Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]([NH:24][NH2:25])=[O:23])[N:16]=2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)(=[O:4])=[O:3].[CH3:26]OC(OC)OC.CS(O)(=O)=O.CO>O.ClCCl>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:15]2[N:19]=[CH:18][N:17](/[CH:20]=[CH:21]\[C:22]3[O:23][CH:26]=[N:25][N:24]=3)[N:16]=2)[CH:8]=[C:9]([C:11]([F:12])([F:14])[F:13])[CH:10]=1)(=[O:4])=[O:3]
Reactant: COC(OC)OC
Reactant: CS(=O)(=O)c1cc(-c2ncn(/C=C\C(=O)NN)n2)cc(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1cc(-c2ncn(/C=C\c3nnco3)n2)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 19.5 %

Procedure:
In a 3-neck 25 mL round-bottomed flask, (Z)-3-(3-(3-(methylsulfonyl)-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylohydrazide (0.300 g, 1.0 eq.) under N2 atmosphere was added trimethylorthoformate (0.26 g, 3.0 eq.) and Methane sulphonic acid (0.027 g, 0.1 eq.). Reaction mixture was refluxed at 80° C. for 1 h. The progress of the reaction was followed by TLC analysis on silica gel with 10% methanol: dichloromethane as mobile phase and visualization with UV, SM Rf=0.25 and Product Rf=0.41. The resulting yellow reaction mass was poured in 30 mL water and extracted with 3×20 mL ethylacetate. Organic layer was washed with brine solution followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 0.250 g of crude compound. The crude reaction mixture was purified by column chromatography using silica 60/120 using methanol: dichloromethane as mobile phase. The column (2×10 cm) was packed in dichloromethane and started eluting in Methanol in gradient manner starting with fraction collection (25-mL fractions) from 1.5% to 2.5% methanol in dichloromethane. Compound started eluting with 1.5% methanol in dichloromethane. Fraction containing such TLC profile was collected together to obtain pure compound (0.060 g), Yield (20%) 1H NMR (400 MHz, CDCl3) δ 9.76 (S, 1H), 7.2-8.6 (m, 7H), 7.39-7.41 (d, J=10.8, 1H), 5.58-5.88 (d, J=11.2 Hz, 1H), 5.39 (S, 2H), 4.70-4.73 (m, 1H), 1.39-1.41 (d, 6H): LCMS for C21H19F3N4O3 [M+1]+ 432.4 found 432.96 at RT 4.217 min.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH3:16])[CH:7]=1)[CH2:3][CH2:4][OH:5].C[O:18][C:19](=O)[C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:29]Br.C(N(CC)CC)C>CN(C=O)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]([C@H:2]([N:1]2[CH2:29][C:21]3[C:20](=[C:25]([N+:26]([O-:28])=[O:27])[CH:24]=[CH:23][CH:22]=3)[C:19]2=[O:18])[CH2:3][CH2:4][OH:5])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH3:16]
Reactant: COC(=O)c1c(CBr)cccc1[N+](=O)[O-]
Reactant: CCOc1cc([C@H](N)CCO)ccc1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc([C@@H](CCO)N2Cc3cccc([N+](=O)[O-])c3C2=O)ccc1OC

