2.05 g (95% of theory) of N-(4-methoxypteridin-2-yl)-N'-(2,2,2-trichloroethoxysulfonyl)-urea in the form of yellow crystals melting at 93° C. (decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([F:11])=[CH:4][C:3]=1[CH2:12][C:13]([O:15]CC)=[O:14].Cl[Sn]Cl.[CH3:21][CH2:22]O>>[CH2:21]([CH:12]([C:3]1[CH:4]=[C:5]([F:11])[C:6]([NH2:8])=[CH:7][C:2]=1[F:1])[C:13]([OH:15])=[O:14])[CH3:22]
Reactant: CCOC(=O)Cc1cc(F)c([N+](=O)[O-])cc1F
Reactant: CCO
Agent: Cl[Sn]Cl
Product: CCC(C(=O)O)c1cc(F)c(N)cc1F
Reaction time: 18 h
Yield: 52 %

Procedure:
To a stirred solution of ethyl 2,5-difluoro-4-nitrophenylacetate (5.88 g, 25.4 mol) in EtOH (100 mL), was added SnCl2 (17.2 g, 76.3 mmol) at rt. The stirring was continued for 18 hours at reflux. After removal of the solvent, the residue was dissolved in CHCl3 (100 mL) and poured into ice water-4M NaOH (40 mL of 4M NaOH in 300 mL of ice-water), extracted with CHCl3 (100 mL×2), dried over anhydrous MgSO4, and concentrated under a reduced pressure. The residue was chromatographed on silica gel (middle pressure chromatography system YAMAZEN YFLC-5404, linear gradient of hexane-EtOAc from 9:1 to 7:3, φ50 mg×500 mg, 15 ml/min) to give ethyl 4-amino-2,5-difluorophenylacetic acid (2.85 g, 52%) as a colorless oil. 1H-NMR (CDCl3) δ 1.28 (t, J=7.3 Hz, 3 H), 3.51 (s, 2 H), 3.78 (br s, 2 H), 4.15 (dd, J=7.2 Hz, 14.2 Hz, 2 H), 6.47 (dd, J=7.5, 10.4 Hz, 1 H), 6.88 (dd, J=6.7, 11.0 Hz, 1 H); MS (FAB) m/z 216 (M++1).
Reaction SMILES: [CH3:1][C:2]1(C)[CH2:6][O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([NH:16][CH2:17][CH:18]([OH:25])[CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=N1.S(=O)(=O)(O)[OH:28].O>C(O)CC>[OH:25][CH:18]([CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[CH:21]1)[CH2:17][NH:16][C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:4]([O:5][CH2:6][CH2:2][CH3:1])=[O:28])=[CH:8][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CC1(C)COC(c2ccc(C(C)(C)NCC(O)Cn3ccnc3)cc2)=N1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CCCO
Product: CCCOC(=O)c1ccc(C(C)(C)NCC(O)Cn2ccnc2)cc1

Procedure:
A mixture of 1-{1-[4-(4,4-dimethyl-2-oxazolin-2-yl)phenyl]-1-methylethylamino}-3-(imidazol-1-yl)propan2-ol (100 mg) and a solution of sulphuric acid in propan-1-ol (5 ml) [prepared by adding concentrated sulphuric acid (4 ml) and then water (5 ml) to propan-1-ol (50 ml) and making up to 100 ml with propan-1-ol] was heated on a steam bath for 18 hours. The mixture was evaporated under reduced pressure. The residue was basified with aqueous sodium hydroxide solution and then extracted with dichloromethane to give a residue which was purified by flash column chromatography on silica using ethyl acetate/triethylamine (9:1) with increasing amounts of ethanol to give propyl 4-{1-[2-hydroxy-3-(imidazol-1-yl)propylamino]-1-methylethyl}benzoate as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([Sn](CCCC)(CCCC)CCCC)=[N:21][CH:22]=1>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.C1(C)C=CC=CC=1>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[N:21][CH:22]=1
Reactant: COC(=O)c1cc(Br)cc(S(C)(=O)=O)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A mixture of methyl 3-bromo-5-(methylsulfonyl)benzoate (1.0 g, 3.4 mmol), 5-methyl-2-(tributylstannyl)pyridine (1.2 mL, 3.5 mmol), tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol), and toluene (10 mL) under argon was subjected to microwave irradiation at 120° C. for 2 hours. The mixture was cooled to room temperature. The precipitate was collected by filtration and rinsed with hexane to afford the title compound as a light brown solid (432 mg). The filtrate was concentrated and the residue was purified via flash chromatography to afford another crop of the product as a light yellow solid (200 mg). 1H NMR (400 MHz, CDCl3): 8.91 (t, J=1.4 Hz, 1H), 8.80 (d, J=1.7 Hz, 1H), 8.61 (s, 1H), 8.58 (d, J=0.8 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 4.00 (s, 3H), 3.15 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7](Cl)=[CH:6][C:5]=1[NH:12]C(=O)C)([O-:3])=[O:2].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[K+].[K+].[Br-]>CS(C)=O>[N+:1]([C:4]1[CH:9]=[C:8]([F:10])[C:7]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:6][C:5]=1[NH2:12])([O-:3])=[O:2]
Reactant: C1CCNCC1
Reactant: CC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1cc(N2CCCCC2)c(F)cc1[N+](=O)[O-]
Yield: 52 %