Procedure:
(1R)-2-[1-(3-Ethoxy-4-methoxy-phenyl)-3-hydroxy-propyl]-7-nitro-2,3-dihydro-isoindol-1-one was prepared by the procedure of Example 1 from (3R)-3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propan-1-ol (3.0 g, 13 mmol), 2-bromomethyl-6-nitro-benzoic acid methyl ester (3.6 g, 13 mmol) and triethylamine (2 mL, 14 mmol) in DMF (40 mL) to give a yellow solid (4.1 g, 81% yield): 1H NMR (CDCl3) δ 1.44 (t, J=7 Hz, 3H, CH3), 2.13-2.31 (m, 2H, CH2), 3.54-3.59 (m, 1H, CHH), 3.71-3.77 (m, 1H, NCHH), 3.87 (s, 3H, CH3), 3.94 (d, J=16 Hz, 1H, NCHH), 4.06 (q, J=7 Hz, 2H, CH2), 4.26 (d, J=16 Hz, 1H, NCHH), 5.70 (dd, J=4, 11 Hz, 1H, NCH), 6.85-6.99 (m, 3H, Ar), 7.55-7.77 (m, 3H, Ar); 13C NMR (CDCl3) δ 14.76, 33.92, 45.80, 51.30, 55.98, 58.65, 64.63, 65.84, 111.39, 113.22, 119.75, 122.91, 124.13, 126.74, 130.66, 132.11, 143.84, 146.66, 148.68, 149.33, 164.22.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[N:26])[CH:20]=2)[N:15]=1)=O)(C)(C)C>C(O)=O>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[C:25]#[N:26])[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1nc(-c2cccc(C#N)c2)no1
Solvent: O=CO
Product: N#Cc1cccc(-c2noc(C3CCCCN3)n2)c1
Temperature: 45 °C
Yield: 77.4 %

Procedure:
2-[3-(3-Cyano-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidine-1-carboxylic acid tert-butyl ester (8.1 g) was mixed with 96% formic acid (80 mL) and heated at 45° C. for 1 h. The reaction mixture was concentrated in vacuo. The residue was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The organic layer was dried with sodium sulfate and concentrated again. The residue was triturated with hexanes to give 4.5 g (73.4%) of the title compounds as a white solid. 1H NMR (CDCl3), δ(ppm): 8.41 (s, 1H), 8.33 (d, 1H), 7.78 (dd, 1H), 7.61 (t, 1H), 4.15 (dd, 1H), 3.20 (m, 1H), 2.84 (m, 1H), 2.14 (m, 1H), 1.55–2.00 (m, 5H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:33])[N:24]([CH2:29][CH2:30][C:31]#[N:32])[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:20]=[C:19]([Cl:34])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[C:31]([CH2:30][CH2:29][N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:23](=[O:33])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=[C:19]([Cl:34])[CH:20]=1)(=[O:39])[NH2:32]
Reactant: CC(C)CN(CCC#N)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(CCC(N)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 18 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-isobutyl-carbamoyl]-phenoxy}ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.059 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.047 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:13][CH:14]([C:19]1([CH3:24])OCC[O:20]1)[C:15]([O:17][CH3:18])=[O:16])[C:6]2=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]2[C:7]=1[C:6](=[O:12])[N:5]([CH2:13][CH:14]([C:19](=[O:20])[CH3:24])[C:15]([O:17][CH3:18])=[O:16])[C:4]2=[O:25]
Reactant: COC(=O)C(CN1C(=O)c2c(Cl)ccc(Cl)c2C1=O)C1(C)OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)C(CN1C(=O)c2c(Cl)ccc(Cl)c2C1=O)C(C)=O

Procedure:
Methyl 2-(4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-3-oxo-butyrate was prepared (69 mg, 39%) in the same manner as described in the above example 6 (1) from methyl 3-(4,7-dichloro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.20 g, 0.52 mmol) and p-toluenesulfonic acid monohydrate (50 mg), and the obtained product was identified with the following NMR data.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C1C(=O)N([Br:17])C(=O)C1>>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:17]
Reactant: N#Cc1ccc(N)cc1
Reactant: O=C1CCC(=O)N1Br
Product: N#Cc1ccc(N)c(Br)c1

Procedure:
The title compound was prepared from 4-aminobenzonitrile (2.04 g, 17.2 mmol) and NBS (3.07 g, 17.2 mmol) according to the procedure in Example 16, step (b) (2.53 g, 75%). Mass Spectrum (ESI, m/z): Calcd. for C7H5BrN2, 196.9 (M+H), found 196.7.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.CN.O1CCCC1.F[P-](F)(F)(F)(F)F.[N:40]1(OC(N(C)C)=[N+](C)C)[C:44]2N=CC=CC=2N=N1>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:40][CH3:44])=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 35 %