Procedure:
2-Nitro-4-fluoro-5-(piperidin-1-yl)aniline (13.0 g, 52%) was prepared by an analogous procedure as described in preparation 1 (step 3) using N-(2-nitro-4-fluoro-5-chloro phenyl)acetamide (25.0 g, 0.107 mol) (obtained in preparation 1, step 2), piperidine (45.8 a, 0.537 mol), potassium hydroxide (9.0 g, 0.16 mol) and dimethyl sulfoxide (100 mL). mp 112-113° C. IR (KBr) 3472, 1234 cm-1 ; 1H NMR (CDCl3) δ 1.60 (m, 2H, CH2), 1.70 (m, 4H, (CH2)2), 3.22 (m, 4H, N(CH2)2), 5.88 (d, J=7.6 Hz, 1H), 6.08 (brs, 2H, NH2), 7.78 (d, J=14.2 Hz, 1H) ; Mass (m/z) 239 (M+.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][NH2:7].[C:12](Cl)(Cl)=[S:13].O>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[CH2:5][CH2:6][N:7]=[C:12]=[S:13]
Reactant: S=C(Cl)Cl
Reactant: COc1ccccc1CCN
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1CCN=C=S
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 2-methoxyphenethylamine (1.98 g) in diethylether (20 ml) was added dropwise under ice-cooling thiophosgene (1.54 g). The mixture was stirred at room temperature for 1 hour. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give (2-methoxyphenethyl)isothiocyanate (1.80 g, yield: 71%) as brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:36])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([OH:34])([CH3:33])[CH3:32])[N:26]=3)[CH:22]=[CH:21][C:20]=2[CH3:35])[C:5]([CH3:18])=[N:6][C:7]=1[O:8]CC1C=CC(OC)=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3](=[O:36])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([OH:34])([CH3:32])[CH3:33])[N:26]=3)[CH:22]=[CH:21][C:20]=2[CH3:35])[C:5]([CH3:18])=[N:6][C:7]=1[OH:8]
Reactant: COc1ccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)nc(O)c(Cl)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution 5-chloro-3-{5-[2-(1-hydroxy-1-methyl-ethyl)-pyrimidin-4-yl]-2-methyl-phenyl}-6-(4-methoxy-benzyloxy)-2-methyl-3H-pyrimidin-4-one from Step I (661 mg, 1.31 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). The solution was stirred at ambient temperature for one hour. Concentration in vacuo provided the title compound as a yellow solid (assume theoretical yield). MS (M+H): 387
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](OC)(=[O:24])[C:21]([CH3:23])=[CH2:22]>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[C:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=C(C)C(=O)OC
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=C(C)C(=O)OCCCCCCCC/C=C\C/C=C\CCCCC
Yield: 1032.5 %