Procedure:
A mixture of 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (120 mg, 0.35 mmol), a solution of methylamine in tetrahydrofuran (2M, 1 mL, 2.0 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (200 mg, 0.53 mmol) and N,N-dimethylformamide (4 mL) was stirred at room temperature for 5 hr. The mixture was evaporated under reduced pressure, ethyl acetate/tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted with ethyl acetate/tetrahydrofuran (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (45 mg, 41%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:29]>O1CCOCC1>[NH2:29][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OCC(O)Cn1cc(-c2ccc(Oc3ccccc3)cc2)c2c(Cl)ncnc21
Reactant: N
Solvent: C1COCCO1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2CC(O)CO
Temperature: 120 °C

Procedure:
3-[4-Chloro-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-7-yl]propan-1,2-diol (0.6 g) was dissolved in 1,4-dioxane (60 ml) and concentrated aqueous ammonia (60 ml, S.G. 0.880) was added. The mixture was stirred and heated at 120° C. for 18 hours in a pressure vessel. The mixture was evaporated under reduced pressure to give a residue which was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried and evaporated to give a residue which was purified by flash column chromatography on silica using ethyl acetate/industrial methylated spirit (9:1) as the mobile phase to give 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]propan-1,2-diol. The structure was confirmed by 1H nmr and mass spectra.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][C:22]#[N:23])=[CH:9][N:8]=1.[Se](=O)=[O:28]>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][CH:26]=1)[C:6]([C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[C:10]([CH2:21][C:22]#[N:23])=[CH:9][N:8]=1)=[O:28]
Reactant: O=[Se]=O
Reactant: COc1cccc(Cc2ncc(CC#N)c3cc(OC)c(OC)cc23)c1
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)c2ncc(CC#N)c3cc(OC)c(OC)cc23)c1
Yield: 42.8 %

Procedure:
The above 1-(3-methoxybenzyl)-4-cyanomethyl-6,7-dimethoxyisoquinoline (152.7 mg, 0.438 mmol) was dissolved in 10 ml of ethyl acetate, then selenium dioxide (48.8 mg, 58.8 mg, 0.529 mmol) was added. The mixture was refluxed for 1 hr. The crude mixture was filtered through a thin layer of silica gel and washed with ethyl acetate. After the evaporation of solvents, the residue was purified through a flash column chromatography using ethyl acetate and hexane (2/1) to give 1-(3-methoxybenzoyl)-4-cyanomethyl-6,7-dimethoxyisoquinoline as a solid (68 mg, 42.8%).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:18])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[CH2:21]([N:13]1[C:14]2[C:9](=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:10][NH:11][C:12]1=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1NCc2c(cccc2Oc2ccccc2)N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1NCc2c(Oc3ccccc3)cccc2N1Cc1ccccc1
Temperature: 25 °C

Procedure:
The product of 2c above, 5-phenoxy-3,4-dihydro-(1H)-quinazolin-2-one (0.08 g, 0.33 mmol) was dissolved in dimethylformamide (3 mL) and stirred at room temperature under argon. Sodium hydride (0.0084 g, 0.35 mmol) was added and the mixture heated to 55° C. in an oil bath. Gas evolution occurred and a clear solution resulted. Benzyl bromide (0.060 g, 0.35 mmol) was added and the reaction mixture was heated at 55° C. for 1 hour. The solvent was evaporated in vacuo, to give the crude product which was flash chromatographed on silica gel eluted with 0–4% methanol in methylene chloride to give a white amorphous solid. Recrystallization from ethyl acetate hexane gave the title compound as a white crystalline compound. mp 171–173° C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[C:13]([SiH2:17][O:18][C:19]([CH3:43])([CH3:42])[C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]3)=[C:30]([O:40][CH3:41])[CH:29]=2)[CH:21]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([SiH2:17][O:18][C:19]([CH3:43])([CH3:42])[C:20]1[CH:25]=[C:24]([NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[N:23]=[C:22]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]3)=[C:30]([O:40][CH3:41])[CH:29]=2)[CH:21]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: COc1cc(Nc2cc(C(C)(C)O[SiH2]C(C)(C)C)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(C)(C)O[SiH2]C(C)(C)C)cc(Nc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-(trifluoromethoxy)aniline and [4-(tert-butyl-dimethyl-silanyloxymethyl)-6-chloro-pyridin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish gum (Yield=56%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][N:25]([CH3:31])[C@@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:24][N:25]([CH3:31])[C@@H:26]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:27]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CS(C)=O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CN(C)[C@@H]1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and (R)-N,N-dimethylpyrrolidin-3-amine (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 10-35% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (60 mg, 97%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6 H) 2.22-2.35 (m, 2 H) 2.90 (d, J=3.79 Hz, 6 H) 3.78-3.91 (m, 1 H) 4.01-4.16 (m, 2 H) 4.35 (d, J=6.57 Hz, 2 H) 6.26 (d, J=2.27 Hz, 1 H) 7.15 (s, 1 H) 7.60 (d, J=8.34 Hz, 2 H) 7.99 (d, J=8.34 Hz, 2 H) 8.04 (d, J=2.27 Hz, 1 H) 9.88 (br. s., 1 H) 10.77 (s, 1 H). ESI-MS: m/z 409.3 (M+H)+.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([NH:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=[C:9](Cl)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([NH:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=[C:9]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cc(NC2CCCC2)nc(NC2CCCC2)n1
Reactant: C1CNCCN1
Product: c1c(NC2CCCC2)nc(NC2CCCC2)nc1N1CCNCC1
Yield: 81.9 %