Procedure:
The method of Example 1 was substantially repeated with cis,cis-9,12-octadecadien-1-ol (25.0 g, 9.38 mmol), methyl methacrylate (40 mL, 38 mmol), phenothiazine (0.1 g), and tetraisopropyl titanate (1 mL). When the head temperature rose to 99° C. (pot 112° C.), the reaction mixture was cooled. The material was filtered through activity grade I alumina (30 g, Woelm), and the column was rinsed with ethyl acetate. The combined filtrates were concentrated on a rotary evaporator, finally down to 0.5 mm, to give 32.4 g of light-yellow cis,cis-9,12-octadecadienyl methacrylate. Analysis by HPLC (dichloromethane:ethyl acetate:isopropyl alcohol, 90:10:1, silica gel column) showed that no unreacted octadecadienol was present. 90 MHz 1H NMR: δ 6.03 (1H, broad s, methacrylate vinyl), 5.47 (1H, m, methacrylate vinyl), 5.30 (4H, m, vinyl), 4.09 (2H, t, J=7, OCH2), 2.75 (2H, broad t, J~6, doubly allylic CH2), 2.2-1.1 (27H, m), and 0.89 (3H, t, J~6, --CH2CH3). The NMR spectrum indicated the presence of about 10 mole % methyl methacrylate.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=3[N:19]=2)[C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)(=[O:4])=[O:3].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C1COCC1>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:2]([C:5]2[CH:6]=[C:7]([C:14]3[NH:15][C:16](=[O:27])[C:17]4[N:22]([CH3:23])[N:21]=[C:20]([CH2:24][CH2:25][CH3:26])[C:18]=4[N:19]=3)[C:8]3[O:12][CH2:11][CH2:10][C:9]=3[CH:13]=2)(=[O:4])=[O:3])[CH2:31][CH2:30]1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)cc4c3OCC4)nc12
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)cc4c3OCC4)nc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 6a (1.25 g, 0.003 mole) was dissolved in THF (10 ml) and added to a solution of 1-methylpiperazine (1 ml) in THF (10 ml). The resulting mixture was stirred at room temperature for 1 h. The THF was then removed in vacuo, and the residue was treated with cold water (50 ml). The resulting white precipitate was filtered under suction, washed with water (2×10 ml), drained and recrystallized from 90% ethanol, thereby yielding 7a.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:9][CH:10]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@H:31]([NH2:36])[CH2:32][C:33]([OH:35])=[O:34])=[CH:22]1.C([BH3-])#N.[Na+]>CO.C1COCC1.C(OCC)(=O)C>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([CH2:30][C@H:31]([NH:36][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:32][C:33]([OH:35])=[O:34])=[CH:22]1
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccccc1
Reactant: N[C@H](CC(=O)O)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCN[C@H](CC(=O)O)Cc1c[nH]c2ccccc12)CCc1ccccc1

Procedure:
Combine N-t-butoxycarbonyl-N-(2-oxo-ethyl)-2-phenyl-ethylamine (5.10 g, 19.16 mmol) and (S)-2-(1H-indol-3-yl)-1-carboxymethyl-ethylamine hydrochloride salt ((S)-tryptophan methyl ester hydrochloride salt) (4.90 g, 19.23 mmol) in methanol (50 mL) and stir for 10 minutes. Add sodium cyanoborohydride in solution (19.0 mL, 1M in THF, 19.0 mmol) and stir under an inert atmosphere for 18 hours. Concentrate in vacuo to obtain a residue. Dilute the residue with ethyl acetate and extract with water. Separate the layers, dry the organic layer over MgSO4, filter, and evaporate in vacuo. Chromatograph on silica gel eluting with 50% ethyl acetate/hexane to give the title compound.
Reaction SMILES: C(O[C:6]([N:8]([C:41](OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH:37]3[CH2:39][CH2:38]3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1CC[CH2:50][CH2:49]1>>[CH:37]1([C:33]2[CH:34]=[C:35]([CH3:36])[C:30]([N:27]3[CH2:28][CH2:29][N:24]([C:22]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][C:17]5=[O:21])=[CH:15][C:10]=4[C:9]([N:8]4[CH2:41][CH2:50][CH2:49][CH2:6]4)=[O:40])=[O:23])[CH2:25][CH2:26]3)=[N:31][CH:32]=2)[CH2:38][CH2:39]1
Reactant: C1CCNC1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCC3=O)cc2C(=O)N2CCCC2)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 814 and pyrrolidine (36 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (45 mg) was obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])(=[O:3])N.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])([OH:20])=[O:3]
Reactant: NC(=O)c1cc2c(=O)c3ccccc3ccn2c1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2c(=O)c3ccccc3ccn2c1

Procedure:
To 2-carbamoyl-11H-pyrrolo[2,1-b][3]benzazepine-11-one (27 g., 0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C. is added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to yield 2-carboxy-11H-pyrrolo[2,1-b] [3]benzazepine-11-one.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:32](Cl)(=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>O.O1CCOCC1>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[CH:15][N:14]=[C:13]3[NH:17][N:18]=[C:19]([N:20]4[CH2:25][CH2:24][N:23]([C:32](=[O:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:22][CH2:21]4)[C:12]=23)[CH:7]=[CH:8][CH:9]=1
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: Clc1cccc(Nc2ncnc3[nH]nc(N4CCNCC4)c23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCCCCC(=O)N1CCN(c2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)CC1

Procedure:
Analogously to Example 26, 100 mg (0.248 mmol) of 4-(3-chloro-phenylamino)-3-(piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrmidine dihydrochloride and 103 mg (0.74 mmol) of potassium carbonate in 10 ml of water are reacted with 81.5 mg (0.37 mmol) of lauric acid chloride in 10 ml of dioxane and extracted. Column chromatography (SiO2; methylene chloride/ethyl acetate/acetic acid=50:50:1) yields 4-(3-chloro-phenylamino)-3-(4-[n-dodecanoyl]-piperazin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20)=22.6; FAB-MS: (M+H)+=512.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:15][CH2:16][CH2:17][N:18]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)CC1C=CC=CC=1)[C:6]2=[O:38].[H][H].C(Cl)(Cl)[Cl:42].CO>[Pd]>[ClH:42].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]([CH2:15][CH2:16][CH2:17][NH:18][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:6]2=[O:38]
Reactant: COc1ccc(CCN(CCCn2cnc3cc(OC)c(OC)cc3c2=O)Cc2ccccc2)cc1OC
Reactant: ClC(Cl)Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(CCNCCCn2cnc3cc(OC)c(OC)cc3c2=O)cc1OC
Product: Cl

Procedure:
1-(6,7-Dimethoxy-4(3H)-quinazolinone-3-yl)-3-[N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane-hydrochloride was prepared analogous to Example 6 (b) by debenzylation of 1-(6,7-dimethoxy-4-(3-H)-quinazolinone-3-yl)-3-[N-benzyl-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane in the presence of palladium-on-charcoal (10%) with hydrogen. Rf -value (chloroform/methanol = 9.1) : 0.45. M.p.: 192 -194° C.
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20].CN(C)C=O.[N-:26]=[N+:27]=[N-:28].[Na+]>C1(C)C=CC=CC=1>[N:26]([C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH3:16])[CH:14]=3)[C:6]=2[N:5]([CH2:17][CH2:18][CH3:19])[CH2:4][C:3]=1[CH3:20])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC)C=C1C=N2
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCN1CC(C)=C(N=[N+]=[N-])C2=C1N1CN(OC)C=C1C=N2
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1.5 g of intermediate A1 are stirred into 10 ml N,N-dimethylformamide. 1 g NaN3 is added at room temperature. The mixture is heated up to 60° C. and stirred for 5 hours. 100 ml toluol are added. The organic layer is separated and washed with 3×30 ml water. 90 ml of the solvent are removed. The reaction product precipitates. The crude product is purified by crystallisation from toluol.
Reaction SMILES: C([NH:7][C:8]1[N:9]=[C:10]([OH:41])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:36]([O:38]CC)=[O:37])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:26])[N:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1)(=O)C(C)(C)C.Cl>[OH-].[Na+]>[NH2:7][C:8]1[N:9]=[C:10]([OH:41])[C:11]2[CH2:17][CH:16]([CH2:18][CH2:19][C:20]3[S:21][CH:22]=[C:23]([C:25]([NH:27][C@H:28]([C:36]([OH:38])=[O:37])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:26])[N:24]=3)[CH2:15][NH:14][C:12]=2[N:13]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1csc(CCC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)n1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nc(O)c2c(n1)NCC(CCc1nc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cs1)C2
Temperature: 25 °C
Reaction time: 84 h
Yield: 72.7 %

Procedure:
To a 25 mL 14/20 round bottom flask was charged 0.067 g (0.11 mmol) of diethyl N-{2-[2-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-4-thiazolylcarbonyl}-L-glutamate dissolved in 3 mL of 1N sodium hydroxide. The reaction was stirred at room temperature for 84 hours The solution was cooled down in an ice bath and acidified with 1N hydrochloric acid to pH 3. The precipitate was filtered, washed with 25 mL water, and dried in a vacuum oven at 60° C. to give 0.036 g (70%) of N-{2-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]-4-thiazolylcarbonyl}-L-glutamic acid m.p. 210-212° C. as a tan solid. Rf =0.08 (50% methanol/chloroform); 1H NMR (300 MHz, DMSO d6) δ 1.69-2.09 (m, 8H), 2.26 (t, J=7.1 Hz, 2H), 2.80 (t, J=8.2 Hz, 2H), 3.05-3.17 (m, 2H), 4.34-4.41 (m, 1H), 5.93 (s, 2H), 6.26 (s, 1H), 8.12 (s, 1H), 8.33 (d, J=7.7 Hz, 1H), 9.70 (br s, 1H).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14]>O.C(OCC)(=O)C>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:35][CH:36]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]=[C:24]2[CH3:48])=[CH:21][CH:22]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCc1nc(C)n(-c2ccc(C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogen carbonate (2.6 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C. for 30 min, 4′-{[1-(4-tert-butylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.12 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.51 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.91 g, 72%).