Procedure:
2,4-Bis(cyclopentylamino)-6-chloropyrimidine is reacted with piperazine according to the method of Example 4. The title compound is obtained in a yield of 81.9%, m.p.:142°-148° C.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4[CH:21]=[C:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:23]=[CH:24][C:19]=4[O:18][CH2:17]3)[C:9]2=[O:31])C=CC=CC=1.C1(C(C2C=CC=CC=2)N2C3C(=CC(C)=CC=3)C3(C4=CC5OCOC=5C=C4OC3)C2=O)C=CC=CC=1>>[NH:27]1[CH2:28][CH2:29][CH2:30][CH:25]([C:22]2[CH:23]=[CH:24][C:19]3[O:18][CH2:17][C:10]4([C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[NH:8][C:9]4=[O:31])[C:20]=3[CH:21]=2)[CH2:26]1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1ccc(-c3cccnc3)cc12
Agent: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2C(c1ccccc1)c1ccccc1
Product: O=C1Nc2ccccc2C12COc1ccc(C3CCCNC3)cc12

Procedure:
Following the procedure as described in EXAMPLE 1.28, and making non-critical variations using 1′-(diphenylmethyl)-5-pyridin-3-ylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 1′-(diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, the title compound was obtained that was used in the next step.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH2:24][CH2:25][CH2:26][C@H:27]2[CH2:31][CH2:30][CH:29]=[C:28]2[C:32]2[CH:37]=[CH:36][C:35]([C@@H:38]([OH:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:34][CH:33]=2)=[CH:22][CH:23]=1)=[O:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:64]([C:67]1[CH:75]=[CH:74][C:70]([C:71](O)=[O:72])=[CH:69][CH:68]=1)([O-:66])=[O:65].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH2:24][CH2:25][CH2:26][C@H:27]2[CH2:31][CH2:30][CH:29]=[C:28]2[C:32]2[CH:33]=[CH:34][C:35]([C@H:38]([O:44][C:71](=[O:72])[C:70]3[CH:69]=[CH:68][C:67]([N+:64]([O-:66])=[O:65])=[CH:75][CH:74]=3)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:36][CH:37]=2)=[CH:22][CH:23]=1)=[O:18]
Reactant: CCCCC[C@H](O)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)c1ccc(C2=CCC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Diisopropyl azodicarboxylate (DIAD, 53 μL, 0.27 mmol) in 1 mL THF was cannula transferred to an ice cold solution of 43 (46 mg, 0.11 mmol), Ph3P (66 mg, 0.25 mmol) and 4-nitrobenzoic acid (50 mg, 0.30 mmol). The solution was allowed to warm to room temperature and after 2.5 h, 20 mL saturated NaHCO3 solution was added. The resulting mixture was extracted with ethyl acetate (2×25 mL) and the combined solution was dried (Na2SO4), filtered and evaporated. The residue was purified by flash chromatography using a Combiflash unit by Teledyne Isco (12 g silica gel, 0%→15% ethyl acetate/hexanes) to give the title compound (40 mg, 0.069 mmol, 63%).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH:4]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([NH:23][C:24]([C:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=3[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])[CH:19]=2)[C:14]=1[Br:39])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].O>CO>[Br:39][C:14]1[C:15]2[C:20](=[CH:19][C:18]([NH:23][C:24]([C:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][C:27]=3[CH2:35][CH2:36][CH2:37][CH3:38])=[O:25])=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[O:12][CH:4]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:40])=[O:2]
Reactant: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1oc2ccccc2c1C(=O)Nc1ccc2c(Br)c(OC(Cc3ccccc3)C(=O)O)ccc2c1
Yield: 81.9 %

Procedure:
A mixture of 2-{1-bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-3-phenyl-propionic acid methyl ester (139 mg, 0.231 mmol), prepared in the previous step, and 1 N NaOH (231 μL, 0.231 mmol) in 75 mL of methanol was refluxed for 4 h. By TLC starting material remained. Water (10 mL) and 1 N NaOH (231 μL, 0.231 mmol) were added and the mixture refluxed for 18 h (overnight). The reaction was filtered and 2 mL of 1 N HCL was added to the filtrate. The filtrate was concentrated under reduced pressure to remove the methanol. The solid formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (111 mg, 81%) as a white solid, mp 191-195° C.
Reaction SMILES: [C:1]1([C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C[Mg+].[Br-].[C:25]1(C(O)=O)C2C(=CC=CC=2)C=CC=1>C(OCC)C.S(Cl)(Cl)=O>[CH3:25][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[C:11]([C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)=[O:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C(O)c1cccc2ccccc12
Reactant: O=C(c1cccc2ccccc12)c1c[nH]c2ccccc12
Agent: C[Mg+]
Agent: [Br-]
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1[nH]c2ccccc2c1C(=O)c1cccc2ccccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 1133.2 %

Procedure:
2-Methylindole 1 (10 g, 76 3 mmol) was dissolved in diethylether (100 ml) under nitrogen atmosphere and cooled to 0° C. MeMgBr (3M) solution (26.7 ml, 80.15 mmol) was added dropwise and allowed to stir at room temperature for 3 hours. In the meantime, 1-naphthoic acid (13.13 g, 76 3 mmol) was dissolved in thionyl chloride (50 ml) and refluxed for 90 min, then the solvent was removed under vacuo and the residue was dissolved in diethylether (50 ml). The resulting solution was added dropwise to the indole reaction mixture at 0° C. and then allowed to stir at room temperature for 2 hours. A solution of ammonium chloride (200 ml) was added to the reaction mixture and the resulting mixture was stirred at room temperature overnight. The solid that was formed was collected by filtration, washed with water and hexane then dried in a dessicator over phosphorous pentoxide to give 9.7 g (45%) (2-methyl-1H-indol-3-yl)(naphthalen-1-yl) methanone 2 as a cream solid.
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Br)C1C=CC=CC=1.[OH-].[K+]>O1CCOCC1>[CH2:1]([O:20][C@@H:21]1[C@@H:22]([CH2:23][OH:36])[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](CO)O2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
In 50 ml of dioxane was dissolved 10 g of 2'-deoxy-5'-O-trityl-5-fluorouridine. To the solution were added 2.9 ml of benzyl bromide and 14.6 g of particles of potassium hydroxide. The mixture was stirred at room temperature for 1 hour. The solvent was distilled off and the residue was dissolved in 80 ml of a 80% solution of acetic acid to undergo reaction at 50° to 60° C. for 2 hours. The reaction mixture was cooled with ice for 1 hour, the trityl alcohol was separated by filtration and the mother liquor was concentrated. To the concentrate was added ethanol and the mixture was stirred. The crystals precipitated were separated by filtration and dried, affording 5.0 g of the title compound in a yield of 72%.